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FOREWORD

The editors’ of the 12th edition of The Ashburn Clinic Drug Manual take pleasure in presenting this updated edition.

Since the publication of the 11th edition in 1993, there have been a significant number of new psychopharmacological agents available for the treatment of psychiatric disorders.

The most significant developments have been in the production of new antidepressants and new antipsychotics. The new generation antipsychotics Risperidone, Olanzapine, Quetiapine and Clozapine have all brought significant benefits to selected patients.

The new antidepressants, which include the SSRI’s, Nefazodone and the reversible MAOI’s have rapidly found a place in the treatment of a wide variety of depressive and anxiety disorders. Whilst possibly not as effective as the old trycyclic antidepressants in the treatment of severe melancholic depression, they appear to be more acceptable to patients suffering more moderate forms of depression and a variety of anxiety disorders.

Psychiatric disorders impose a very large cost burden upon the wider community and there is a great need to ensure that barriers to access to these effective treatments are kept as low as possible, especially in these times of escalating health care costs where effective outpatient care is considerably less expensive than inpatient care.

Prescribers must exercise care to ensure that these recently available and relatively expensive pharmaceuticals are used only when clearly indicated. Patients and doctors alike need to avoid the risk of seduction by the idea that normal human unhappiness and worry can be ameliorated with a pill. We have a growing problem with drug and substance abuse in out society, and as prescribers need to take a lead in defining attitudes, using medications judiciously and only as an integrated part of a complete assessment management plan. Social and psychological factors must always be taken into consideration in the overall treatment of psychiatric disorders.

It is hoped that this 12th edition will provide help and information to those seeking to maximize the wise prescription of medicative treatment.

DR STEPHANIE du FRESNE

DR JOHN ADAMS

PROFESSOR TREVOR SILVERSTONE

Chapter 1

THE ANTIPSYCHOTIC DRUGS

Use and Classification

Indications 1 2 3 Acute psychosis, including mania. Maintenance treatment of schizophrenia. Acute and chronic organic psychosis, especially if there is agitation, restlessness or confusion. 4 Also used in lower doses in anxiety disorder and more disturbed periods of personality disorders. This usage is less well established, and the disadvantages of side-effects may outweigh the benefits.

Effects The antipsychotic drugs are most effective in controlling the ‘positive’ symptoms of schizophrenia (thought disorder, hallucinations and delusions). This, in turn, generally leads to a reductions in psychotic agitation and, to a lesser extent, schizophrenic apathy and withdrawal . They do not act primarily by sedation. Patients must be warned that these drugs potentiate alcohol and some sedatives. Drowsiness may limit driving and the operation of heavy machinery, especially early in treatment.

. it has gained such widespread currency that that it is probably here to stay for some time. who show early signs of a possible schizophrenic illness are treated with an antipsychotic drug as soon as possible. most of which block serotonin 5-HT2 receptors in addition to D2 receptors. Although this term has been applied in a largely arbitrary manner and is of limited scientific value.It is now recommended that patients. It is hoped that such ‘early intervention’ will reduce the likelihood of more chronic symptoms developing. The older antipsychotic drugs. are less prone to cause EPS or to cause a sustained rise in prolactin levels. They bind to dopamine receptors in both the limbic system and the striatal areas. are often referred to as typical antipsychotics. that is those introduced into clinical practice before 1990. Classification of antipsychotic drugs All the effective antipsychotic compounds share the pharmacological property of blocking dopamine D2 receptors in the limbic system of the brain and it is generally believed that it is this which underlies their clinical efficacy. Where they differ from one another is in the nature and site of other receptors they act on. particularly younger patients. Newer antipsychotics. the latter giving rise to extrapyramidal symptoms (EPS) such as parkinsonism and akathisia (see below). This reduced propensity to cause EPS has led to them being referred to as atypical antipsychotics.

Since then it has come to be one of the two standard compounds against which other substances are compared (the other is haloperidol . particularly the incidence of extrapyramidal reactions. was soon found to have pronounced calmative effects in disturbed psychotic patients and was introduced into clinical practice in 1952. Chlorpromazine. and minor changes in their molecular structure can profoundly influence their therapeutic activity and the severity of unwanted effects. Phenothiazines have a large number of pharmacological properties. Haldol] (c) Thioxanthenes Flupenthixol [Fluanxol] (d) Diphenylbutylpiperidines Pimozide [Orap] (e) Dibenzoxazepines Loxepine [Loxapac] .I.see below). synthesised in 1950. All the drugs in this group have a phenothiazine nucleus with one of the following side-chains: (i) Aliphatic Chlorpromazine [Largactil] (ii) Piperazine Trifluoperazine [Stelazine] (iii) Piperidine Thioridazine [Melleril] (b) Butyrophenones Haloperidol [Serenace. Typical antipsychotics (a) Phenothiazines The discovery that the phenothiazine derivative promethazine possessed sedative and antihistamine activity encouraged the synthesis of other compounds in this group.

On the other hand. The major differences between them lie in their side-effect profile. hepatic or cardiac failure need special consideration in deciding dosages. II. been substantiated. the sedative action of phenothiazines. such as chlorpromazine. . this can be a determining factor in drug selection. Atypical antipsychotics (a) Dibenzodiazepines Clozapine [Clozaril] (b) Benzisoxazoles Risperidone [Risperdal] (c) Thienobenzodiazepines Olanzapine [Zyprexa] (d) Dibenzothiazepine Quetiapine [Seroquel] Drug Selection All the antipsychotic drugs in common use (other than clozapine) are approximately equally effective in clinically equivalent doses. Earlier claims that atypical antipsychotics were particularly effective in ameliorating the negative symptoms of schizophrenia have not.The aliphatic and piperidine phenothiazines and dibenzoxazepines are low potency antipsychotics and need to be given in relatively high dosage. can be useful for patients who are disturbed during the night. unfortunately. Patients suffering from renal. butyrophenones and diphenylbutylpiperidines are high potency drugs which are effective in smaller doses. For instance. in patients with vascular disease haloperidol may be preferred to a phenothiazine compound as it carries less risk of causing hypotension.

It should only be done after careful consideration. and close monitoring ensured. medication is continued for 9-12 months before being slowly discontinued.It is generally considered good practice to use only one antipsychotic compound at a time if possible. They can make dose adjustments in response to side effects more difficult as it may not be clear which of the drugs is responsible for a particular symptom. A better approach is to try an antipsychotic drug of a different group. There is a wide variation in individual dose-responsiveness. after one psychotic episode. When a patient has failed to respond to antipsychotic drugs of two pharmacological classes given in adequate dose for a sufficient length of time (two to three months) he/she can be described as ‘drug-resistant’. When starting treatment for the first time it is probably advisable to use a newer atypical antipsychotic as they are less likely to cause EPS and thereby prejudice compliance. . Clozapine (see below) may be effective in a substantial proportion of such patients and is worthy of consideration despite the increased risk of blood dyscrasia. the reasons carefully documented. There is no evidence that combinations of antipsychotic drugs improve efficacy. If symptoms recur the medication should be immediately restarted and consideration given to long-term maintenance treatment with antipsychotic medication . Continued Treatment In general. Increasing the dose above the usual recommended therapeutic range does not usually lead to increased effectiveness. In making a decision about maintenance treatment the risk of relapse needs to be weighed against the long-term risk of tardive dyskinesia (see below).

The dose of depot neuroleptics should be tailored to the individual patient. such as haloperidol. Dosage adjustment with advice to take the medication before retiring for the night is usually all that is required.At least 50% of schizophrenic patients fail to comply with oral maintenance regimes and consequently relapse. and kept below the minimum effective dose. eg: starting work. 2 Autonomic Side-effects: (a) Postural hypotension Patients should be warned of the possibility of dizziness on rising If treatment is started with high doses the patient may need to be kept in bed to avoid falls. the use of one of the long-acting parenteral drugs may be indicated. . The patient is then observed for signs of adverse reaction over the next week. may be helpful. and caution needs to be exercised in driving or handling complex machinery when starting treatment with an antipsychotic drug. When starting a depot neuroleptic (see below). In such cases. Antipsychotics can have a protective effect for schizophrenic patients returning to a stressful or critical environment and increased stress. may necessitate a temporary increase in dose. Immediate treatment is by lying down. The maintenance medication of chronic patients should be reviewed regularly. with the feet elevated.5mg fluphenazine decanoate).25mg to 12. Switching to a less sedative compound. it is usual to give a 'test dose' (eg: 6. Side Effects and their Treatment 1 Drowsiness is common.

butyrophenone and diphenylbutylpiperidine derivatives but less with drugs which have an intrinsic anticholinergic activity. such as clozapine. giving rise to what is often called an 'oculogyric crisis'. urinary retention. olanzapine and quetiepine are less prone to be associated with extrapyramidal symptoms because of their associated 5-HT2 receptor blocking action. does have a potential to cause EPS. haloperidol). blurred vision. followed by hyperextension of the neck and opening of the mouth. constipation. such as thioridazine. They are equally frequent with thioxanthine.The drug should be changed to one less likely to cause this side-effect (e. which is thought to counter the effects of dopaminergic blockade in the striatum. . The attack may last several hours before subsiding spontaneously and can be a very distressing experience. It occurs in some 2 to 10 per cent of patients treated with antipsychotic drugs. It begins with a fixed stare which then gives way to a turning upwards of the eyes. although classified as an atypical antipsychotic. Among the phenothiazines they are more common with those compounds having a piperazine side-chain. mydriasis. 3. particularly at higher doses.g. perphenazine. Anticholinergic (atropinic) psychosis may occur (treatment page 31). (a) Acute dystonia is an involuntary contraction of skeletal muscles most frequently occurring in the head and neck. (b) Anticholinergic effects Dry mouth. usually appearing within a day or two of starting treatment. Risperidone. Extrapyramidal effects (EPS) occur in up to 40 per cent of patients treated with typical antipsychotic drugs. Atypical antipsychotics. being commoner in younger male.

Typically it begins within a week or two after starting treatment. (c) Akathisia is a condition characterised by motor restlessness. They may even feel compelled to get up from their chair and walk about. is referred to as the ‘buccolinguo-masticatory’ (BLM) syndrome. especially elderly females. The mask-like facies. It occurs in some 20 per cent of patients receiving antipsychotic drugs. being commoner in older patients. or walk on the spot when standing and show a coarse tremor of the feet. jaw and neck. Milder cases present mainly with subjective feelings of inner restlessness. As the condition progresses motor symptoms become evident. with a stiffening of the limbs. The first. There would appear to be two distinguishable subtypes. Parkinsonism has been observed in 20 to 40 per cent of patients receiving antipsychotic drugs and is dose-related. It ranges from infrequent lateral movements of the jaw . lack of facial expression. (d) Tardive dyskinesia is a chronic syndrome of hyperkinetic involuntary movements which often begins repetitive movements of the lips and tongue. a characteristic coarse tremor of the hands and head at rest. Patients typically rock from foot to foot. going on to involve the face. especially referable to the legs. a subjective feeling of tension and an inability to tolerate inactivity which gives rise to restless movement. arms and hands. and by far the most common. and even the trunk. stiffness and motor retardation may be mistaken for schizophrenic apathy.(b) Parkinsonism mimics idiopathic parkinsonism very closely. and comes on within the first few weeks of treatment. plus sialorrhoea and seborrhoea.

It may be masked by high doses of antipsychotic drugs and first appear on reduction or withdrawal of the drug. though often incomplete improvement in the dyskinetic . It is rarely seen before treatment with one or more antipsychotic drugs has been continuously administered for at least 6 months. The risk of developing irreversible dyskinesia is such that efforts must be made to use the minimal effective dosage of drugs and for as short a time as possible. and is uncommon before 4 or 5 years. and there is usually a gradual. mainly of the BLM type. and in some patients they are observed for the first time on stopping antipsychotic drugs. Of the many and complex risk factors studied for the development of Tardive Dyskinesia. There appears to be an association with previous EPS. Although generally suspected as being a consequence of prolonged antipsychotic drug treatment. In the truncal type the limbs and trunk display choreiform movements and myoclonic jerks. as tardive dyskinesia occurs more frequently in patients who have exhibited parkinsonian symptoms or akathisia. stopping treatment may well lead to a sharp exacerbation of the symptoms.together with puckering and pouting of the lips and slight tongue movements which distend the cheek. antipsychotic drugs should be reduced or withdrawn. increasing age and higher neuroleptic dose have the clearest associations. Tardive dyskinesia. has been reported in 10 to 30 per cent of patients suffering from chronic schizophrenia and is commoner in the elderly. If possible. to a clinical picture dominated by unceasing movements of the lower face associated with frequent mouth opening and protrusion of the tongue.

This is a medical emergency and urgent treatment is required. 4 Skin (a) Allergic rash may appear in the first few weeks. especially where there is dehydration. Drugs which may be helpful include the dopamine depleting compound tetrabenazine (Nitoman). and those on large doses. In a proportion of cases the syndrome continues on to muscle break down (rhabdomyolysis). . Altered consciousness. The muscle relaxant drug dantrolene and the centrally acting dopamine receptor agonist bromocriptine both appear to reduce recovery time. are seen as being particularly at risk. and vigorous supportive measures with particular attention to electrolytes and hydration. Active steps should be taken to reduce body temperature by cooling. stopping neuroleptic drugs. Cautious reintroduction of antipsychotic drug treatment after an interval of 2-3 weeks can usually be undertaken without a recurrence of NMS. Severely psychiatrically ill. autonomic nervous system dysfunction. The hallmarks of the disorder are hyperthermia. Recommended management includes a thorough search for other causes of fever. or GABA agonists such as benzodiazepines or baclofen.symptoms. renal failure and death. Treat with an antihistamine and change to a different antipsychotic. and severe extrapyramidal signs. 4. may be present. and abnormal laboratory investigations such as raised leukocyte count. medically ill. Neuroleptic Malignant Syndrome (NMS) is a rare but potentially fatal complication of neuroleptic treatment. liver enzymes and creatinine kinase levels.

It is an allergic phenomenon occurring 1-5 weeks after starting the drug. Treatment is by substituting a high-potency drug . 6 Convulsions Chlorpromazine. In women. rarely. but the pigment may take many months to fade.(b) Photosensitivity can be a problem in summer. particularly chlorpromazine. lens and retina. but epilepsy is not a contraindication to its use. Fits usually occur only with very high doses. lactation may occur. As this is most common with chlorpromazine a change to another antipsychotic drug may be necessary. and completely reversible. and if necessary an anticonvulsant can be added. 5 Cholestatic Jaundice is a rare complication of treatment with phenothiazines. The drug should be stopped and liver function tests and a blood screen performed. 7 Endocrine changes can occur secondary to the rise in prolactin caused by the typical antipsychotics. Patients should be warned to avoid excessive exposure. (c) Oculocutaneous pigmentation is seen in patients treated chronically on high doses of phenothiazines. Male patients may develop impotence. haloperidol and other typical antipsychotics lower the seizure threshold. especially with fair skinned patients. menstruation may become irregular and. and advised to use a barrier cream. It is a blue-grey discolouration of exposed skin and may be associated with pigment deposits in the cornea. When changing to an .

The significance of these ECG changes remains unclear. and certain atypicals such as clozapine and olanzapine. but many patients report a marked increase in hunger and an increased consumption of sugar-containing foods. weekly for the first 8-12 weeks. . monthly thereafter. The pathogenesis of this weight gain is not known. Regular monitoring of the blood count of patients taking clozapine is mandatory. possibly a consequence of 5-HT2 receptor blockade. 10 Weight gain Weight gain. and in particular Thioridazine.atypical antipsychotic drug. As far as other antipsychotic drugs are concerned such blood dyscrasias are very rare 9 Cardiovascular effects Prolonged ventricular repolarisation can be found commonly in patients on phenothiazines. often amounting to frank obesity. female patients should be warned about the increased fertility that may accompany this . When weight gain becomes troublesome a low-calorie diet should be instituted. and take appropriate contraceptive measures. 8 Leukopenia and/or agranulocytosis occurs in approximately 1% of patients treated with clozapine. Treatment should be stopped at any significant fall in the white count. is disturbingly common among patients receiving long-term treatment with antipsychotic drugs. especially patients treated with phenothiazine compounds such as fluphenazine.

used in all the conditions listed as indications for antipsychotic medication. In acute psychoses. suspension 100mg in 5ml. Chlorpromazine is painful and locally irritating as an injection. increasing until symptoms are controlled. the initial dose is 400-600 mg/day in divided doses. Suppository 100mg. 50 and 100mg tablets. If used. Its use in anxiety disorders is not advisable as it may result in dysphoric mood and it may also lead to extrapyramidal symptoms. It is seldom necessary or beneficial to exceed 900 mg daily. then gradually reducing to a maintenance dose of 100-400 mg daily. injection sites must be rotated. syrup 25mg/5ml. .CLINICAL APPLICATIONS OF ANTIPSYCHOTIC DRUGS (a) PHENOTHIAZINES (i) ALIPHATIC SIDE CHAIN Chlorpromazine (Largactil) This is the prototype of the phenothiazines. 25. It carries a higher risk of cholestatic jaundice than other antipsychotics. It is among the more sedative of the phenothiazines and is prone to cause postural hypotension. injection 50mg/2ml in 2ml ampoules. Dosage 10.

in severe cases 75 mg daily increasing cautiously to a maximum of 600 mg daily. It may cause marked hypotension. as they may be more sensitive to the side effects eg: 25 mg q. but extrapyramidal effects are rare. It has marked sedative effects which makes it particularly useful in psychotic patients who have significant sleep disturbance. Side effects: As for chlorpromazine. Other aliphatic side chain phenothiazines Methotrimeprazine (Nozinan) Related to promethazine with which it shares an antihistamine action. 100mg 25 mg/ml Initial dosage 25 mg daily in mild cases. Dosage: Tablets Injection 25.In elderly patients it is wiser to start with smaller doses. maybe given the major dose in the evening. Also used in pain management. . or insomnia.i. Indications: Useful for controlling anxiety in alcoholics and excited schizophrenics. Patients who suffer from daytime drowsiness.d. Frequently upsets visual accommodation.

though leucopaenia has been reported rarely. photosensitivity and agranulocytosis do not occur.5 mg-25 mg (rarely up to 100 mg). Usually given as the depot preparation fluphenazine decoanate where it is useful for longer-term maintenance treatment.5 ml ampoules containing 12. but fewer autonomic side-effects and little drowsiness. Duration of effect 2-4 weeks. Jaundice. Occasionally depressive reactions.(ii) PIPERAZINE SIDE CHAIN Fluphenazine Indications: As for chlorpromazine. when anti-parkinsonian drugs may be required. Side effects: Extrapyramidal side-effects. Patients are often aware of when the drug 'wears off' and hence the necessary frequency of injections. Lethargy and drowsiness may occur in the first few days. with risk of suicide. Dosage: Injection 0. Side effect: More extrapyramidal side effects than chlorpromazine.4 weeks. particularly in patients non-compliant with oral medication. The peak serum level is reached after 36 hours.5 mg 1 ml ampoules containing 25 mg Concentrate 1 ml ampoules containing l00 mg Usual dosage 12. Fluphenazine Decanoate (Modecate) Indications: Chronic schizophrenia. particularly in the first few days after an injection. every 2. occur .

capsule 15 mg Liquid Forte 5 mg/5 ml Injection 1 mg in l ml Initial dose 5-10mg/day. Antinaus) This drug is little used in psychiatry being more useful as an anti-emetic. 5 mg.in schizophrenic patients begun on fluphenazine decanoate. 2. Side effects: As for chlorpromazine. 5 mg is approximately equivalent to 100 mg chlorpromazine. increases up to 20 mg/day occasionally needed. . May be more useful for withdrawn patients as it is less sedatives. but less sedation. Trifluoperazine (Stelazine) Indications: As for chlorpromazine. Dosage: Tablets 1. so careful supervision is necessary. Prochlorperazine (Stemetil. especially in migraine. Extrapyramidal symptoms are more common. hypo-tension or anticholinergic effects.

organic psychosis . Sometimes produces ejaculatory retardation or retrograde ejaculation. Dosage: Tablets 10. Must not be used in prolonged high dosage (over 400 mg/day) as it has been reported to cause retinal pigmentation with irreversible damage to vision.d. impulsive acting-out behaviour and severe tension and anxiety states. 100 mg.begin with 10mg t. .s . 25. other patients 25-50 mg t.iii) PIPERIDINE SIDE CHAIN Thioridazine (Melleril. Geriatric patients. especially as an adjunct in the treatment of agitated depression. Aldazine) Indications: As for chlorpromazine. Side effects: As for chlorpromazine but less sedative and much less likely to cause hypotension or extrapyramidal symptoms. Its marked sedative effects may be useful in inhibiting aggression. May be useful in nonpsychotic disorders. 200 mg 'Retard' Solution Suspension 30 mg/ml 3% 50 mg/5 ml 1% Psychotics 100-800 mg daily. so often better tolerated. 50.s.d. Pericyazine (Neulactil) Indications: As for chlorpromazine.

A long acting injectable phenothiazine. Pipothiazine decoanate (Piportil) Indications: Chronic schizophrenia.Dosage: Tablets Syrup 2. 1 ml and 2 ml ampoules Usual dosage 50-100 mg every 3-6 weeks (Generally given every 4 weeks). for psychoses 20 to 60 mg daily. Occasionally depression and orthostatic hypotension may occur. duration of action 3-6 weeks.5 mg/5 ml Forte syrup 10 mg/5 ml For behaviour disorders use 5 to 20mg daily. recommended maximum 200 mg every 4 weeks. but jaundice and agranulocytosis not reported. . 10 mg 2.5. Side effects: As for chlorpromazine. Dosage: 50 mg/ml. Side effects: Extrapyramidal reactions are the most frequent.

Useful in the treatment of excited schizophrenic states. Even lower doses may be effective. Haloperidol has a high incidence of parkinsonian side-effects. The oral dose for patients who have been on an I. regime is 1/2-2 times the 24 hour total with 1/3 of the dose given at night.if required a sedative may be added (page 59) or another antipsychotic such as chlorpromazine used instead (not as well as). 1. severe tics. Haloperidol potentiates the effects of analgesics so may be useful in treating severe pain Dosage: Tablets Injection Liquid 0. these are usually readily controlled by the anti-parkinsonian drugs. Haloperidol is not particularly sedating . Worth trying in patients with Gilles de la Tourette's Syndrome.5 and 5 mg: 5 mg in 1 ml 2 mg/ml.5. mania and organic psychoses and acute psychoses in medically ill patients. 2 mg haloperidol is approximately equivalent to 100 mg chlorpromazine.M. spasmodic torticollis and stuttering. For the treatment of an acute psychotic episode haloperidol in doses greater than 10mg has been shown to have no corresponding therapeutic advantage. Usual . Use in low dosage in anxiety not recommended as limited by extrapyramidal side-effects.(b) OTHER ‘TYPICAL’ ANTIPSYCHOTIC DRUGS (i) BUTYROPHENONES Haloperidol (Serenace) Indications: As for chlorpromazine.

little drowsiness. sweating and hyperpyrexia have been reported. 50-100mg for mild symptomatology. even at low doses and adolescents are particularly susceptible.maintenance oral doses are 3-12 mg daily. Thus antiparkinsonian drug should be continued for a week or more after the drug is stopped. anticholinergic effects or photosensitivity. Occasional excessive salivation. The daily dose of oral haloperidol x 10 . though this seems to be very rare. 150. 1 mg/day may occasionally be helpful for patients with anxiety disorders.200mg for moderate symptomatology. Dosage: 50mg/ml. with residual side-effects continuing for many days. no hypotension. 1ml and 5ml. The combination of haloperidol and lithium has been reported to be associated with an acute encephalopathy. Haloperidol is only slowly eliminated from the brain.20 = the approximate monthly dose of haloperidol decanoate. Side effects: No hepatic or leucopaenic effects. . Given 4-weekly. Haloperidol decanoate (Haldol) Indications: Long-acting depot haloperidol for the maintenance treatment of chronic psychoses. Extrapyramidal reactions are common.

a more sedative drug is often more useful. but more sedative then. 5 mg is approximately equivalent to 100 mg chlorpromazine. the usual dosage being 8 mg initially (range 4-20 mg). Thiothixene has been used for parenteral regimes for the control of acutely disturbed patients. 10 mg 4 mg in 2 ml Usual dosage 10 mg mane. . Dosage: Tablets Injection 2 mg.5mg/ml 10 mg/2 ml Neuroleptic dose orally 10-25 mg daily. Injection 5-25 mg I.Droperidol (Droleptan) A short-acting butyrophenone with rapid onset. repeated hourly. increasing if needed up to 60 mg daily. However. Used mainly in the management of disturbed patients. It is similar to. (ii) THIOXANTHENE DERIVATIVES Thiothixene (Navane.M. Dosage: Tablets Injection 10 mg 2. haloperidol. but has little sedative effect and may be particularly beneficial in the withdrawn patient. 4-6 hourly. Thixit) Indications: As for chlorpromazine.

. Antiparkinsonian medication may be required. Extrapyramidal side effects are the most common. It has also been reported to have an antidepressant action. No photosensitivity. Side effects: As for thiothixene. Zuclopenthixol acetate (Clopixol acuphase) A single injection of 50-150mg produces a rapid reduction in psychotic symptoms which persists for over 72 hours. especially in the first few days after injection. Dosage: Depot injections 20 mg/ml. up to a maximum of 100 mg weekly. but hepatic and erythropoietic effects not reported. injection. and trifluoperazine or another more sedative drug may be more appopropriate.Side effects: As for chlorpromazine. Patients who are anxious or excitable may find that thiothixene’s relatively activating effect increases their agitation. by deep l M. Useful in emergency treatment. Flupenthixol decanoate (Depixol) Indications: Maintenance treatment of chronic schizophrenics. Is said to cause less depression of mood than fluphenazine. 100mg/ml 20-100 mg over 2-4 weeks. especially those who are withdrawn or apathetic.

. If ECG changes occur. Not as useful for acute phases. Pimozide is contraindicated in patients with a history of cardiac arrhythmias or congenital prolonged QT intervals. at weekly intervals. Because of its relatively long half-life of 50 hours it may not need to be given more frequently than once every 3-4 days. It is recommended that an ECG be performed before treatment and periodically during treatment. A more specific D2 blocker. There may be prolongation of the QT interval on the ECG. reputed to have greater impact on ‘negative’ symptoms. Side effects: Remarkably free of extrapyramidal side effects. Dosage: Tablets 2 mg. 10mg Initial dose is 2 mg mane increasing up to 10 mg if necessary. The maximum dose should not exceed 20mg/day. treatment should be reviewed and dosage reduced.(iii) DIPHENYLBUTYLPIPERIDINES Pimozide (Orap) Indications: Chronic schizophrenia. Increases in dose should be made in doses of 2-4mg/day. Said to have specific effects in monodelusional psychosis.

Has some 5-HT2 blocking action and therefore might be more properly be classified as an atypical antipsychotic. give in divided doses twice daily. and has strong antipsychotic effects. (c) ATYPICAL ANTIPSYCHOTIC DRUGS (i) DIBENZODIAZEPINES Clozapine (Clozaril) Indications: Clozapine has weak dopamine D2 receptor blocking activity. Effective with acute and chronic symptomatology in schizophrenia. 5-HT2 and NA alpha2 autoreceptors. Usual therapeutic range 50mg to 100mg per day. Dosage: Capsule 50mg Orally. increasing over 7-10 days until there is effective control. but blocks D1. the use of clozapine should be reserved for schizophrenic patients ‘resistant’ to standard treatment. Due to potentially serious side effects (below). including in the elderly. Side effects: Extrapyramidal effects occur. It produces rapid and marked sedation. May also be useful in the management of aggressive behaviour disorders.(iv) DIBENZOXAZEPINES Loxapine (Loxapac) Indications: Management of psychotic disorders. . Initial dose 50mg once daily. Use with extreme caution in patients with a history of convulsive disorders.

and monthly counts thereafter. which can go on to potentially fatal agranulocytosis in up to 1%. with weekly leucocyte counts for the first 18 weeks of treatment. up to 50% of whom can improve with clozapine. On starting treatment close monitoring is required. At any sign of infection a further white cell count should be done as soon as possible and clozapine stopped if it has fallen.(see above). In addition. Dosage: Tablets 25mg and l00mg Initial recommended dose is 25mg to 50mg per day gradually increasing to 300mg per day in divided doses over 14-21days. During the first period of treatment. It is the only available antipsychotic in which efficacy in otherwise drug-resistant patients has been convincingly demonstrated. patients should have normal leucocyte counts before therapy. clozapine should not be used in association with any other medicines likely to cause leucopaenia. Weight gain. in some 5% of patients. can prove a . The risk of leucopenia is increased in the elderly. Side Effects: WARNING: Because of the association of clozapine with a fall in the white blood cell count (leucopenia). transient autonomic side effects such as increased salivation and a rise in body temperature may occur. often leading to clinical obesity. Usual therapeutic dose range 300-600mg per day. Maintenance dose 150-300mg/ day. Recommended maximum dose 900mg/day. Clozapine produces few extrapyramidal re-actions.

Adjust no more frequently than every other day up to the optimal dosage of 0. It bocks a wide variety of receptors with high 5-HT2 : D2 ratio. 4 mg 1 mg/ml For psychosis start at 2mg daily. It may be more effective . (ii) BENZISOXAZOLES Risperidone (Risperdal) Indications: In the initial treatment of first-episode schizophrenia and as an alternative treatment for patients unable to tolerate typical antipsychotics because of side-effects.problem. Maximum dose 1mg bd. EPS do occur at higher doses. Blocks D2 and 5-HT2 receptors. 3. Dosage: Tablets Solution 1.25mg twice daily. It can produce sedation and orthostatic hypotension. Geriatric patients start with 0. increase to 4-6mg daily. Side Effects: Although less prone to cause EPS than haloperidol. This may lead to poor compliance and increase the risk of non-insulin dependent diabetes. 2.5mg twice daily. (iii) THIENOBENZODIAZEPINES Olanzapine (Zyprexa) Indications: In the treatment of acute schizophrenia and the prevention of relapse.

than risperidone, but if true, this has to be weighed against its greater propensity to cause weight gain.

Dosage:

Tablets

2.5, 5, 10 mg.

Initial recommended dose is 5-10mg daily, increasing to 10-20mg per day according to clinical response.

Side Effects: The main side effects are sedation and weight gain.

(iv)

DIBENZOTHIAZEPINES

Quetiapine (Seroquel) Chemically related to clozapine but with far less risk of leucopenia. Has a wide spectrum of pharmacological actions, blocking D2 and 5-HT2 receptors plus an action on histaminergic and adrenergic receptors. As effective in schizophrenia as standard antipsychotics but with a significantly lower incidence of extrapyramidal side effects.

Dosage:

Tablets

25 mg, 100mg, 200mg

Doses should be increased gradually over several days, starting with 25mg and progressing to 300-450mg daily using a ‘starter pack’. Women of child-bearing age,

switching from a typical antipsychotic to quetiapine, should be warned that their fertility may be increased as it does not cause the same rise in prolactin levels.

Side Effects: Headache, somnolence and dizziness are the most common.

Anti-Parkinsonian Drugs

Extrapyramidal side effects often occur with the typical antipsychotic drugs (see above) and to some degree with risperidone. The first step is to adjust the dose to the lowest effective dose. Another strategy is to switch to another, atypical antipsychotic ( see above). However, as it is often necessary to continue medication with a depot (typical) antipsychotic in patients above the threshold of extrapyramidal manifestations, antiparkinsonian drugs may be given to control these side-effects. With these precautions anti-parkinsonian drugs have a place in the treatment of extrapyramidal side-effects of antipsychotic drugs. The prophylactic administration of anti-parkinsonian drugs when the antipsychotic medication is begun, and before any extrapyramidal side-effects have appeared, remains controversial. Certainly a high proportion of patients may gradually come off anti-parkinsonian drugs after 2 to 3 months, whilst still taking the previous dose of tranquilliser. Elderly females are less likely to be able to do so. On the whole it is probably best to use these drugs only when extrapyramidal side-effects appear.

Extrapyramidal effects, especially akathisia, can be particularly distressing; it may be misinterpreted as an increase in psychotic activity. It is wise to warn patients (and their relatives) of these side effects and to give a small quantity of an anti-parkinsonian drug to be used if needed. Some patients on depot anti-psychotics find that they need antiparkinsonian drugs the first week or so following an injection.

in divided doses.V. . They have no place in the treatment of tardive dyskinesia.M. may even exacerbate it. may be treated with physostigmine. They can all adversely affect memory in the elderly. Usual dose 1 to 3 tablets daily. This can rarely result in a toxic psychosis which. if it occurs. Dosage: Tablets Injection 2 mg 2 mg/2 ml I.As most of the anti-parkinsonian drugs are anti-cholinergic agents (see below) there is a risk of summation when prescribed with anti-psychotic drugs with similar side-effects (eg trifluoperazine). Benztropine mesylate (Cogentin) An anticholinergic with antihistamine properties. They have been suspected of having a mild euphoriant effect which has led to misuse by some patients. 100 mg 60 mg (Norflex) Usual dose 100 to 300 mg daily. They should be used at as low a dose as possible and for the shortest possible time. Orphenadrine (Disipal) Dosage: Tablets Injection 50 mg (Disipal). or I. Anticholinergic Anti-parkinsonian Drugs There is little clinically significant difference between the drugs in this group.

d. This drug can be quite useful for a patient who is otherwise resistant to treatment for drug-induced parkinsonism and may be better tolerated in the elderly. .5-60 mg daily.Procyclidine (Kemadrin) Dosage: Tablets S mg Usual dose 7.i. It has mild antipsychotic anti-emetic and anti-histamine effects. Its sedative effect and its ready availability by injection make it useful for the acutely disturbed patient with extra-pyramidal symptoms. Amantadine (Symmetrel) Dosage: Capsules 100 mg Usual dose 200 mg daily. It is a phenothiazine which paradoxically acts also as an anti-parkinsonian drug. Others Promethazine (Phenergan) Dosage: Tablets Injection 10 mg and 25 mg 25 mg/ml Usual dose 25 mg q.

increasing to 160 mg daily. 40 mg.Propranolol (Angilol. Dosage: Tablets 10 mg. Cardinol) A beta adrenergic recptor blocking drug reported to be effective in reducing akathisia. . 160 mg Initial dose of 40 mg twice daily.

or both. . also referred to as mood disorders.Chapter 2 DRUG TREATMENT OF MAJOR AFFECTIVE DISORDERS a) b) Antidepressants Drugs used in Mania and Mood stabilisers (a) ANTIDEPRESSANTS i) General The affective disorders. or an illness in its own right. which usually warrants treatment with an antidepressant drug. The currently available antidepressant drugs all act by enhancing neurotransmission in one or other. When the change in mood is severe and persistent it falls into the category of major depressive episode (MDE). of these pathways which arise from groups of specialised neurones located in the brainstem and are widely disseminated to areas of the cerebral cortex in the frontal and temporal lobes. particularly those associated with noradrenaline and/or serotonin. or lowered as in depression. are those conditions in which there is alteration of mood to such a degree as to cause serious distress or disruption of normal life. The mood may be abnormally elevated as in mania. MDE are believed to be related to changes in neurochemical pathways within the brain. Depression may either be a symptom of reaction to adverse circumstances.

Some subcategories of depression respond to particular types of antidepressants better than others. and MAOI better in ‘atypical’ depression with reversed vegetative symptoms (ie hypersomnia and hyperphagia). the non-selective MARI are thought to be more effective than SSRI in patients with the more severe. melancholic type. For example. monamine oxidase. whatever the particular mechanism whereby monamine neurotransmission is enhanced. Recent studies suggest that.Antidepressants can classified according to their pharmacological action within these pathways: 1) Inhibition of reuptake of monoamines into the presynaptic neurones (monoamine reuptake inhibitors [MARI]) a) Non-selective inhibitors of monamine (serotonin and noradrenaline) reuptake b) Selective serotonin reuptake inhibitors (SSRI) c) Selective noradrenaline reuptake inhibitors (NARI) 2) Stimulation of presynaptic autoreceptors 3) Inhibition of the enzyme. which inactivates monoamines in the brain (monamine oxidase inhibitors [MAOI]) There is little significant difference between the various groups of antidepressant drugs in their overall efficacy. . This is also true for ECT. they all increase the level of ‘neuroprotective proteins’ within the forebrain and limbic system. in most clinical trials about 60-65% patients respond to some degree although less than 50% achieve full remission within the 6-8 weeks of most trials.

Antidepressants generally take 10 to 14 days before noticeable improvement occurs. Additional symptoms in major depression are sleep and appetite disturbance. and there may be a place for a therapeutic trial in the absence of an endogenous pattern. the right drug and the right dose. feelings of guilt and worthlessness. as we have seen. such patients should be questioned carefully about other symptoms of depression and if these are present. of internal tension and the inability to feel pleasure the whole picture subject to diurnal fluctuations with exacerbation in the morning' that drug therapy is likely to be effective. Many factors enter into the choice of which drug to choose first. None are absolute and perhaps the most important is that the physicians should first prescribe those drugs with which they are most familiar. many patients present with complaints of anxiety and often illdefined somatic symptoms rather than complaining of 'depressed mood'. In the outpatient setting.‘lassitude. appropriate antidepressant treatment begun. Although this rule is not universally reliable. More than forty years of clinical experience have substantiated Kuhn's original observation that it is when 'vital' signs of depression are present . Drug choice is thus often more . a slowing down and difficulty in thinking and acting. impaired concentration.Principles of Use: Optimal use of anti-depressant drug therapy involves the basic requirements of having the right diagnosis. it remains the surest guide to appropriate use. suicidal thoughts and impulses. The aim of treatment is to alleviate the depression and. feelings of depression and inhibition. none of the antidepressants offer any real significant advantage in effectiveness. for patients with a MDE of moderate severity.

abuse potential or other special considerations. particularly while on a sedative antidepressant. such as paroxetine. 3 Depression with anxiety Here. nefazedone. fluoxetine. SSRIs may cause hyponatraeuria and serum sodium should be monitored in the elderly. Some guidelines for treatment in selected patient groups are: 1 The Elderly – Here depression is often complicated by the physiological effects of aging with reduced liver and renal function concurrent medical illness.affected by what the prescriber wishes to avoid in the way of side-effects. 2 Patients with a high suicide potential When this is judged to be high. Drug regimens should be kept simple and starting doses should be low (about half the recommended initial dose). increased slowly and with frequent monitoring of side effects. suicide risk. the SSRI may have an advantage . small quantities of an antidepressant drug with low toxicity. The use of SSRIs and moclobemide have increasingly been used for first line treatment due to their low toxicity and lack of anticholinergic side-effects. Patients also need advice about the use of alcohol and driving. other medications and degrees of mental confusion. or moclobemide should be prescribed initially. It should be noted that many antidepressants are highly toxic to children and patients should be advised to store them safely at home.

This has been shown to improve about a third of patients with resistant depression in clinical trials. remember.4 Obsessional Symptoms with Depression SSRIs and Clomipramine have been found to be useful in OCD and may offer an advantage. the simultaneous prescription of an SSRI and a TCA can lead to elevated plasma levels of the TCA with resultant toxicity (d) Add lithium. With amelioration of the underlying depression the antipsychotic can usually be tapered off. the addition of thyroid leads to feedback inhibition of endogenous thyroid production. as. in the first instance. It requires careful monitoring of the plasma level of lithium (e) Add thyroid hormone. This requires monitoring of thyroid status. 5 Severe depressions with psychotic features Treatment with a combination of antidepressant and antipsychotic is often required. i) Non-selective inhibitors of monoamine reuptake . 6 Resistant depression There are a number of strategies which help patients who fail to respond within 4-6 weeks to treatment with an antidepressant at the recommended dose : (a) Increase the dose to within the limits of tolerability (b) Switch to an antidepressant of a different pharmacological class (c) Try a combination of antidepressants but.

especially in those who are predisposed. In the elderly. it is not uncommon to find a prolongation of the Q-T interval. are prone to cause pronounced anticholinergic side effects such as dryness of the mouth. which can proceed to a frank dysrhythmia or ventricular tachycardia. Other untoward effects include postural hypotension and excessive sweating. are the cardiotoxic properties which some of these drugs possess. a) Tricyclic antidepressants (TCA) Imipramine. some 60-65% of patients respond over a period of 2-3 weeks. chronic heart disease and epilepsy. the tricyclics are epileptogenic and may precipitate epileptic seizures. imipramine and amitriptyline while effective. constipation. As with other antidepressants. congestive cardiac failure is not uncommon. In view of all these possible side effects. The first drugs in this group to be introduced into clinical practice. prostatism. Amitryptyline causes weight gain. tricyclic (MARI) drugs should be used most cautiously in patients with glaucoma. Furthermore. secondary to its appetite-stimulating effect. especially in overdose or in patients with a pre-existing heart disease. Where they differ is in their side-effect profile. difficulty in micturition which can lead to urinary retention in men with prostatic hypertension and difficulty in visual accommodation. In addition to these autonomic and cardiac effects. Inhibitors of serotonin and noardrenergic reuptake. overdose with TCA’s leads to loss of consciousness in 1-3 hours with . Following this a number of other TCA have appeared (see below).A. which in cases of overdose occasionally progresses to fatal ventricular fibrillation. More dangerous. the first compound found to effective in the treatment of MDE was introduced into clinical practice almost 50 years ago. None seems be more effective than imipramine. Amitriptyline is the most likely to cause problems in this respect.

It is especially suitable for the agitated depressive as it has a tranquillising and sedative action as well. 25. Amitriptyline (Amitrip. increasing to a total daily dose of 150 mg. Side effects and their treatment . 50 mg 75 mg 10 mg/5 ml Dosage: Initial dose of 50mg nocte. Amitriptyline is discussed as the prototype together with its side effects and their treatment. Individual drugs and their differences are discussed later. Because of the dangers associated with overdose and the frequency of untoward side effects TCA have been largely superseded by SSRI as the first line treatment for a MDE. Tablets Capsules Syrup 10. epileptic seizures and death if not adequately treated. If necessary.catastrophic fall in blood pressure. cardiac arrhythmias. Tryptanol) Indications: Major depressive episode. dose may be increased to 300mg daily.

Dryness of mouth.effects. a fact which is often overlooked or ignored. (see page…. Doxepin is the choice in these patients if a TCA is to be used but generally a SSRI would be chosen first. despite a specific remedy (physostigmine. although uncommon. Manifestations of these side. The patient should be advised to get slowly out of bed or up from chairs and to avoid standing in one position for too long. often misdiagnosed as D. Hot baths are best avoided.). constipation and blurring of vision are the most frequent. They may be irksome. Toxic Psychosis. This can be especially troublesome in the elderly. Tricyclics are best avoided in patients suffering from prostatic hypertrophy as acute retention may be induced.'s. is important as it is a serious condition. Anti-cholinergic side effects: These are extremely common and the patient is best forewarned of them.T. severe psychosis or organic brain syndrome and is poorly treated. Considerable care must be taken when giving tricyclics to patients with known cardiac disease because of their tendency to either produce or aggravate arrhythmias. . but the patient is far more likely to tolerate them if the possibility is known and it is pointed out that they are a harbinger of relief from depression and likely to resolve in a few weeks. being available. together with additional suggestions for alleviation are: (a) Postural hypotension: This is common in the first few weeks of treatment and blood pressure usually returns to normal in a month.Medical contra-indications: The usual cautions regarding renal and hepatic disease apply.

Occasionally an alternative drug may be needed. Sucking peppermints or other confectionery is not advisable as it leads to tooth decay.(b) Blurred vision: If pilocarpine eye drops are ineffective and the dose of tricyclic cannot be reduced. (e) Paralytic ileus: This is rare but serious. be stopped and the patient admitted to hospital for appropriate treatment. (d) Constipation: This often improves as depression is alleviated. Bulk laxatives may be helpful. There is no satisfactory treatment apart from stopping the drug. . The drug should. compensatory glasses may rarely be needed. (c) Dryness of the mouth: This is very common. Normal function returns in a few months. A decrease in frequency of bowel motions does not usually matter and the patient should be assured of this. (g) Excessive sweating: Flushing with marked sweating is not uncommon. of course. (f) Sexual dysfunction: Impotence and delayed ejaculation are reported occasionally. Swabbing the gums with glycerine two or three times a day is useful.

Tremors.') It may be reversed rapidly by intravenous or intramuscular physostigmine 2 mg. depending on the mental condition of the patient. dry mouth and thirst and rapid pulse. The tricyclic should he reduced if possible. flushed skin. muscle twitching. Such patients are probably bipolar and lithium treatment should be seriously considered. This is a pro-cholinergic drug which passes the blood brain barrier. The more gross motor manifestations are uncommon and frequently do not respond to anti-parkinsonian drugs. ('Red as a beet. blind as a bat and mad as a hatter. (see page … for the management of overdoses) a stomach wash-out performed. A major tranquilliser may be temporarily useful. .(h) Toxic psychosis (Atropine psychosis. anticholinergic psychosis): This presents as an acute brain syndrome. dry as a stone. Other rough guides to the efficacy of treatment are pulse and salivation rate. The physostigmine usually needs to be repeated about every 2-3 hours. Seizures: The seizure threshold is lowered and epileptic patients may need increased doses of anti-convulsants. with marked visual hallucinations. hyper-reflexia and extra pyramidal symptoms: Often a fine tremor of the hands is found. The psychosis may need to be treated for several days. The offending drug must be stopped and if the condition is due to over-dosage. Euphoria and mania: This may be managed by ceasing the anti-depressant.

25 mg 50 mg sustained release . If a problem. Tablets Capsules 10. Jaundice. Diuretics are usually effective. may be treated with Vitamin B complex tablets I b. Paraesthesias: Uncommon. SSRIs with Clomipramine have either nil or negative effects on weight. clomipramine or moclobemide. In the patient who has lost a lot of weight as a consequence of their depression. Weight Gain . It is useful in treating juvenile enuresis. Doxepin often encourages weight restoration. paroxetine. Said to cause less confusion in the elderly. but these side effects are exceedingly rare. Simple dietary restrictions are advised. Weight gain: This may be due to the appetite being improved as the depression lifts. liver damage and agranulocytosis: Isolated reports have appeared. consider changing to fluoxetine. Anorexiant drugs are not indicated. Imipramine (Imipramin) Indications: As for amitriptyline.Oedema: Unusual forms of oedema are occasionally seen.d.Often a feature of older TCAs and a major cause of noncompliance in young women.

but less sedative and less weight gain. It is also useful in phobic and obsessional disorders. Side effects: As for amitriptyline. Clopress) [Retail pharmacy – specialist]. Specialist endorsement required. with continuance of . For enuresis 25-75 mg nocte is given.Dosage: In depression 100 to 300 mg daily may be needed. Rarely itching. This usually disappears after a couple of days. Indications: As for amitriptyline. Some patients suffer from headache and muscle aches after the first dose. Tablets 25 mg Dosage Range: 100 to 300 mg daily. Clomipramine (Anafranil. rashes and photosensitivities may occur. Has a greater inhibitory effect on serotonin reuptake than other TCA which probably underlies its usefulness in OCD. Side effects: As for amitriptyline.

Dopress) Indications: As for amitriptyline. Doxepin (Sinequan. Dothiepin (Prothiaden. lower anti-cholinergic effects. Capsules Tablets 25 mg 75 mg Dosage Range: 75 to 225 mg daily. Encourages weight gain. Side effects: As for amitriptyline. Anten) Indications: As for amitriptyline.the drug. 25 and 50 mg Dosage: As for amitriptyline. It also has an anxiolytic action helpful in the agitated patient. . Capsules Tablets 10. 25. It should not be used in combined antidepressant treatment. A delay of 1 week is advised before using MAOIs. 50 and 75 mg 10.

but especially where sleep disturbance is a presenting symptom. May be less sedative. Norpress) Indications: As for amitriptyline. Less cardiotoxic than most tricyclics. Tripress) Indications: As for amitriptyline. Tablets Liquid 10 mg and 25 mg 10 mg/5 ml Dosage: Usual range 100 to 300 mg daily. Side effects: As for amitriptyline. Tablets Capsule 25 mg 25mg and 50 mg . Trimipramine (Surmontil.Side effects: Similar to but less severe than amitriptyline. Required doses may be less than for amitriptyline. Nortriptyline (Allegron.

In high dose has significant epileptigenic effect.Dosage: Doses as for amitriptyline. Maprotiline (Ludiomil) [Retail Pharmacy – specialist] Indications: A quadricyclic drug. but more sedative.psychiatrists only. Side effects: As for amitriptyline. Tablets 25 and 75 mg Dosage: Usual range 75 to 200 mg daily. Mianserin (Tolvon) [special authority only] Indications: a) Approval granted for treating depression only in those patients: . Said not to suppress REM sleep. Low cardiotoxicity. . as for amitriptyline.with co-existent bladder neck obstruction or cardiovascular disease. b) Specialist must make application . or .who have failed trials with other antidepressants and who have been maintained on Mianserim prior to 1993.

100mg 75mg . 75. specialist only] A potent inhibitor of serotonin and noradrenaline reuptake and a weak inhibitor of dopamine reuptake with no anticholinergic properties.c) Prescription must be written by a psychiatrist. White cell suppression has been reported in 1 in 1015. (b) Non-tricyclic. Tablets 10 mg and 30 mg Dosage Range: 30 to 120 mg daily. requires monitoring of blood count regularly. Indications: Major depressive episode. Possible faster onset of action than other antidepressants. Dosage: Tablets Sustained release 25.5. dual-action reuptake inhibitors of seotonin and noradrenaline Venlafaxine (Effexor) [special conditions. 37. Side effects: Drowsiness may occur initial]y.000. Claimed to have little or no anticholinergic effects and little cardiotoxicity. 50.

As effective as other antidepressants. Can be increased in increments of 75mg/day no more frequently than every 4 days. somnolence. can increase up to 45mg daily. Mirtazepine ( ) Enhances central noradrenaline neurotransmission by blocking pre-synaptic alpha-2 autoreceptors and enhances serotoninergic neurotransmission by direct stimulation of serotonin neurones.Dosage range: Starting dose – 75mg/day in divided doses. an increase in appetite and weight gain are the most commonly reported side effects. up to a maximum 350mg/day’ Side effects: Nausea and other gastrointestinal symptoms. Dosage: Tablets mg Start at 15mg daily. Neutropenia has been reported and it is recommended that mirtazepine is stopped in any patient developing signs of infection with a low white blood cell count. . with possibly a faster onset of action. Side effects: Dry mouth.

This presumed to be secondary to the enhancement of dopaminergic neurotransmission. constipation. postural hypotension) . ii) Selective monamine reuptake inhibitors a) Selective serotonin reuptake inhibitors (SSRI) Selective serotonin reuptake inhibitors (SSRI) are now generally accepted as the treatments of first choice in depression and anxiety-depression states. Is prone to cause seizures. Weight loss. Inhibitors of noradrenaline and dopamine reuptake Buproprion (Wellbutrin) Related to the stimulant anorectic compound diethylproprion and has more stimulant activity other antidepressants. Can precipitate mania in the predisposed.B. Their major advantages over the standard tricyclic MARI lie in their lower propensity to cause anticholinergic side-effects (dry mouth. and their . insomnia and agitation. Increase in 100mg steps not more frequently than every 3 days to a maximum of 150mg tid. An increased risk of halucinations and/or delusions. Side effects: Restlessness. Indications: Depression Dosage: Tablets 100mg Commence with 100mg bd.

making them less prone to cause cognitive problems. such as sertraline (Zoloft). particularly in the elderly. attract no subsidy and can only be prescribed on a named patient basis. paroxetine (Aropax) and citalopran (Cipramil) are subsidised and available on GP prescription. This form of response is rare but has . it is certainly worth trying an alternative SSRI. usually one single dose in the morning. There have been reports of patients having a dramatic improvement in mood. They are not more effective than the tricyclic MARI. outlook and even according to some. It is available on specialist recommendation. fluoxetine (Prozac). As it has similar therapeutic effects to the SSRI PHARMAC lists Nefazodone under this category in the Pharmaceutical Schedule. nor do they act more quickly They tend to have a more simple dosage schedule. In New Zealand. is said to improve compliance . It is chemically unrelated to the other SSRIs and exerts dual effects of serotonergic neurotransmission through blockade of serotonin type 2(5-HT2) receptors plus inhibition of serotonin re-uptake. They are also less likely to cause impairment in psychomotor function. Unlike other SSRI Nefazodone requires a twice daily dosage schedule because of its shorter half-life. if there is a poor clinical response to the first trial of medication. Patients may exhibit a specific response to the different SSRI. along with fewer troublesome side effects. Most are available for GP prescribing but some require specialist authorisation. Other SSRI. This. Clinical opinion differs as to whether Nefazodone (Serzone) is a SSRI or not.absence of cardiotoxicity which leads to greater safety in overdose. a change in personality.

certainly been observed and may be due to a longstanding dysthymic disorder which has responded to the SSRI.

“Serotonin Syndrome”: A syndrome which includes symptoms of tremor, myoclonus, diarrhoea, confusion, hypomania, agitation, hyper-reflexia, shivering, incoordination, fever and diaphoresis has been reported following treatment with all serotonin enhancing drugs. These include L-tryptophan, MAOI, SSRI and TCA, especially clomipramine. Because of their selective effect on serotonin the SSRI may have a higher incidence of ‘serotonin syndrome’. Its occurrence is rare but, when it occurs the medication should be immediately discontinued and appropriated supportive measures taken.

SSRI currently available in New Zealand are:

Fluoxetine (Prozac 20, Fluox, Lovan)

Indications: Fluoxetine is indicated for the treatment of depression and its associated anxiety. It has low incidence of the anticholinergic side-effects seen with TCAs and is apparently safe in over-doseage. It is of equal efficacy to the TCAs as an antidepressant and does not stimulate weight gain so is particularly useful in depressed patients with concurrent eating disorders. Useful in the elderly because of simple dosage schedule, low side effect profile and margin of safety. Tablet Capsules 20 mg 20mg.

Dosage: Usual dose is 20mg mane. If no response after 4 weeks may increase to 40mg mane. Probably no indication to go above 40mg daily although higher doses appear safe. Effective daily dose may be as low as 10mg. May be taken with or without food. Fluoxetine has been shown to be effective in the treatment of OCD and Bulimia Nervosa where the therapeutic dose is 60 mg mane. As the half life is long there is no need for divided doses.

Side Effects and Cautions: Whilst being almost totally free of anticholinergic, cardiovascular and antihistaminic side-effects, fluoxetine does have a side effect profile of its own. The most troublesome side effects are nausea, headache, nervousness, insomnia. These tend to be limited to the initial period of treatment but can be sufficiently troublesome to warrant discontinuation. Another common side effect, which is often not volunteered, is lowered sexual interest and reduced inability to reach orgasm.

Because of the long half-life of fluoxetine and its active metabolites five weeks should elapse between discontinuation of fluoxetine and commencement of a non-reversible MAOI. Combined use should be avoided. Caution should be exercised when using fluoxetine with a TCA or lithium as it has been known to significantly increase serum levels of these drugs. Hyponatremia can occur, particularly in the elderly.

If sleep disturbance is a persistent problem a small dose of a sedative TCA may be added at night (eg trimipramine 25 mg or amitriptyline 25 mg). The combined use of SSRIs

and TCAs has been criticised by some authorities who state these drugs should never by used together, however so long as one is aware the blood level of the TCA may be doubled by the SSRI the judicious combination as recommended above is clinically useful and apparently safe.

Historical note: Fluoxetine was released in the USA in December 1987 and rapidly became the most prescribed antidepressant drug because of its efficacy and low incidence of side effects. Widespread concern and much legal activity was stimulated by an article in the American Journal of Psychiatry (Feb 1990) suggesting that fluoxetine induced patients to become both suicidal and homicidal. To date investigations by the FDA and the CSM in Great Britain have not substantiated these claims and both organisations are continuing to support the safety of fluoxetine. On current evidence there is rarely need for concern on this score.

Paroxetine (Aropax) A selective serotonin reuptake inhibitor similar to fluoxetine but with a shorter half-life and a more powerful auxiolytic action. Useful in OCD and Panic Disorder.

Tablets

20 mg

Dosage:

Depression and Anxiety: usual dose 20 mg mane, upper limit 60 mg.

Levels in breast milk are found to be similar to serum levels so should not be used or used with caution in breastfeeding mothers. a sensation of small electric shocks in the periphery. . It is usually mild and generally passes in a few days. Panic Disorder. Generally this side effect is not volunteered spontaneously and should be enquired about at follow up. Symptoms include nausea. agoraphobia: 40 mg mane but usually necessary to increase to 60 mg daily. Can be troublesome with regard to sexual function by inhibition of orgasm especially in males. Paroxetine does not appear to increase serum lithium levels in the way that fluoxetine does. Withdrawal symptoms can be lessened or avoided by tapering the dose to 10 mg for several weeks before discontinuing. The mean half-life of paroxetine is 20 hrs. flu like symptoms. tremor and anxiety as well as a wide variety of other minor discomforts. Can be taken on tid schedule if patient finds the post-dose sedation helpful.OCD: 40 mg mane but may need to increase to 60 mg mane. A withdrawal syndrome has been noted in a significant percentage of patients discontinuing paroxetine. Side effects: Similar to fluoxetine but may cause some sedation.

Citalopram is indicated for the treatment of depression. Citalopram is found in breast-milk in very low concentrations suggesting it may be useful in breastfeeding mothers if used with caution. As with other SSRIs it should not be used in combination with MAOIs. Experience in overdose suggests a wide margin of safety. A 14 day washout period should be allowed for patients taking MAOIs previously and a 7 day period allowed between discontinuing citalopram and beginning MAOIs. .Citalopram (Cipramil) Citalopram is the most selective serotonin reuptake inhibitor (SSRI) yet described with no or minimal effect on noradrenelin. Safety in pregnancy is not established.3 week intervals to a maximum of 60 mg daily (40 mg daily in elderly). Tablets 20 mg Dosage: 20 mg daily with increases at 2 . increased sweating headache and tremor being the most common. dopamine or gamma aminobutyric acid uptake. somnolence. The effects on the infant are not known. The side effect profile is similar to other SSRIs with nausea. It has been found useful in the treatment of social phobia.

Monitor therapeutic response and side effects as dose increases.100 mg bd increasing every 5 days by 100 .Nefazodone (Serzone) [Retail pharmacy – specialist] Has a double action on serotonin. usual adult dose range 300 . Side effect profile is similar to the other SSRI with nausea and………being the most common. Serzone is recommended for the treatment of depression accompanied by anxiety and sleep disturbance. Safety in pregnancy has not been established. 100. 200 mg Dosage: Begin with dose of 50 .200 mg to a maximum dose of 600 mg daily. Animal studies suggest some concentration in milk so should not be used in breastfeeding mothers. Experience of over-dosage suggests a high degree of safety. .600 mg daily. both of which enhance serotoninergic neurotransmission: it is a relatively weak reuptake inhibitor and a powerful blocker of presynaptic 5-HT2 receptors Tablets 50.

Anxiety. hypochondriacal symptoms. It has no effects on serotonin or dopamine neurotransmission at clinically effective doses. a rise in heart rate with no accompanying ECG abnormalities has been noted in clinical trials but its clinical significance is uncertain. lethargy and fatigue are prominent symptoms . iii) Monoamine oxidase inhibitors (MAOI) MAOI can be very effective in the treatment of so-called `atypical' or `neurotic' depression where the vegetative symptoms are frequently the obverse of those seen in the more typical depressive illness. can increase to 20mg Side effects: Relatively few. Impotence and urinary hesitancy in men.b) Selective noradrenaline reuptake inhibitors (NaRI) Reboxetine ( ) Appears to be equal in efficacy to TCA and SSRI in the treatment of depression. Dosage: Tablets mg Start at 8mg daily in divided doses. with an increase rather than a decrease in appetite and sleep.

broad beans and meat extracts. a) Non-reversible inhibitors of monamine oxidase Tranylcypromine (Parnate) Indications: Depressive illness. may be useful in some obsessive-compulsive and phobic states. obsessive-compulsive disorders.In the past MAOI have been indicated for depressive illness that has not responded to an adequate trial of tricyclic drugs or that has previously responded well to MAO inhibitors. When the action of this enzyme is blocked unmetabolised tyramine passes from the intestine into the blood stream where it can cause severe hypertensive reactions (‘cheese reaction’). Monamine oxidase is the enzyme responsible for the metabolism of tyramine contained in foods such as cheese. allows much greater dietary freedom. The reversible MAOI. Tranylcypromine is discussed as the prototype of the non-reversible MAOIs and moclobemide is discussed as the prototype of the reversible MAOIs. and phobic states. It has a stimulant effect which may be useful in the retarded patient . moclobemide. Tablets 10 mg Dosage: Commence with 10 mg morning gradually increasing if necessary up to 40 mg mane. MAOI may be helpful in clinical atypical depressions.

it increases the occurrence of weight gain. Alcohol is safe in moderation except Chianti. furthermore. It usually begins with a severe head. Provided these simple precautions are taken there is little risk of untoward reaction. and L-dopa. usually they are given a card listing them at the time the drug is dispensed. sympathomimetics such as adrenaline. sweating and often restlessness. Broad beans are often listed but in fact it is only the pods that are dangerous. All patients prescribed these drugs must be told in detail which foods they should not eat. In some cases this condition has led to subarachnoid haemorrhage and death.Major Side Effects (a) Hypertensive episode (‘cheese reaction’): Patients must be warned against eating cheese and extracts of meat and yeast (Marmite and Vegemite). Cough and cold remedies containing sympathomimetic constituents must also be avoided. amphetamine and its derivatives. usually in the context of an overdose. pounding of the heart.ache. Cough and cold remedies and nasal sprays may be dangerous. ephedrine. Drugs to be avoided are tricyclic antidepressants. Combining a tricyclic MARI with a MAOI does not bestow any significant therapeutic advantage in uncomplicated depression. neosynephrine. orthostatic hypotension and impotence. Such a hypertensive reaction is a serious condition. It is generally recommended that tricyclic MARI should not be . Fatal reactions have rarely occurred.

and give a card specifying the drug used. nor do they have any anticholinergic activity. MAOI are not cardiotoxic. I ampoule (10 mg) and repeat this in 10 minutes if the blood pressure has not returned to satisfactory limits. The use of phentolamine carries certain risks in itself and it should not be used outside of a well-equipped hospital situation unless absolutely necessary. and appropriate treatment. . A safer way of lowering the blood pressure rapidly is for the patient to take a 10mg nifedipine (Adalat) capsule which should be bitten and swallowed with a small quantity of water. The dose may be repeated if necessary to achieve satisfactory blood pressure levels. Immediate treatment of a hypertensive reaction involves giving intravenous phentolamine ('Rogitine'). On very rare occasions other foods and drugs may cause a hypertensive reaction. This method does not carry the risk of hypotensive overshoot which can occur with phentolamine. outlining the “forbidden foods” and drugs. For further treatment see Overdoses.prescribed for at least 14 days after stopping treatment with MAOI. sleep disturbance and weight gain. Treatment of a hypertensive crisis may need to continue for up to 24 hours if the offending substance is still being absorbed. When given alone MAOI are prone to cause postural hypotension. It is therefore wise to describe the symptoms to the patient. symptoms of a hypertensive crisis. page 75.

. For treatment see Overdoses. lignocaine or 'Xylocaine ' seem reasonably safe. Phenelzine (Nardil) Indications. but may cause anticholinergic effects..(b) Hypotensive reaction: Pethidine (U. lowering of seizure threshold. drowsiness. As for tranylcypromine. Cocaine derivatives. insomnia. hypotension. an equal number of insomnia and some of weight gain. page 75. meperidine) and morphine can lead to severe hypotensive crisis (cardiovascular collapse). It does not have the stimulant action of tranylcypromine and is less likely to be associated with hypertensive crisis. There is no need to avoid adrenaline in dental injections. A few patients complain of drowsiness. See the section on tricyclic side effects for treatment. e.g. Side effects: As for tranylcypromine. Minor side effects: (usually dose related) Restlessness. Tablets 15 mg Dosage: 30-75 mg daily is the usual dose.S. as does pentazocine ('Fortral').

(200mg tds or 300mg bd). This allows much greater dietary freedom as the risk of a hypertensive reaction with tyramine-containing foods is much less. 300 mg Dosage: Begin with initial dose of 100mg tds and increase if necessary to maximum of 600mg daily. . Average adult dose 450mg daily. Moclobemide does not impair vigilance and is not sedative. Indications: Depressive illness. No dose reduction needed in the elderly or those with renal impairment.b) Reversible inhibitors of monoamine oxidase Moclobemide (Aurorix) A reversible inhibitor of mono-amine oxidase type-A (RIMA). patients with phobic disorders and panic disorder and for those at risk of overdose. Caution in cases of severe hepatic impairment. may offer special benefits in the elderly. Do not increase dose until after one week from commencement as bio-availability increases throughout this time. Tablets 150mg.

Cimetidine prolongs the metabolism of Moclobemide. dry mouth. Animal studies do not indicate the likelihood of difficulties in pregnancy. Do not use in children or pregnant or nursing mothers. the usual dose of Moclobemide should be halved in patients taking cinmetidine. headache. agitation. NB: Still a 2 week washout recommended for SSRI to Moclobemide transfer. nervousness. as no information is currently available for these situations. sleep disturbance. Depressed patients with high levels of excitation or agitation should not be treated with Moclobemide unless an anxiolytic is used as well. Treatment with Moclobemide does not necessitate dietary restrictions in patients with normal dietary habits. These effects may be due to the underlying illness and none occurred with an increased frequency of more than 5% compared with placebo. The following transient effects have occasionally been observed: anxiety. Treatment with a TCA or other antidepressant can be initiated directly without a washout period when discontinuing Moclobemide treatment or vice versa. blurred vision. . gastrointestinal disturbance.Major Side Effects and Cautions Moclobemide is very well tolerated and has few side effects.

Also changing to and from TCAs to a MAOI can be done . It is best initiated by a specialist on an inpatient basis. Mono-amine oxidase inhibitors (MAOIs) are an alternative and effective group of drugs which may have some specific indications although not as yet clearly defined. or the MAO inhibitor may be added to a tricyclic regime. improvement may occur if they are combined. This may also be effective in phobic and obsessive-compulsive conditions. moclobemide. Since the introduction of the new generation of antidepressants in the early 1990s there has been a threefold increase in cost of antidepressants for only a 7% increase in usage. in combined treatment. The usual procedure is to give the MAO inhibitor in the morning and the tricyclic in the evening.(vi) COMBINED M. When choosing an antidepressant however it is worth keeping in mind a recent analysis of the situation regarding antidepressants in Australia. both drugs are commenced at a low dosage at the same time.O. The recent introduction of the reversible MAOI. Both drugs are increased within the usual range as necessary. Tranylcypromine should be avoided. has made this restriction unnecessary and has opened the way for MAOIs to be used preferentially in certain clinical situations. Generally.A. The major disadvantage to the use of MAOIs in the past has been the strict requirements to avoid tyramine containing foods and sympathomimetic medications such as many common cold remedies. INHIBITORS AND TRICYCLICS In a few patients with depression resistant to either group of drugs given separately. as should clomipramine.

Tricyclics antagonise the action of the adrenergic neuroneblocking drugs and probably also methyldopa. If changing from a TCA to another MAOI. It is possible that this effect is less marked with doxepin. a three-day drug free period is needed. methyldopa. Mianserin has been reported to have little or no interaction with the anti-hypertensive effects of clonidine and methyldopa. When a patient on antihypertensive therapy develops depression.g. The newer drugs however widen the therapeutic range and have a place in the treatment of particular patient populations. e. Conversely. propranolol. the antidepressant drugs may seriously affect the treatment of high blood pressure. Inpatients with treatment resistant depression have been treated with a combination of MAOI and TCA but this needs to be carefully monitored and should not be attempted on an outpatient basis. Changing from MAOI to a TCA requires a 10-day drug-free period. As a general rule it is best to avoid the use of antidepressant drugs in patients on anti-hypertensive therapy (other than a diuretic). Antidepressants and Hypertension: Some antihypertensive drugs (and other medical drugs) may precipitate depression. reserpine. . this therapy must be reviewed and any possible offending drug replaced by a suitable substitute. The MAO inhibitors may cause marked potentiation of the ganglion-blocking drugs. It is good practice to know one or two antidepressant drugs really well and to use them consistently.more rapidly with moclobemide. clonidine and occasionally guanethidine.

c) the prevention of recurrences. usually in hospital. Often the antipsychotic can be stopped after a few weeks and the mood stabiliser continued indefinitely in maintenance dosage. with his non.stop activity. . In less severe cases treatment as an outpatient is often possible. the antipsychotic drugs are frequently used in the acute phase of mania but rarely in maintenance treatment thereafter. Most published guidelines recommend starting treatment with a mood stabiliser (see below). (i) Antipsychotic drugs As they act rapidly. but. in more severe cases it is usually necessary to use an antipsychotic drug in the first instance.BIPOLAR DISORDER The treatment of bipolar disorder can be considered under three headings: a) an acute manic episode. constant pressure of talk. a) MANIA The severely manic patient. b) a depressive episode (‘bipolar depression’). A regime that has been found useful in the management of the manic patient has been to start the antipsychotic drug at the same time as commencing treatment with a mood stabiliser such as lithium carbonate. (See page …… for treatment of acute psychotic excitement). as mood stabilisers such as lithium and valproate take longer to act. bellicose self-confidence and inability to focus on any activity for more than a moment. requires urgent treatment. and are generally less effective in reducing the overall level of disturbance.

Haloperidol (see page…. and who are unreliable in their compliance. This can be gradually decreased to as the symptoms settle. When haloperidol is used in treating the acutely manic patient. a more sedative antipsychotic such a chlorpromazine or olanzapine (see page….. They include lithium and a number of anticonvulsants. benefit from long-term treatment with a depot antipsychotic (see chapter ). Lithium Lithium was the first drug to shown to be effective in the treatment of mania and the prevention of further episodes. it is very rarely necessary to exceed a maximum dose of 20mg in any 24hr period. particularly those prone to recurrent episodes mania.Some patients. ii) Mood stabilisers Mood stabilisers are drugs which have been shown to be effective in the treatment of an acute manic episode and have the potential to reduce the frequency of further episodes. . However. lamotrigine and gabapentin. carbamazepine. by John Cade of Melbourne. such as sodium valproate. can be said to have ushered in the era of modern psychopharmacology.) is widely used for this purpose and has the advantage that it can be given as an injection to patient unwilling to take oral medication. This discovery in 1949..) may be preferable if the patient is prepared to accept oral medication.

methotrimeprazine. risperidone or olanzapine is often needed to calm the more excited patient before lithium takes its effect. may be needed during the first few days until improvement or side effects are noted. An antipsychotic such as haloperidol. and is worth trying in combination with antidepressants in cases of refractory depression. show toxic symptoms at therapeutic serum levels. Priadel) Indications: It is most useful in the prophylaxis of recurrent affective disorders (see below). It may be useful in schizo-affective psychosis. Also. Once controlled the dose is reduced to maintenance levels.9 mmol/l. Lithiomyl. again usually the elderly. Usually this requires a dose of 750 to 1. chlorpromazine. It is emphasised that the serum level and clinical state should determine the daily dose. A few patients. some. usually elderly. but if this produces undesirable side effects then twice-daily dosage is . After stabilisation.Lithium carbonate (Lithicarb.250 mg/day but the elderly may need as little as 500 mg/day. Dosage: Tablets: 250 mg and 400 mg Capsules: 250mg Slow release tablets (Priadel): 400mg For control of acute mania 750 – 1250mg. ensuring the serum concentration remains between 0. do well on serum levels lower than the usual range. the entire maintenance dose can be taken at night.5 and 0. but it also has a calming effect in mania after a few days.

Also. some. It is wise to give the patient and a close relative a card warning about the signs and symptoms of toxicity. For control of acute mania 750 – 1250mg.9 mmol/l. then weekly for the first month. usually elderly. Blood for lithium levels should be taken 12 hours after the night dose and before any morning tablets. monthly for 3 months. then weekly for the first month.warranted. 250 mg and 400 mg tablets.250 mg/day but the elderly may need as little as 500 mg/day. do well on serum levels lower than the usual range. . Usually this requires a dose of 750 to 1. show toxic symptoms at therapeutic serum levels. An antipsychotic such as haloperidol. risperidone or olanzapine is often needed to calm the more excited patient before lithium takes its effect. but if this produces undesirable side effects then twice-daily dosage is warranted. A few patients. 3 monthly for a year and then as often as it would appear indicated by past experience with the patient. Blood levels are usually taken at the end of the first week.5 and 0. It is wise to give the patient and a close relative a card warning about the signs and symptoms of toxicity. the entire maintenance dose can be taken at night. monthly for 3 months. chlorpromazine. again usually the elderly. Blood for lithium levels should be taken 12 hours after the night dose and before any morning tablets. After stabilisation. ensuring the serum concentration remains between 0. It is emphasised that the serum level and clinical state should determine the daily dose. 3 monthly for a year and then as often as it would appear indicated by past experience with the patient. may be needed during the first few days until improvement or side effects are noted. Once controlled the dose is reduced to maintenance levels. Blood levels are usually taken at the end of the first week.

polydipsia and polyuria. It is wise to stop lithium treatment during acute renal infections. thirst. Pregnancy: As a general rule lithium is not advised during pregnancy. Preliminary tests: A baseline series of tests should be performed immediately prior to starting lithium. loose stools.Contra-indications: None are absolute. Dosage often needs adjusting as renal clearance increases during pregnancy then returns to normal after birth. it should be recommenced immediately post-partum as this is a high-risk period for relapse. serum creatinine. but lithium should be given cautiously to those with renal or cardiac disease and those in concurrent diuretic treatment. as the risk of foetal malformation involving the cardiovascular system is greater in the children of women prescribed lithium during pregnancy than that of women not so exposed. if possible. . thyroid function tests and an ECG in those over 40yrs. fine tremor. Thus. Side effects: Initial and harmless: Nausea. urea. pregnancy should be planned so that lithium can be stopped a week or two before conception and recommenced after the first trimester. These are: electrolytes. Annual check-up: Renal function tests and thyroid function tests should done annually. but has not produced toxicity. Lithium is excreted in breast milk producing a serum concentration half that of the mother in the infant. If a manic-depressive patient has been off lithium during pregnancy. particularly in the first trimester.

Hypothyroidism may occur. the lithium dose should be reduced. sluggishness. but if a source of embarrassment. Levels above 1. Neurological defects mimicking strokes may present and may not remit completely after treatment of toxicity. and is treated in the usual way with thyroid replacement.d. eg: propranolol 40 mg t./l indicate impending toxicity.Persistent but harmless. vertigo and dysarthria. Symptoms heralding intoxication. There is no need to cease lithium but a review of the patient's clinical state and need for lithium should be carried out.s. A fine tremor of the hands is usually of little consequence. as the sodium loss induced may lead to lithium toxicity. Vomiting and diarrhoea. If a thiazide diuretic is used.5 meq. coarse tremor of the hands. If toxicity is supected lithium should be stopped immediately and the serum level determined. Serum levels are normally halved each day after the drug has been stopped. sudden onset of polydipsia and polyuria. For treatment of severe toxicity see page…… . is helpful. Long term. do not use diuretics unless essential. . sleepiness. None of these conditions usually warrants the discontinuance of lithium. For polyuria and polydipsia the patient should be advised to drink plenty of fluid. Moderate weight gain can most suitably be controlled by avoiding sugar-containing drinks. Oedema of the face and ankles. a beta blocker.

Carbamazepine (Tegretol. Dosage: Tablets 200. controlled release 200. The risk of blood dyscrasias warrant monitoring in the early stages Sodium valproate (Epilim) Indications: At least one controlled trial has shown it be as effective as lithium in acute mania but there is less evidence for its value in the prevention of recurrences. 500mg 800 mg daily in 2 divided doses increasing by 200 .3 days until symptoms come under control. 200. Evidence would suggest lithium and carbamazepine may have a synergistic effect and may be tried in combination if either alone fails to produce satisfactory results. ataxia. A plasma level of 45-125mcg/ml is probably optimal. gastrointestinal symptoms and drowsiness. A . Side-effects: Dizziness.400 mg every 2 . Teril) . Start at low dose and increase gradually. Indications: Clinical trials have produced evidence that carbamazepine has antimanic. 400mg. 400mg 400-1600mg daily in divided doses. Skin rash in up to 15%. and prophylactic effects in bipolar disorder especially in patients with mixed affective disorder those with a rapid cycling course who often are less responsive to lithium. Dosage: Tablets 100.

They help moderate disturbed behaviour and promote sleep. ataxia and gastrointestinal disturbances. iv) Prevention of relapse Prevention of relapse is the major therapeutic challenge in the overall management of bipolar affective disorder. headache. Most patients relapse at least once. Once started it should probably be continued indefinitely.. Side effects: These include sedation. Although valproate causes less risk of blood dyscrasia than carbamazepine. it is probably advisable to monitor the blood count in the early stages of treatment. Clonazepam has found favour for this indication in New Zealand. (c) Benzodiazepines This group of compounds can be valuable as adjunctive medication in the treatment of an acute manic episode. Weight gain can be troublesome and total alopecia has been reported. Lithium is still recommended by most authorities as the drug of first choice for the long-term management of bipolar disorder.). many several times. (a) Lithium In a large number of double-blind clinical trials lithium has been found consistently to be superior to placebo. Most studies indicate that the optimal plasma level for . although there is no evidence that it is more effective than other members of this group (see page….loading dose of up to 20mg/kg/day has been shown to produce a more rapid anti-manic action.

a level below this is usually ineffective. Here. There is evidence that folic acid can protect against this. (b) Anticonvulsants Carbamazepine Controlled trials of carbamazepine have shown it to be as effective as lithium in the prophylaxis of bipolar disorder. greatly increases the likelihood of a manic relapse occurring within the next 14-21 days. at least during the first few weeks of treatment with carbamazepine.5-0. and in those prone to rapid-cycling. a neural tube defect occurred in 1% of the offspring of mothers taking carbamzepine during pregnancy. women taking an oral contraceptive should be advised to adopt an alternative contraceptive practice. even after several years successful prophylaxis.prophylaxis is 0. Stopping lithium abruptly. In patients who relapse on lithium. Between one third and one half of the patients prescribed lithium stop taking it against medical advice. or combining it with lithium may prove effective. Because carbamazepine causes liver enzyme induction. one above is frequently accompanied by side effects which prejudice compliance. the combination of carbamazepine and lithium may be more effective than either drug given alone. . It can be teratogenic. accounting for approximately half of all relapses. switching to alternative mood stabiliser (see below). In approximately a third of patients continuous lithium fails to prevent relapse.9mmol/l.

Dosage:. A 'foetal valproate syndrome'. seizures and feeding problems in the infant. folic acid may prevent this. Its place in the maintenance treatment of bipolar disorder remains to be established. characterised by both major (mainly cardiac) and minor congenital malformations and by jitteriness. 100mg .3% of offspring. has been described in the offspring of epileptic mothers who took valproate during the first trimester of pregnancy.Sodium valproate Open studies have indicated that valproate may have a role in the prevention of manic episodes in bipolar patients but. Tablets 25. It appears particularly effective in patients with a rapid cyling pattern of illness. may benefit from combining the two. there have been controlled trials confirming this. 50. or who cannot tolerate them. Valproate can be useful for those who do not respond to lithium or carbamazepine. Lamotrigine (Lamictal) Lamotrigine given as an add-on treatment can benefit patients who fail to remain well on other treatments. Patients who have failed to respond to treatment with either lithium or valproate given separately. Spina bifida occurs in 1. as yet.

Depot neuroleptics given to patients with recurrent mania who are non-compliant with lithium or carbamazepine significantly reduce the frequency of manic episodes. Dosage: Capsules 300. 100mg daily for the next two weeks. facial oedema and lymphadenopathy (Stevens Johnson syndrome). . (c) Antipsychotics Conventional antipsychotic drugs are widely used in the maintenance treatment of bipolar disorder. blurred vision. 400mg Start at 300mg/day.Need to build up slowly: 50mg daily for 2 weeks. somnolence. Side effects: Dizzines. Gabapentin (Neurontin) This may help in the maintenance therapy of bipolar disorder when given as adjunctive therapy to patients who relapse on standard treatments. usually in combination with lithium. o then increase by 100 mg daily every 1-2 weeks to reach a maintenance dose of 2-400mg daily given in divided doses. build up slowly to 300mg bd. Side effects and toxicity: The most serious is a skin rash with fever. ataxia.

. treatment with clonazepam may help reduce the likelihood of relapse. patients should be given a supply of diazepam. clonazepam or temazepam to take if they experience difficulty in sleeping and then advised to seek a clinical review.(d) Benzodiazepines As insomnia is a frequent harbinger of relapse. In patients subject to stressful events.

E.. 8 Chloral hydrate and its derivatives are effective and are cheaper than their modern equivalents. and…. perhaps asking the patient to keep a sleep diary for a week to establish a ‘base-line’. 6 7 Adequate muscular relaxation training is much safer in chronic insomnia.. Patients taking tranquillisers and tricyclic anti-depressants should be encouraged to take them at night. There is little clinical justification for giving hypnotics for more than a few days at a time and patients rapidly become dependent on hypnotics. 3 4 5 Depression is often the cause of insomnia. .Chapter 3 HYPNOTICS AND ANXIOLYTICS When treating sleep disturbance. All hypnotics alter the E.G. pattern and normalization may take a long period.. (a) BENZODIAZEPINES For treatment of overdose see page …. Careful enquiry as to sleeping habits and caffeine intake is essential. it is important to remember:- 1 2 Insomnia is a symptom and not a disease.

20 Oxazepam Temazepam Triazolam 6. there are significant differences in speed of onset and duration of action.3 Half-life times can be a guide to appropriate clinical use. Diazepam is rapidly absorbed when taken orally. Oxazepam is slowly absorbed and much slower in penetration Lorazepam is somewhere between these two in speed of action. the main use of benzodiazepines is in the symptomatic management of anxiety and stress-related conditions.8 5. a short-life one such . Plasma half-lives for parent drug and active metabolite have been given in hours as: Flurazepam Chlordiazepoxide Diazepam 50-100 50-100 50-100 Alprazolam Lorazepam Lormetazepam Clonazepam 12-15 9-16 8-12 Nitrazepam Flunitrazepam Bromazepam 18-34 25.30 12. Given intravenously its action is particularly rapid although it is slowly and erratically absorbed after intramuscular injection. Although there seems to be little difference among benzodiazepines in terms of effectiveness.Apart from their use as hypnotics. A long half-life compound such as diazepam would be most appropriate for sustained anxiety.8 2. reaches the brain quickly and can therefore be used to give prompt relief of panic attacks. In contrast. Many controlled trials have shown their superiority over placebo and barbiturates in relieving these conditions.

as Lorazepam for episodic attacks. although it is not clear that it has any great advantage over other benzodiazepine compounds. As awareness of the problems associated with benzodiazepine dependence becomes more widespread a syndrome of rebound withdrawal is being recognised more frequently. depending on half. sometimes leading to seizures. there is evidence that they can intensify depression and without treatment of the underlying condition. Triazolam and Temazepam meet these requirements. Ideally a hypnotic should act rapidly. Symptoms of benzodiazepine withdrawal are the same as those of alcohol and barbiturate withdrawal except that they tend to be later in onset and more attenuated. Whereas they may in these circumstances give immediate symptom relief. anxiety and insomnia. have a short half-life and not accumulate. If these drugs are given in large doses and then suddenly stopped there occurs a withdrawal syndrome with restlessness. Oxazepam is short-acting but absorption is too slow for emergency use. are really contraindicated in such circumstances. The medium half-life compounds Nitrazepam and Flunitrazepam are suitable as hypnotics with continuing daytime anxiolytic action. A possible exception to this is alprazolam which is reported to be effective in moderate depression. Patients who have taken short-acting benzodiazepines for long enough to become dependent and to develop tolerance (variable between individuals . Half-life times are also significant as regards withdrawal effects and dependence.life duration. A note of caution is necessary in relation to the use of these drugs for anxiety secondary to depression. Clonazepam is widely used in the treatment of mania.

. If this can be achieved the patient will often be astounded at how much better they feel once drug free for several weeks. and cognitive impairment from long-term use is a possibility that always must be kept in mind. Persuading the patient to give up their medication is difficult. Usual dose l to 2 tablets. particularly in the elderly. Benzodiazepines do have an adverse effect on cognitive function. suitable for the treatment of resistant insomnia. More potent than its cogeners. This is rapidly relieved by taking another dose . A frequent drug of abuse ‘in the street’. Moving to a longer acting benzodiazepine and then progressively reducing the dose may help. Total cessation of withdrawal symptoms may take many months. but withdrawal may often require inpatient admission.and between different members of the benzodiazepine group) appear to have periods of rebound withdrawal anxiety between doses. The danger of benzodiazepine dependence can be reduced by avoiding the long-term use of these drugs whenever possible and always gradually reducing the dose when stopping. One further note of caution needs to be sounded.thus reinforcing the dependency and falsely reconfirming for the patient that they suffer chronic anxiety. (a) (1) Benzodiazepines used Primarily as Hypnotics Flunitrazepam (Rohypnol): 2 mg tablets.

Normison): 10 and 20 mgm capsules. Usual dose 1-2 tablets. .Flurazepam (Dalmane): 15 and 30mg capsules. Usual dose 0.125mg tablets.125 mg tablets. Usual dose 15 mg. Insoma 5.5 mg for elderly and/or debilitated patients. Has rapid and short action. Nitrados): 5 mg tablets and capsules. with 7. Rapid and short action similar to Temazepam.5-1 mg. and little different from nitrazepam. Recent concern about mental state changes on the higher dose range of Triazolam have prompted the Health Department to withdraw all but the 0.125-0. Loprazolam (Dormonoct): l mg tablets. Dose 10-30 mgm. Usual dose 0.5mg. Closely related to. Triazolam (Halcion): 0. Has rapid and short action. Lormetazepam (Noctamid): 1 mgm tablets. Doses should be kept to an absolute minimum. Temazepam (Euhypnos.5 mg and 15 mg tablets. Nitepam. Midazolam (Hypnovel): 7. Nitrazepam (Mogadon. Dose 1-2 mgm.

0. Dosage: 0.5 mg daily in divided doses. Usual dose: (a) Anxiety states .5 mg to 4. 1. (b) Neurotic Depression .5 to 4. can occasionally cause paradoxical stimulation and possible hostile outbursts. nor in patients whose diagnosis is of major (endogenous) depression. There is also evidence to indicate that Alprazolam may have a more severe withdrawal syndrome than some other benzodiazepines. .5 mg.(a) (2) Benzodiazepines Used Primarily in the Treatment of Anxiety Alprazolam (Xanax): Indications: Reported to have special application in the treatment of mixed anxiety/depressive states. and in neurotic depression. nor those with psychotic symptoms. blurred vision. It should not be used in patients with psychomotor retardation.0mg daily in divided doses.1. As with other benzodiazepines. Side Effects: Drowsiness. light-headedness.0 mg tablets.25 mg. gastro-intestinal symptoms and autonomic manifestations.0.

0 to 12.5 mg.0 mg t.s.d.d.d.5 to 3.0 mg tablets. to t. 6. Chlordiazepoxide (Librium): Indications: It is recommended for the short-term relief of anxiety and tension in neuroses. and 25 mg 10 mg In neuroses 5-10 mg t. Side effects: Well tolerated with usually little sedation. indicated in the treatment of severe generalised anxiety.s. .0 mg b. Fatigue and drowsiness may occur. It has an intermediate length half-life.d. Usual dosage: Usual dosage: Outpatients 1. Dosage: 1. Inpatients 6.Bromazepam (Lexotan) Indications: High potency benzodiazepine. is the usual dose.0 mg. Dosage: Tablets Capsules 5. 3. 10.s.

It is used in epilepsy. Diazemuls inj): Indications: It has been recommended for short-term treatment of anxiety and tension. Dosage: Tablets 0.2-0.see page 46. loss of libido.Side effects: Dizziness. Skin rashes. headaches. failure of ejaculation and constipation have been reported. Clonazepam (Rivotril) Indications: Although marketed primarily as an anticonvulsant for use in epilepsy. and 10 mg 2 and 5 mg . nausea. 2mg For agitation and/or anxiety 0.5mg prn up to 1. It can also be effective in panic disorder. 5. D-Pam Pro-Pam oral. probably being the drug of choice in status epilepticus.5. ataxia and drowsiness occur. Dosage: Tablets Capsules 2.5mg daily Diazepam (Valium. Long term effects . because of its sedative action clonazepam is widely used in psychiatry as an adjunctive treatment in the management of manic episodes.

see page 46.Syrup Injection 2 mg/5 ml 10 mg/2 ml Usual dose 6 to 40 mg daily in divided doses.d.s. 1 and 2. Dosage: Tablets Sublingual tablet 0. to t. Side effects.5 mg 1 mg Usual range 1 mg b. Mild ataxia and drowsiness occur in excessive dosage. Long-term effects . Side effects: Drowsiness may occur initially. Ataxia and confusion have been reported in high dosage. Long term effects . Lorazepam (Ativan.see page 46.d.5. . Lorapam): Indications: Anxiety. It has been shown that diazepam can precipitate serious depressive illness and that it can aggravate existing depression.

Oxazepam (Serepax. for whom it is an excellent sedative in withdrawal states (see page 62). Dosage: Tablets 10. Claimed to relieve anxiety in alcohol withdrawal. (b) OTHER HYPNOTICS Chloral Hydrate: 600-1.75 mg to 15 mg). It is well tolerated by the elderly. Chlormethiazole (Hemineurin) 300 mg capsules. This drug is well tolerated by the elderly and rapidly eliminated. Deaths by overdose (combined with alcohol) have been reported.8 I/V infusion.200 mg in syrup or 500 mg caps (Noctec). A short acting hypnotic with a half-life of 5 hours. Dependence may occur especially in alcoholics. Ox-Pam. Benzotran): Indications: Said to reduce symptoms of anxiety and tension. It is a short acting sedative with a half-life of less than four hours. 7. One or two tablets act rapidly. 15 and 30 mg 45-120 mg/day in divided doses.5 mg tablets. (Range 3.5 mg. 250 mg/5 ml syrup and 0. Zopiclone (Imovane): A cyclopyrrolone compound. . Adult dose 7.

Dependence potential is said to be less pronounced than with the benzodiazepines. the dose increased if necessary within wide limits. Most troublesome side effect appears to be unpleasant aftertaste. Reported to have no CNS depressant effect. (c) OTHER ANXIOLYTICS Beta blockers Although primarily used in the treatment of hypertension. as they do not produce drowsiness as found with the benzodiazepines. In the CNS it acts as a serotonin partial agonist and thus has similar properties to the serotonergic antidepressants. They are most effective in acute situational anxiety with somatic symptoms. A history of asthma or cardiac failure contraindicates this treatment.Induces and sustains sleep without reduction of REM sleep and with preservation of slow wave sleep.s.d.d. Skilled performance is unaffected. this group of drugs has anxiolytic properties. Has been . hence its antidepressant properties and slow onset of action. no apparent abuse liability.. Is very well tolerated by most patients. The usual dose is one of the smallest tablet size of any betablocker taken b. Depression has occurred with propranolol. no withdrawal symptoms and few side effects. or t. Negligible residual effects and rebound insomnia not a feature. Buspirone (Buspar) A non-benzodiazepine anxiolytic.

.d. Dosage: 5 mg. related to the phenothiazines. which can be useful in some cases of anxiety. and diarrhoea. Initial dose 5 mg t. noticeable after 7 . Should not be used with MAOI's. 10 mg tablets. While benzodiazepines have been the mainstay of drug treatment in anxiety for decades. Dosage: Tablets 25.30 mg in divided doses. there has been a determined search for effective alternatives. Slow onset of improvement of symptoms.10 days. Hydroxyzine (Serecid) An antihistamine. 50mg 25-50mg up to four times daily. largely because of the tendency of benzodiazepines to produce tolerance and dependence. Optimal daily dose 20 . Side effects: Dizziness. headache.s.reported to have augmentation effect when used together with other antidepressants. Side effects: Drowsiness (d) CHOICE OF ANXIOLYTIC Unfortunately there is no ideal anti-anxiety drug. nervousness.

(Specific phobias are probably best treated exclusively with psychological treatment. In an acute anxiety reaction. (ii) Panic Disorder Tricyclic antidepressants (TCA). particularly moclobemide. particularly imipramine have proved helpful. and SSRI. Drugs are best administered as part of a comprehensive treatment plan which includes psychological treatment. short-term treatment with a benzodiazepine is likely to afford symptomatic relief.) (i) Generalised Anxiety Disorder (GAD) The recommended first-line treatment for GAD is with an SSRI antidepressant or an antidepressant with a dual action such as venlafaxine. . (iii) Social phobia MAOI.There are five distinct anxiety syndromes recognised in DSM-IV for which anxiolytic drugs have an important place in treatment. If the symptoms are limited to performing or speaking in public (performance anxiety) treatment with a beta-blocker should be tried first. as have monoamine oxidase inhibitors (MAOI). have been shown to be superior to placebo in clinical trials. or an acute exacerbation of anxiety. Buspirone may be be tried if these prove ineffective.

.(iv) Obsessive Compulsive Disorder (OCD) A serotonin reuptake inhibitor (SSRI) such as paroxetine. (v) Post-traumatic Stress Disorder (PTSD) Here too. are the preferred first-line drugs. or a tricyclic antidepressant (TCA) with pronounced serotoninergic reuptake inhibition. such as clomipramine. drug treatment should start with an SSRI or moclobemide.

Attention must be paid to underlying causes. clinical trials have shown that better control can be achieved with single drug treatment. D. The general principles of drug treatment in epilepsy are: 1 Always attempt to control seizures using a single drug. Senior Lecturer in Medicine (Neurology) at the University of Otago for updating this chapter. Use well-tried and less toxic drugs first. (a) GENERAL Although drugs are helpful in epilepsy they are by no means the entire treatment. On the contrary. Using more than one drug increases the risk of drug interactions and adverse effects. giving sufficient time for an adequate trial. and there is no evidence that it provides better seizure control. . to avoidance or anticipation of precipitating factors. 2 Choice of drug should be based on the seizure type. Hammond-Tooke.Chapter 4 DRUG TREATMENT IN EPILEPSY We wish to thank Dr G. as well as to the personal and social aspects of having such a condition. properly monitored.

possible toxicity develops. Carbamazepine. careful titration of dose is necessary.3 Therapy with phenytoin may be initiated with an appropriate maintenance dose or even with a loading dose. 4 Dosage intervals range from once daily (phenytoin. other drug therapy is required or compliance is suspect. Anticonvulsants have a low therapeutic ratio so the dose required to reduce seizures is only slightly less than the toxic dose. phenobarbitone. The target range of commonly used drugs should be used as a guide and careful clinical monitoring is preferable to rigid adherence to these values: Phenytoin 10-20 mg/l Carbamazepine 5-8 mg/l Sodium Valproate50-110 mg/l Ethosuximide 40-80 mg/l . Serum level monitoring is an important aid to effective drug. 5 Only when single drug options have been exhausted should one resort to combination regimens. and most other anticonvulsants should be introduced gradually to minimise side effects. use particularly when response to treatment is poor. primidone) to three or four times a day in the case of carbamazepine. although the controlled release preparation of carbamazepine may be used twice a day. Because of this.

200 and 400mg Syrup 100mg/5ml . Also used in trigeminal neuralgia. Indications: Effective in partial and generalised tonic-clonic seizures. and psychomotor changes in children. Where there is psychosis or depression in association with epilepsy. there is the problem of anti-psychotic and antidepressant drugs lowering seizure threshold and also interfering with anticonvulsant serum levels. making carbamazepine and sodium valproate preferable choices in children. Dosage: Tablets: standard and controlled release. Phenytoin and phenobarbitone are particularly likely to do this. Teril (Pacific).7 Anticonvulsants may cause impairment of cognitive function. which is not uncommonly so in temporal lobe epilepsy. There is some evidence to suggest that newer anti-depressants maybe less epileptogenic. b) DRUGS OF 1st CHOICE Carbamazepine: 'Tegretol' (Geigy).

nausea.Starting dose 100 mg twice daily. Allergic skin rashes. Side Effects: Anorexia. Forte suspension 100mg/5ml Ampoules: 100mg/2ml and 250mg/5ml Usual adult range: 200 to 400mg per day. three to four times daily with standard preparation.000 mg per day. Blood dyscrasias may occur in long-term therapy . mg/kg/day Paediatric starting dose: Dosage interval: nce or twice daily. drowsiness or visual disturbances may occur. vomiting. and in tonic-clonic status epilepticus. Dosage: Capsules: Tablets: Suspension: 30 and 100mg (infatab) 50mg 30mg/5ml. . Maintenance range 400-2. headache. Dosage interval: twice daily with controlled release preparation. dizziness. Not effective in generalised absence attacks and may aggravate them. Phenytoin: 'Dilantin' Indications: Effective in partial and generalised tonic-clonic seizures. with slow increase until response is obtained.

000mg daily. 200mg.Side effects: Slurring of speech. swelling of lymph glands. and blood dyscrasias. double vision. Side Effects: May potentiate sedative effects or other drugs. 500mg 200mg/5ml Starting dose: Maintenance range: Dosage interval: 200mg twice daily. Sodium valproate: 'Epilim' : Indications: Primary generalised epilepsies. twice daily. Dosage: Tablets: Syrup: 100mg. Weight gain. Temporary hair loss. 400 to 2. prophyllaxis of febrile convulsions. (including absence seizures). mainly in children under the age of three years. Absence seizures. Occasionally hirsutism may warrant withdrawal. more rarely. partial seizures. Hepatotoxicity which can be fatal. incoordination and ataxia with. Hyperplasia of the gums may be a problem in children. teratogenicity. . Ethosuximide: 'Zarontin' : Indications. Gastro-intestinal side effects.

and agranulocytosis can occur.Dosage: Capsules Syrup 250mg 250 mg/5ml Range 500 to 1. Headaches.5 and 2 mg 2. status epilepticus. (c) DRUGS OF 2nd CHOICE Clonazepam: 'Rivotril' : Indications: Myoclonic and generalized tonic-clonic seizures. Side Effects: Gastro-intestinal symptoms. three to four times a day. dizziness and psychiatric manifestations have also been reported. drowsiness.5 mg/ml 1 mg/ml Starting dose: Maintenance range: Dosage Interval: 0. Dosage: Tablets Oral drops Ampoules 0. . leucopenia.5-1mg per day 2 to 8mg per day.500 mg daily.

occasional behavioural changes including aggression. Phenobarbitone Sodium or Gardenal Sodium: Indications: Effective in partial and generalised tonic-clonic. 30. Side effects: Similar to clonazepam. Clobazam: 'Frisium' : Indications: Adjunctive therapy in partial or generalised epilepsy and monotherapy in certain forms (Lennox-Gastaut and catamenial). clonic and tonic seizures. 60mg 200mg/ml .Side Effects: Drowsiness. Dosage: Tablets 10 mg Starting dose: Maintenance range: Dosage interval: 10mg at night. Drowsiness. Phenobarbitone (PSM). Dosage: Tablets Injections 15. 20-40mg daily once or twice a day. dizziness and dryness of mouth have been reported.

drowsiness. ataxia. Very occasionally blood disorders have been described.): Indications: Effective against partial and generalised tonic. Primidone: 'Mysoline' (I.clonic seizures. Nausea. hyperkinetic and aggressive with it.500mg per day. once or twice a day. Dosage: Tablets 250mg Starting dose: Maintenance range: Dosage interval: 125-250mg per day 250. Children may be irritable. once or twice daily.C.Starting dose: Usual maintenance dose: Dosage interval: 30-60mg/day 6-240mg daily.1. dizziness.I. . Side effects. vomiting. Side Effects: Sedative effect limits its value.

Tolerance develops quickly. Its intermittent use for seizures occurring before and during menstruation is often effective. and are funded only if prescribed by approved specialists. Dosage: Tablets Capsule 250 mg 500 mg (sustained action) Usual dose 250. The following are registered in New Zealand for “add on” therapy. (e) NEW ANTI-EPILEPTIC DRUGS In recent years new anti-epileptic drugs have become available. although it is likely that they will be used as monotherapy in the future.1.(d) ADJUVANTS Acetazolamide: 'Diamox' : Indications: Effective in both tonic-clonic and absence seizures. It should not be used in liver failure. rashes and paraesthesiae. . They are subject to restrictions because of their expense.000 mg daily. fever. Side effects: High doses may cause drowsiness.

Lamotrigine: ‘Lamictal’ :

Action: Inhibits release of glutamate.

Indications: Add on treatment in any seizure type, especially primary generalized seizures and Lennox-Gastaut syndrome.

Dosage:

Tablets 25 mg, 50 mg, 100 mg.

Starting dose: day. Maintenance range: With valproic acid:

50 mg once daily for 2 weeks, then 50 mg twice a

200-400 mg/day in divided doses. 100-200 mg/day.

With enzyme inducing drugs: 500 mg/day.

Side effects: Skin rashes occur in about 3%. Other side effects are dizziness, diplopia and ataxia, blurred vision and somnolence.

Vigabatrin: ‘Sabril’:

Action: A GABA aminotransferase inhibitor.

Indications: Partial seizures with or without secondary generalization as add on treatment. It is not effective for absences or myoclonic seizures.

Dosage:

Tablets 500 mg

Starting dose: Maintenance range:

2 g/day 2-4 g/day

Side effects: These include drowsiness, dizziness and weight gain, irritability, headache, depression, confusion and psychosis. Intramyelinic oedema has been described in rats and dogs.

Gabapentin: ‘Neurontin’:

Indications: Add on treatment for resistant partial and secondary generalized tonicclonic seizures. Not effective for absences and myclonic seizures.

Dosage:

Tablets 300 mg, 400 mg.

Starting dose: 300 mg once daily; increase by 300 mg per day to 300 mg three times daily. Upper range: 2400 mg daily.

Side effects: The commonest side effects are sleepiness and unsteadiness, usually occurring in the first 2-3 weeks of treatment and resolving in two weeks or less. Other side effects are fatigue, headache, feeling sick and vomiting. Serious side-effects rarely occur.

(f) TREATMENT OF STATUS EPILEPTICUS

This is a medical emergency. The following is a suitable protocol:

1 2 3 4

Secure the airway, measure blood pressure and give oxygen. Take blood for glucose, and electrolytes. Give thiamine 100mg intravenously, followed by dextrose 25-50g. Slow intravenous injection of Diazepam 10mg. Be prepared to ventilate the patient if necessary.

5

If ineffective, infuse phenytoin 15mg/kg (maximum 1g) no faster than 50mg/minute, monitoring the blood pressure and ECG.

6

If seizures continue, use phenobarbitone 10mg/kg in children or 90-120mg in adults by slow intravenous injection over 10 minutes. Repeat, if necessary after 10-15 minutes.

7 8

Alternatively, paraldehyde 10ml intramuscularly may be tried. If the above is unsuccessful, a general anaesthetic should be administered.

It is essential to recommence or start maintenance therapy as soon as possible. by nasogastric tube. if necessary. .

is 100-200 mg chlorpromazine (or its equivalent) 6 hrly. This may be accomplished by using adequate doses of antipsychotics. syrup forms are very useful. combined where necessary with sedatives. . If oral preparations are able to be used. Drugs during pregnancy. A suitable regime. Drugs during breastfeeding. (a) ACUTE PSYCHOTIC EXCITEMENT Occasionally. Attention deficit hyperactivity disorder. Drugs used in personality disturbance. Chlorpromazine has the added advantage of being quite sedative. a patient at home or in hospital is so severely disturbed or excited that emergency control is necessary. Withdrawal regimes.Chapter 5 SPECIAL DRUG REGIMES (a) (b) (c) (d) (e) (f) Acute psychotic excitement. for instance.

Suitable agents are Haloperidol 5-15 mg IV or IM.100 mg IM may be used but the injection is locally irritating. .2. Clonazepam 2 mg t. or if there is doubt about whether the patient will take the medication. or 200 mg orally is a potent sedative which may be useful. Diazepam 10-20 mgs orally is suitable (intramuscular diazepam should be avoided because of its poor distribution). close observation needs to be maintained. 1 .8% solution may be used IV 40-100 ml initially over 3-5 mins. has been thought by some to have a specific ‘antimanic’ effect. A place may still occasionally exist here for the use of barbiturates. and vital signs should be noted regularly. .s. but has the added advantage in this situation of being more sedative. 6 hrly. then 500.Injectable regimes may be necessary if more rapid action is required. and Thiothixine 4-8 mg IM. In a hospital setting chlormethiazole 0. In the management of a sedated patient. Added sedation with a benzodiazepine compound such as diazepam or lorazepam may be needed to achieve full control Skilled clinical judgment is often needed to weigh up the dangers to the patient of uncontrolled psychosis against confusing the clinical picture with sedation or benzodiazepine-induced disinhibition. and attention paid to fluid intake. Its action is similar to haloperidol. sodium amytal 250500 mg given slowly IV. Routine care of the unconscious patient should be given.d. Chlormethiazole may be used orally as 192 mg capsules. Chlorpromazine 50. and therefore may be particularly useful in acutely disturbed manic patients.000 ml over the next 6-12 hrs to maintain a light sleep. A further alternative is Droperidol 10-15 mg IV or IM.1.

advanced dependency features e. hypertension (30% contribution by alcohol).(b) WITHDRAWAL REGIMES It is emphasised that the treatment of withdrawal states is only the beginning of a prolonged psychiatric programme. spider naevi. peripheral neuropathy. There are two main types of withdrawal syndromes: . palmar erythema. alcohol on the breath. In all cases a detailed alcohol and drug history is a necessary precursor for management and this would include a physical examination for evidence of the stigmata of alcoholism such as enlarged liver.g. I Alcohol Withdrawal from alcohol is a potentially life threatening condition particularly in those who have a high prolonged daily consumption (greater than 15 units per day). malnutrition. regular morning drinking and a past history of complicated alcohol withdrawal. Wernicke-Korsakoff’s syndrome. G-I problems etc.

The hallmark of DT’s is an organic delirium with clouding of consciousness. 2 Major Withdrawal (Delirium Tremens or DT’s) This occurs 48 to 72 hours after cessation of alcohol and should be considered as a medical emergency and has a mortality said to be in the range of 5% to 10% of all patients even if treated. Hospitalisation is recommended.1 Minor Withdrawal This occurs within hours of cessation of drinking and has the following symptoms and signs: restlessness. Other symptoms and signs include severe agitation. tachycardia. In approximately 15% of patients withdrawing from prolonged. tremor. sweating. nausea. insomnia. anxiety. headache. hypotension. Generalized seizures and hallucinations may also occur as outlined above. hypomagnesaemia and . MANAGEMENT 1 General In both minor and major types of withdrawal attention must be paid to hydration and metabolic parameters (particularly hypoglycaemia. Hallucinations may also occur in approximately a quarter of all cases and they usually have a visual and tactile nature (occasionally auditory). high alcohol consumption generalised seizures occur most commonly within 48 hours after stopping drinking. fever and paranoid ideation.

— Parenterovite 1 amp or orally 50 mg twice a day. Chlormethiazole (Hemineurin) is still occasionally used in acute withdrawal states but there is special concern relating to respiratory depression and the rapid development of dependence — its use is generally not recommended. as a loading dose and reassess 2 hours later.V. Vitamin B1 (thiamine) administered in all cases to prevent encephalopathies and may be either given I. if vomiting.V.hypokalaemeia) as well as physical investigations looking for intercurrent illness (e. head injury). . Common benzodiazepines used include diazepam (Valium) 10 – 20 mg orally or slowly I. In general the dose of benzodiazepine should be titrated to the severity of the withdrawal symptoms/signs. Studies have shown that lower doses are required with flexible regimes compared to fixed dosage regimes./I.g. Doses of up to 60 to 80 mg a day may be used initially and gradually titrated down over 7 to 10 days.M. Well lit. quiet surroundings generally lessen the distress of the patient.g. 2 Benzodiazepines Benzodiazepines are useful medications to treat the symptoms of withdrawal especially since they have anxiolytic and anti-seizure properties. pneumonia) and other physical conditions associated with excess alcohol consumption (e. Chlordiazepoxide (Librium) can be used in up to 100 mg per day or oxazepam (Serepax) 120 mg per day — this benzodiazepine has a relatively short half life and no active metabolites.

ADJUNCTS TO TREATMENT Disulfiram (Antabuse) This drug interferes with the oxidation of alcohol leading to the accumulation of acetaldehyde which produces the aversive disulfiram-alcohol interaction — flushing. Phenytoin (Dilantin) in doses of 400 mg P.3 Complications Generalized seizures are treated if they arise or if there is a past history of seizure activity during withdrawal. It is contraindicated in those people who have significant hepatic renal and cardiac insufficiency and also in those with coexisting severe psychiatric conditions. The recommended dosage is now lower than used previously — starting off with 100 to 200 mg daily. It should be understood that the aversive effects of disulfiram persist for 4 . nausea. or I. stat with 100 mg 6 hourly for 5 days or sodium valproate (Epilim) 600 mg stat with 400 mg 8 hourly for 5 days. vomiting.V. Avoid in pregnancy. tachycardia and anxiety. Severe agitation and hallucinations may also be treated with low dose haloperidol 2 – 5 mg 6 hourly orally or intramuscularly. This reaction various in intensity and should only be used in patients who will adhere to the therapy and who have continued counselling support.O.

fluoxetine (Prozac) and paroxetine (Aropax) may decrease the appetitive drive or craving for alcohol once the patient has stopped drinking. impotence. Other medications currently not freely available in New Zealand are showing promise and these include naltrexone (an opioid antagonist) and acamprosate (acting on GABA). . Both of these drugs have been shown to reduce relapse rate in dependent alcoholics and to decrease craving. Other medications There is increasing evidence that the use of SSRI’s (selective serotonin re-uptake inhibitors) e.g. Rarely drug rashes. At these lower dosages side-effects are generally uncommon but may include drowsiness. hepatotoxcity and organic brain syndromes may occur. Calcium Carbimide (Dispan) This acts in a similar manner to Disulfiram but the reactions are generally milder and it has a shorter duration of effects of 12 to 24 hours. The usual dosage as used in depression is employed. The dosage regime is 50 mg twice daily.to 7 days from the last dose. In studies overseas these drugs have been shown to be particularly effective in those alcohol dependent people who also have depressive symptoms. neuropathy. fatigue and a metallic taste.

Benzodiazepine dependence is common and moderate to severe withdrawal symptoms are seen in approximately 40% of patients who have been on benzodiazepines for 6 months or more. There are also a number of side-effects which become apparent on long term use of benzodiazepines and this includes a sense of dysphoria or detachment. depersonalisation. flu-like illness. In general there are few if any indications for long term prescribing of benzodiazepines to new patients. Other withdrawal effects include alterations in perceptions (hypersensitivity to light. hypotonia. Precipitation of major psychiatric condition or generalized seizures are two of the more serious effects of withdrawal from benzodiazepines. If a benzodiazepine is to be prescribed it is recommended that it is short term only and for a maximum continuous supply of 2 to 4 weeks. disinhibition. muscular aches and pains.II Benzodiazepines This class of medications has recently been scheduled under the Controlled Drug Section of the Misuse of Drugs Act 1975. restlessness. This places restrictions for prescribing to those patients who are dependent (only by gazetted drug clinic doctors or those doctors authorised in writing by a drug clinic doctor or doctors who have been gazetted for the purpose of drug treatment) and may only be prescribed for one month per prescription. anxiety/panic attacks. menstrual and cognitive deficits. depression. headaches and anergia. . noise. rebound insomnia. taste and smell). sedation.

Particular care should be exercised with the elderly due to their slower elimination of the drug and increased neuro-sensitivity. Other strategies include switching over a short acting benzodiazepine to a long acting one (e. BAD. After enlisting the cooperation of the patient a gradual withdrawal regime may be implemented. depression etc). seizures or psychosis precipitated) or there are coexisting problems e. examination and investigations may reveal associated physical conditions e. Do not stop the benzodiazepine abruptly. A medical history. A rough rule of thumb — ‘the number of years on the benzodiazepine is the number of months it takes to withdraw’.g.g. Psychological therapies and general support are essential. . HIV/AIDS. In-patient withdrawal should be considered if major events occur (e.g.g. III Opioids Having taken a detailed alcohol and drug history it is important to assess the use of other drugs (especially benzodiazepines and alcohol) as well as co-existing disorders (e. otherwise 4 – 12 weeks gradual tapering of dose. endocarditis.g. hepatitis B & C. depression or previous outpatient withdrawal has failed. diazepam) and/or the use of antidepressants (particularly sedative tricyclics) or propranolol (80 – 160 mg/day may lessen the severity of withdrawal symptoms.

This process takes several days due to the long half-life of methadone and may require initial daily adjustments to dose. positive attitudes from trained staff. pregnancy and poor nutritional status. however has been established in the light of relative failure of abstinent regimes for long term drug users and is part of a ‘harm reduction model’ which has been shown to improve health. There are several components in MMT which promote effectiveness and these include adequate dose of methadone (50 – 150 mg/day). ataxia etc. abscesses. Stabilisation is said to occur if there is an absence of withdrawal symptoms and craving (‘hanging out’) and there is no evidence of over medication (‘stoned’). puncture wounds and observed (if possible) urine drug screens.). Evidence for drug use sought — intoxication (slurred speech. STD’s. diminish I.septicaemia. Methadone Maintenance Treatment (MMT). The methadone is initially consumed once a day at a designated pharmacy. . use and infectious conditions as well as overdose death. Treatment A drug-free (abstinent) lifestyle is the primary goal. Prescriptions of oral methadone (2mg/ml mixture) starts off usually at a dose of 10 – 30 mg (not higher than 40mg initially to prevent overdose) and reassessed after 4 hours with dose change as necessary. an adequate duration. engagement into counselling and services to deal with psychosocial dysfunction and coexisting disorders. pin-point pupils.V.

diarrhoea and a craving for the drug previously used. The most commonly used include: . Adjuncts in withdrawal There are a number of medications used to try and relieve some of the withdrawal symptoms. Inpatient detoxification may be required for severe withdrawals or complicated poly-drug abusers with medical complications and may be rapid (see below). constipation. An opioid withdrawal syndrome includes — restlessness. then oral methadone mixture 15 mg is given 2 hourly until the withdrawal signs/symptoms dissipate. agitation. sweating. muscle cramps. Dose reduction varies from 2 to 5 mg per week. lethargy. This total daily dose may then be reduced by 20% per day if a rapid detoxification is required. skin rashes. decreased libido. dental problems and of course dependence. irritability. If with an inpatient.Methadone does have a number of side effects which are generally alleviated with dosage reduction and includes — night sweats. Withdrawal Usually done as an outpatient with regular counselling/support. sleep disturbance. tremor. nightmares.

It is now available in two forms as a tablet (75 – 150 microgram QID) and as a transdermal patch – Catapres-TTS I (100microgm/day) and Catapres-TTS II (200microgm/day) applied weekly. an alpha-adrenergic agonist. Caution needs to be exercised with sedation and hypotension.V. This may also be combined with naloxone (an opioid antagonist. only active parenterally) to deter I.5 – 15mg at bedtime (maximum duration is 2 weeks). Hyoscine: ‘Buscopan’ 20mg QID for stomach cramps. helps relieve some of the sympathetic overactivity associated with opioid withdrawal.Clonidine. use and is available as Temgesic-nX . Quinine sulphate 300 mg QID for leg cramps. Buprenorphine: ‘Temgesic’ — gaining increasing use due to its relative safety in overdose and ease of withdrawal. Other medications LAAM: ‘lambda alpha acetylmethadol’ — a long acting synthetic opioid only taken every 2 days. Loperamide: ‘Imodium’ 2mg QID for diarrhoea. Zopiclone: ‘Imovane’ 7.

Pregnancy and lactation Recent research has reliably shown a better outcome for both foetus and mother if longterm opioid using women are stabilised on methadone at as low a dose as comfortably possible. The use of addictive drugs should be avoided if there is the likelihood of abuse or dependency. . (c) DRUGS USED IN PERSONALITY DISTURBANCES The use of medications to control personality and behavioural disturbance should never be entered into lightly. symptomatic control of acute anxiety or impulsiveness is necessary. Other psychiatric disorders such as depression. Methadone is not contra-indicated during breastfeeding.Naltrexone — an oral analogue of naloxone used as an aid to an opioid. On some occasions.free life which has been used for rapid detoxification (not freely available in New Zealand). anxiety disorders and transient psychotic episodes may arise in association with personality disorder and should be treated accordingly. and the use of a major tranquilliser in a low to moderate dose over a short period of time may be appropriate. Priority access to MMT is essential to engage in counselling and specialist obstetric/paediatric care.

or IM 300mg every 10 to 14 days (d) ATTENTION DEFICIT HYPERACTIVITY DISORDER: The most commonly diagnosed behavioural syndrome in childhood estimated to affect between 3 and 5 percent of school age children. has been shown to significantly reduce the core symptoms of ADHD and improve attention. There are side effects to the medication and . Little data exists about effectiveness in adults. Treatment is much more than the prescription of psychostimulants. medication and in particular. and there is little data about long-term outcome.Cyproterone acetate or ‘Androcur’: Indications: An anti-androgen for the treatment of severe hypersexuality and sexual deviation in males. It cannot be said strongly enough that aetiology is unclear and this disorder requires very careful expert multidisciplinary assessment and diagnosis. Nevertheless. methylphenidate. 100mg/ml depot injection Usual dose: 50mg twice daily. Dosage: 50mg tablets. Trials to date are predominantly short term.

growth rate impairment. Methylphenidate or Ritalin: Dosage: Usual dose: 10 mg tablets. especially during the first trimester. anticonvulsants and antidepressants. nausea. irritability. psychotropic drugs are best avoided during pregnancy. . Do not use in children under 6 years of age. There are potential interactions with several drugs including anticoagulants.potential dangers to the patient and society in over prescription. 20 mg CR tablets Start with 5 mg once or twice daily. dysphoria and increases in tic disorders. They should only be used when the indications are clear and commanding and benefits outweigh the possible risks. sleep disturbances. Side effects include decreased appetite. as safety has not been established. Psychostimulants have clear abuse potential. Maximum dose: 60 mg daily (e) DRUGS DURING PREGNANCY: As with most drugs. and increase by 5-10 mg weekly until effect observed.

Its use has been associated with congenital anomalies. There should be frequent measurement of serum levels and the dose titrated to the lowest possible clinically effective dose. Renal clearance of lithium rises during pregnancy. The use of lithium in the first trimester has been associated with defects particularly of the cardiovascular system. and symptoms of toxicity or withdrawal in the foetus or neonate.Risks include teratogenicity. and then rapidly declines to normal levels in the weeks after delivery. and some of the existing information is unclear. Lithium should be given in divided doses to avoid high peak serum levels. At delivery consideration should be given to reducing the dose by up to 50% to avoid foetal toxicity. Lithium toxicity in the neonate has often been reported when lithium is used near term. In some there is insufficient information to declare that they are safe. embryotoxicity. Disulfiram (Antabuse) is definitely contraindicated in pregnancy. These toxic effects usually return to normal over a period of weeks. . Information on the newer drugs especially is still being collected. including nephrogenic diabetes insipidus and thyroid depression with goitre. These risks should be carefully assessed not only in treating pregnant women. but also with all patients who may become pregnant. Lithium during pregnancy should be withheld until at least the 10th week if this is possible. prematurity. The exact risks are difficult to quantify.

and reports of malformations do exist.Anticonvulsants unfortunately do not provide a safe alternative. In general. Toxic effects sometimes from the anticholinergic action. and therefore their use in pregnancy cannot be recommended. Both carbamazepine and sodium valproate have been shown to have teratogenic potential. High potency agents in low doses are recommended by some. Again. first trimester use should be avoided where possible and folate supplementation should be used before and during pregnancy. Vitamin K1 has been recommended during the last weeks of pregnancy and for the neonate to avoid bleeding disorders. although again little data exists for the newer agents including Fluoxetine. Little information exists on the newer agents. the risk of foetal malformations needs to be weighed against the risk to the mother and foetus if seizures are not controlled. Minor tranquillisers such as Diazepam are suspect as studies have shown both an association with congenital anomalies and toxic effects in the newborn. The serum level should be closely monitored. and withdrawal effects in the newborn have been reported. It would appear that major tranquillisers are relatively safe. though there does not seem to be a strong association in larger studies. When anticonvulsants are being used for epilepsy. although low potency phenothiazines have been associated with an increase in malformations. The tricyclics have been the most studied. It has been suggested that Lorazepam and Clonazepam do not accumulate to the same degree in the . the antidepressants appear reasonably safe. and therefore they cannot be recommended.

. Some general guidelines are to use low dose monotherapy. Both. Hepatotoxicity has been reported in young children treated with valproate.foetus as Diazepam and may be safer during pregnancy. to use short acting drugs and time doses to give medicines after feeding. Carbamazepine and sodium valproate are probably more compatible with breast-feeding. Other anticonvulsants are probably safe although methaemoglobinaemia has been reported in the baby with phenytoin. (f) DRUGS DURING BREAST-FEEDING: Literature on the safety of psychotropic drugs during breast-feeding remains limited. including the drug. Lithium levels in the infant may rise to 50% of the maternal concentration and therefore because of the risk of toxicity in the baby. however. A decision to use medications and continue breast-feeding requires the parents’ informed consent and assessment of the multiple factors involved. therefore it must be used in breast-feeding mothers with caution. Always continuously evaluate the neonate for side effects. pass into breast milk and carbamazepine has been associated with liver function abnormalities. In general avoid if at all possible. and to evaluate the risk factors of the specific drug. mothers on lithium should only breast-feed with great caution and with frequent monitoring of the blood levels. the age of the infant and risk of non-treatment.

Withdrawal symptoms may occur in the baby when breast-feeding is stopped. it should not be used in nursing mothers. . Shorter half-life benzodiazepines are preferred. The use of tricyclic antidepressants seems safe. as the infant has a slow metabolism of these drugs and accumulation may occur. Moclobemide has minimal concentration in breast milk and may be a useful alternative. A recent suggestion is that paroxetine may be safer than fluoxetine in lactating mothers as it passes less into breast milk. and it is recommended that lactating women take less than 10mg per day. given the degree of passage of clozapine into breast milk and the potentially fatal agranulocytosis that could result. There is little data on the atypical antipsychotics to date. However. SSRI’s are also probably safe though data is still accumulating. Drowsiness has been found in infants whose mothers are taking chlorpromazine. weight loss and EEG changes have been reported in infants whose mothers were taking large doses. therefore weaning should be gradual. apart from doxepin where adverse reactions in the baby have been reported. Haloperidol appears relatively safe.Antipsychotic drugs are in general probably safe. lethargy. With diazepam.

Beasley. it has been decided to include amphetamines. Clear the oropharynx. (a) FIRST AID Assessment. narcotic analgesics and L.Chapter 6 TREATMENT OF OVERDOSES OF PSYCHOTROPIC DRUGS Although this section deals with the management of over-doses of the commonly used psychotropic drugs. Note: The National Poisons Information Centre Phone: Fax: Dunedin Dunedin (03) 474-7000 (03) 477-0509 is available for enquiries at any time of the day or night. bring the tongue forward. of airway.D. The degree of impaired consciousness and/or absent gag reflex are guides to the need for . National Toxicology Group . M. breathing and circulation is always the first priority. We wish to thank Dr.S. Research Fellow. they are subject to abuse and therefore likely to be seen in either the general or the psychiatric hospital. and assess respiration. with support where necessary.University of Otago Medical School for helping update this chapter. Despite the fact that these drugs are rarely used in psychiatric practice.

These agents include phenobarbitone. Syrup of ipecac is falling out of favour even in children and certainly should not be given for overdoses of CNS depressants or convulsants. The standard dose is 50-100 grams (adults) and 1gm/kg (children). nonpharmacological treatments (elevation of lower extremities. give amounts at the upper range. In cases of marked respiratory depression where the full range of ingested agents is uncertain. Charcoal can be taken orally. airway protection is required prior to lavage. For large ingestions of highly toxic agents. IV fluid replacement) is often worth trying first. give naloxone IV (0. carbamazepine and meprobamate. with a few exceptions (such as SR dosage forms). It has also been shown to enhance the elimination of some medicines already absorbed into the body. gastric lavage is now recommended only for patients presenting within one hour of ingestion and in a heavily drowsy or comatose state. Charcoal is currently available as Carbisorb (a pre-mixed aqueous suspension).intubation and/or assisted ventilation.4 .1 mg/kg in children) and also consider IV glucose.2 mg in adults and 0. Whole bowel irrigation is being used increasingly for toxic amounts of . whichever is the larger. containing 50 gm per 100 ml. In the latter case. or alternatively at ten times the estimated dose of drug ingested. For hypotension. However. Repeat dose charcoal is useful for slow-release formulations. (b) DECONTAMINATION Activated charcoal is the mainstay of treatment. or given via nasogastric tube or orogastric tube postlavage.

.agents not well adsorbed to charcoal. and as an adjunct to repeat dose charcoal for certain SR products.

30 mg/kg) with potentially fatal adult doses being around 6gm or more for phenobarbitone but less for shorter-acting barbiturates. Treatment Activated charcoal for significant ingestions. headache. Mild to moderate intoxication can include lethargy. Induction of an alkaline diuresis with intravenous bicarbonate is another option. Respiratory depression occurs relatively early in coma. Both vasodilatation and depression of myocardial contractility can occur. but this is contraindicated in patients with markedly impaired renal output and/or requiring . Cardiac arrhythmias are uncommon. and impaired circulation. it remains a hazard.SPECIFIC TREATMENTS 1 HYPNOSEDATIVES AND ANXIOLYTICS (a) Barbiturates. While cardio-respiratory arrest is less frequent than with shorter acting barbiturates. vertigo. Precede with gastric lavage if seen within one hour of ingestion. pneumonia. Repeat dose charcoal can enhance clearance of phenobarbitone. hypoglycaemia and hypothermia. nystagmus. Significant toxicity may occur at 5 times the therapeutic hypnotic dose and severe effects at 10 times (ie 20 . ataxia. Toxic reactions generally begin at 1-2 hours and peak at 6-12 hours. confusion. The primary danger is depression of central control of respiration. slurred speech. Complications include cardiac failure.

Bronchial toilet bronchoscopy and possible tracheostomy may be necessary. temazepam.ingestion. Coma with serious respiratory depression can occur with triazolam. with fatalities being reported. Give oxygen and artificial ventilation (intermittent positive pressure) if indicated. diplopia and ataxia. confusion. b) Benzodiazepines Signs and Symptoms While the adverse effects from pure benzodiazepine overdose by ingestion are usually relatively mild. Estimate the serum barbiturate level if possible (as this helps in deciding the intensity of therapy). and midazolam. Recovery may be delayed for benzodiazepines with active metabolites. Haemodialysis is worthwhile in severe cases. and withdrawal symptoms may occur. dysarthria. with CNS symptoms often limited to sedation. Treatment Decontamination for amounts ten times the single therapeutic dose is certainly indicated for the short acting class. and is a useful precaution for all agents. Activated charcoal should be .vasopressor or inotropic support of the circulation. there are exceptions particularly with the short-acting agents. Activated charcoal preceded by gastric lavage for large ingestions seen early. Severe cardiorespiratory symptoms often suggest coingested agents. With all classes there is greater risk with the very young and elderly and with alcohol co. where respiratory depression is more likely.

Treatment Charcoal for large ingestions. Monitor respiration and level of consciousness. Further treatment symptomatic.470mg without serious toxicity. anti-convulsants) are drawbacks Many choose not to use it in the overdose situation and rely on supportive treatment. Flumazenil is helpful both diagnostically and therapeutically. and early trials involved mean daily doses of up to 1. (tri-cyclics. In one reported case 250mg produced no symptoms in an adult.given. but its brief action. (d) Chloral hydrate . cost and potential risk with certain co-ingested agents. chloralhydrate. Assisted ventilation may be necessary. (c) Buspirone Signs and Symptoms Few consistent symptoms in overdose.

Pupils are initially miotic and later dilated. give oxygen and place on cardiac monitor. . CNS. (e) Meprobamate Signs and Symptoms Adult fatalities have occurred with around 12gms. ataxia. Nystagmus. repeat dose if necessary. Monitor for respiratory. as may respiratory depression. gastric lavage with airways protection. coma or respiratory depression. Treat ventricular arrhythmias with lignocaine or B-blockers. Follow with charcoal. Lavage may be useful for up to 12hrs. In severe cases there may be hypotension.Signs and Symptoms Toxicity may occur at 30mg/kg and above. lethargy and coma within 1-2hrs. For hypotension give IV fluids and alpha-agonists if necessary. Treatment Decontamination measures if possible within 4hrs for ingestion. Treatment Monitoring of respiratory and cardiovascular status is essential. hallucinations and convulsions may occur. Establish an IV line. In overdose there is the rapid onset of ataxia. If presenting within one hour. Give activated charcoal. Ventricular arrhythmias may develop. circulatory and acid-base status.

blurred vision. The piperidine group (eg thioridazine) appears more cardiotoxic and most fatal outcomes are attributable to this class. some agents from each class have been strongly suspected as rare causes of cardiac deaths even at therapeutic doses. urinary retention (cholinergic-muscarinic). These include postural hypotension and reflex tachycardia (alpha-adrenergic). However. Treatment involves decontamination for moderate to large doses and symptomatic support. 2 ANTIPSYCHOTIC AGENTS a) PHENOTHIAZINES The aliphatic subclass (eg chlorpromazine) are considered the least toxic in overdose. The piperazine class (eg trifluoperazine) contains the most potent agents and extrapyramidal effects are more marked with this group although circulatory effects including hypotension are less common. Extrapyramidal reactions are common and are partly due to dopamine (D2) receptor blockade which is also largely responsible for the therapeutic effect.(f) Zopiclone: ‘Imovane’ Drowsiness. and sedation (H1-histamine). lethargy and ataxia may occur but no serious effects have been reported in the few overdose cases so far. First degree heart block has been reported in one case. Acute dystonic . Signs and Symptoms Many of the effects can be explained by various receptor blockade mechanisms operating.

benztropine (2mg IM or IV) in adults and diphenhydramine (2mg/kg IV over several minutes) in children Malignant neuroleptic syndrome .for acute dystonic reactions. QT. including a repeat dose is useful. generally signalled by ECG abnormalities such as prolongation of PR. Lignocaine and phenytoin are the agents of choice for ventricular arrhythmias. Occasionally more direct cardiotoxicity occurs. Conduction delays are most marked with piperidines. glucose and CPK. Treatment a) General: Decontamination measures are indicated with ingestions over about 10mg/kg Chlorpromazine equivalents or where the dose is uncertain and/or there are significant symptoms.Usually responds to IV fluids and limb elevation.Monitor and maintain acid-base and electrolyte balance. b) Specific: Hypotension . hyperthermia and risk of rhabdomyolysis. There may be CNS depression with stupor or coma or convulsions. electrolytes. .reactions may be seen in about 10% of ingestions. intervals and the QRS complex. Charcoal. Arrhythmias .dantrolene IV. Decontamination may be effective for several hours postingestion due to anti-cholinergic properties. Monitor acid-base balance. Alphaadrenergic agonists are the theoretical vasopressor agents of choice. Extrapyramidal reactions . Rarely there may be a malignant-neuroleptic syndrome with severe extrapyramidal reactions.

DIPHENYLBUTYLPIPERIDINES (Pimozide) There are few published cases of overdose. 80mg) suggest that the predictable effects of drowsiness and extra-pyramidal reactions can occur but may not be severe at these dosages. Lowered seizure threshold. However 2 notified NZ cases (40mg. coma. Cardiac arrhythmias are not common features. spasm or weakness. rhabdomyolysis with renal failure. but ECG abnormalities are less common. with sedation or coma in severe cases. hyperthermia. Treatment is similar to that of the phenothiazines. Significant symptoms in adults have occurred with ingestions ranging between 800-2200mg. Muscle tremor. Hypotension occurs. .b) OTHER ANTIPSYCHOTIC AGENTS BUTYROPHENONES (Haloperidol. DIBENZOXAZEPINES (Loxapine) Convulsions are a risk (it is structurally related to amoxapine which is well known to cause seizures). These include drowsiness. Droperidol) Similar effects to the phenothiazines. hypotension.

antihistaminic and anti-serotoninergic properties. Cardiac monitoring. responding to lignocaine. There is a risk of agranulocytosis with regular dosing. Monitor level of consciousness. has been described. One ingestion of 250mg was reported to be fatal. Orthostatic and/or diastolic hypotension. risperidone) Clozapine interacts with a subgroup of central dopaminergic receptors and in addition possesses potent sympatholytic. Treatment Decontamination is indicated for all but very low ingestions. tetrabenazine. especially if . Convulsions are well-recognised and pulmonary aspiration was a not infrequent complication in one series review. circulatory status and observe for evidence of aspiration pneumonia. Extrapyramidal reactions are less common than with older. Extrapyramidal effects. OTHER (clozapine. or at least ECG. classical neuroleptics. anticholinergic. Ventricular tachycardia.THIOXANTHENES (Thiothixine. even life-threatening toxicity. respiration. flupenthixol) Mild CNS depression is the most common presentation. for at least 24 hours. One review suggested that an overdose of 400mg in a previously untreated patient or a dose increment of 300mg or more in treated patients can cause serious.

Cardiovascular effects include sinus tachycardia and more seriously. agitation or drowsiness. SV.tachycardia unexplained by hypotension. Hypotension. mydriasis. sinus tachycardia. nodal and ventricular tachycardia. Dopamine or noradrenalin are the preferred pressor/inotropic agents. and various arrhythmias including idioventricular rhythm. widened QRS complex. Myoclonic twitching and muscle rigidity may occur. The clinical features are manifestations of a variety of toxic effects on the cardiovascular and nervous systems (CNS and autonomic) plus the respiratory system (often but not always secondary). 3 TRICYCLIC ANTIDEPRESSANTS As there is a possibility of cardiac arrhythmias. is a risk along with hypokalemia. aggravated by arrhythmia or metabolic acidosis. They include anticholinergic effects such as dry mouth. impaired intracardiac conduction with ECG signs such as prolonged PR and QT intervals. blurred vision. including ventricular fibrillation. treatment is a matter of urgency. and observation of urinary output. It has been suggested that all comatose patients should be intubated and a chest radiograph taken on admission and again 24 hours later. Coma or convulsions in severe cases. Signs and Symptoms Usually appear within 4hrs of overdose. . and ventricular fibrillation.

Assess cardiac rhythm. Place on an IV line and cardiac monitor. Phenytoin or lignocaine may be effective in resistant cases. It is a mainstay of treatment. Activated charcoal is indicated for ingestions of 5-7 mg/ kg or more. and serum electrolytes and acid-base balance. .Treatment Serious toxicity may occur with doses over 10mg/kg. Precede with gastric lavage. ECG. This may be useful even up to 4hrs or more after ingestion of these drugs. eg: ICU. but consider dopamine or dobutamine in refractory cases with CVP monitoring. physostigmine should be used only with extreme caution and symptomatic management with ventilatory support where indicated is preferred. For coma. circulation including BP. Intravenous sodium bicarbonate is often useful providing a benefit over and above that associated with correction of acidosis. at least in obtunded patients if seen within one hour of ingestion. Hypotension may respond to IV fluids (eg: colloid) and leg elevation. Arrythmias may reverse with improvement of circulatory. acid-base and electrolyte status. admit to an appropriate facility. Give diazepam or phenytoin for convulsions. With ingestions over 10mg/kg or where the patient is symptomatic.

Various coingested agents can increase toxicity considerably. headache. Hyperpyrexia. convulsions may occur. pulmonary oedema and asystole. Follow with activated charcoal. In more serious cases there is CNS depression (replacing earlier agitation) and cardiovascular collapse with profound hypotension.Symptoms of Poisoning Ingestions over 2mg/kg are considered potentially very serious (excluding Moclobemide. coma. The onset of symptoms is typically delayed 6 -12hrs. with maximum effects later. (nor)adrenalin and dopamine both in the brain and storage sites of the autonomic nervous system. However other toxic mechanisms may also be involved. In mild cases. Give oxygen. severe muscle rigidity. flushing. . Symptoms depend in part on dietary habits and concurrent medication (including previous MAOIs). including some tricyclic antidepressants (those with inhibitory effects on serotonin re-uptake) and the SSRI’s. rhabdomyolysis. place an IV line and monitor cardiovascular and respiratory function. sweating. see page ).4 MONO-AMINE OXIDASE INHIBITORS Inhibition of the MAO enzymes (A and/or B) results in elevated levels of serotonin. General sympathetic and neuromuscular excitability. Signs and . Treatment With excessive or symptomatic ingestions. Gastric lavage should be undertaken if within 1hr of ingestion. palpitations. tremor and dilated pupils may be present.

confusion or agitation. Treatment Decontamination with charcoal for moderate to high ingestions. With severe effects. Either hypo. Monitor for hyperthermia and hypertonia. unresponsive to IV fluids. Hypotension occasionally. Avoid . consider possibility of coingested drugs. noradrenaline is recommended although ideally with haemodynamic monitoring. The major concern relates to potential interactions.For severe hypertension. plus agitation. In one series depressed levels of consciousness and slight increases in blood pressure were seen at doses of 3000-4000mg. even with somewhat higher amounts. If hypotension develops.or hyperthermia. Physical cooling methods and paracetamol may be useful. Drowsiness. sinus tachycardia and mydriasis at higher doses. IV phentolamine (20mg stat +. and observe for at least 24hrs. around 7000-8000mg. Serious effects have been described with co-ingested sertraline. There is little risk of life-threatening cardiotoxicity or respiratory depression. including with antidepressants that inhibit serotonin reuptake. Further treatment symptomatic.repeat in 10mins) or sodium nitroprusside may be the agents of choice. 5 REVERSIBLE MAOI's (moclobemide) Signs and symptoms Nausea and vomiting.

. This can also be a risk with coingested SSRI’s. There may be long-term neurological damage in overdose. intubation and neuromuscular blockade may be necessary. Physostigmine may be contraindicated. but if these persist. Metabolic acidosis may occur as may respiratory depression and coma. 6 OTHER ANTIDEPRESSANTS a) Amoxapine . There may be renal failure which in some cases is related to rhabdomyolysis possibly secondary to convulsions. Precede with gastric lavage if patient seen within one hour of ingestion and is in an obtunded state.concomitant use of clomipramine and other tricyclics which inhibit serotonin reuptake.Toxicity L. fluid and electrolyte balance. possibly secondary to convulsions. phenytoin or chlormethiazole may be effective for convulsions. Treatment Activated charcoal for ingestions over 10mg/kg. 100 is 30mg/kg Signs and Symptoms There is a higher incidence of convulsions and this effect has been described with therapeutic usage also. Monitor and correct acidbase. as mixed overdoses can cause the potentially fatal serotonin syndrome. Monitor CPK and urine for myoglobin if there are recurrent seizures. Diazepam.D.

CNS status and acid-base balance. Further treatment is symptomatic.10mg/kg.) Sinus tachycardia or bradycardia may occur. sinus.b) Maprotiline Signs and Symptoms Miosis. For convulsions. Treatment Activated charcoal with moderate ingestions. dry mouth. diazepam may be effective. In severe cases. Treatment Activated charcoal with ingestions over 5. Monitor circulatory. (There are few reports of more serious effects. hypotension. tachycardia. arrythmia and cardiac arrest. respiratory. Coma may persist for 24hrs. physostigmine is contraindicated. c) Mianserin Signs and Symptoms Drowsiness and hypotension. PR and QRS prolongation and bradycardia. the latter more frequent than with tricyclics. Neutropenia or agranulocytosis is described with therapeutic use. . Coma and convulsions may occur. otherwise phenytoin.

It is readily . tremor. Serum levels of TCA’s and lithium can be increased. tremor. including sertraline in a child. with equilibrium taking several days or weeks. Therefore serum levels do not correlate very well with the severity of effects in acute. tachycardia. Monitor cardiovascular parameters and CNS functioning. as opposed to chronic poisoning. For the rare serious presentation. 7 LITHIUM CARBONATE Lithium is not plasma protein bound but distributes quite slowly into cells. hallucinations and coma. Further treatment symptomatic. Treatment Activated charcoal. In the latter situation adverse effects are common at the top of the therapeutic range. flushing. Drowsiness. Symptoms included prolonged hypertension.d) SSRI's (paroxetine. or may be absent. nausea or vomiting have been noted. fluoxetine. Serotonin syndrome can occur with coingestion of MAOI’s. eg cyproheptadine in the context of mixed ingestions with MAOI’s. hyperthermia. serotonin (5-HT) antagonists have been suggested. However a similar presentation has rarely been described with suspected pure SSRI ingestions. citalopram) Symptoms are generally minor and of short duration. Various coingested agents can increase the toxic risks considerably. The few fatalities reported mainly relate to mixed overdoses.

coarse tremor of the hands. dehydration or cardiac failure which decrease glomecular filtration rate and/or increase proximal tubular reabsorption of sodium and water will promote lithium retention. However. The various CNS effects can be delayed unless ingestions are acute-on-chronic. and/or whole bowel irrigation. while renal effects are less significant than with chronic toxicity. decontamination options include gastric lavage if seen early enough. giving the appearance of cerebral haemorrhage. especially if slow-release formulations are . Hence a vicious circle can develop where the increased reabsorption of lithium consequent on dehydration can exacerbate this condition. vomiting and diarrhoea are more common with acute poisoning. Earliest manifestations include lethargy. Thus conditions such as sodium deficiency. convulsions and delirium. lithium itself can contribute to salt and water loss by impairing renal concentrating ability with resultant polyuria. and is affected by similar factors. Mechanisms are thought to include interference of ion channels involved in neurotransmission.filtered at the glomerulus and the (largely proximal) tubular reabsorption parallels that of sodium. followed by dysarthria and ataxia. and polyuria with polydipsia. With larger doses the above symptoms become worse and are followed by impairment of consciousness leading to coma. Early Signs and Symptoms of Toxicity Nausea. The neurologic signs may be asymmetric. It is one cause of nephrogenic diabetes insipidus with fluid depletion and hyponatremia. Treatment With one-off acute ingestions.

involved. Gastric lavage may be useful up to 12hours with SR products.(Toxic one-off doses are said to be 40mg/kg or more but even just therapeutic amounts in chronic patients). Charcoal is only indicated for any co-ingested agents. With acute-on-chronic cases, stop the lithium and take the serum level. It has been suggested that all symptomatic chronic patients with levels over 1.5 - 2.0 mmol/l should be admitted. IV fluid replacement with normal saline. Screening ECG and continue to monitor ir abnormal. If the serum level is less than 4 meq/ I and the patient's condition reasonable and the serum level falling adequately, (ie: halving every 24 hours), then conservative measures are generally adequate. Check the lithium level 6 hourly to see it is falling adequately. Haemodialysis is the definitive treatment. It may be necessary at comparatively low serum levels in chronic poisoning depending on the clinical circumstances but in the acute case the indications are a level of higher than 4 meq/l and/or deteriorating clinical condition especially coma, convulsions or refractory hypotension. If not in circulatory failure and glomerular filtration is below normal the excretion rate of lithium may be increased by osmotic diuresis (urea or mannitol infusion) and alkalinisation by sodium lactate or bicarbonate. Diuretics are not advised. Half normal or other hypotonic solutions are recommended rather than normal saline to restore sodium and water balance. Signs of intoxication may last several weeks, even after there is no longer detectable lithium in the blood. Some neurologic impairment may be permanent.

8

AMPHETAMINES

Eg: Methedrine, 'Dexedrine', 'Durophet', 'Drinamyl' (dexamphetamine with amylobarbitone), numerous slang terms, eg: 'goof balls', 'purple hearts', 'speed', etc. Amphetamine (phenylisopropylamine) and its analogues stimulate adrenergic receptors both directly and indirectly (by causing release of noradrenalin), and inhibit both the degradation of catecholamines (through MAO inhibition) and their reuptake. The result is marked alpha- and beta- adrenergic stimulation as well as CNS stimulation.

Signs and Symptoms of Poisoning Initial intense stimulant effect, usually commencing within 30-60 minutes. Confusion, anxiety, delirium, hallucinations, profuse sweating, tachycardia. Severe effects include either increasing hypertension or arrhythmias with hypotension, marked hyperpyrexia, rhabdomyolysis, convulsions, coma, and circulatory collapse. With chronic abuse, psychosis with aggression can occur. Withdrawal symptoms are not usually severe. The toxic and lethal doses vary considerably both between specific drugs and individuals, with the degree of habituation an important factor. Death has been reported with as little as 1.5mg/kg of metamphetamine.

Treatment Activated charcoal, certainly with ingestions over 1mg/kg in non-tolerant patients. Habitual users can tolerate 5-8 gms amphetamine daily at least. Convulsions can be treated with diazepam, phenytoin or in extreme cases, phenobarbitol. Labetalol or nitroprusside and lignocaine have their advocates for hypertension/tachycardia and ventricular arrhythmias respectively. Dantrolene for severe muscular hyperactivity.

The amphetamines and fenfluramine are some of the few medications for which acid diuresis can enhance renal elimination. This regime involves use of either ascorbic acid (0.5- I .5 gm) or ammonium chloride 4 gm, every 4-6 hours orally, or a 1-2% solution IV; adjusting dose to maintain urinary pH at 5.5-6.5: monitoring also the serum K. Mannitol and frusemide may be used along with large volumes of fluids, until urine flow is 3-6 ml/kg/hr. The patient needs to be observed for pulmonary oedema and hypertension as well as renal function and thus the procedure is a specialist one. Amphetamine induced psychosis is most rationally treated with specific dopamine antagonists, such as the phenothiazines or butyrophenones. However chlorpromazine may result in a delayed but severe fall in blood pressure and haloperidol is preferred.

9

OPIOIDS

Opium, papaveretum, (Omnopon), morphine, heroin, codeine, methadone (Physeptone), amidone, pethidine (meperidine, Demerol) etc.

Signs and Symptoms of Poisoning The classic triad is miosis, coma and respiratory depression. However pinpoint pupils are not invariable; eg with lomotil (concomitant atropine) or superimposed hypoxia. CNS depression ranging from drowsiness to deep coma, with risk of aspiration. Bradypnoea or apnoea in severe cases. The blood pressure is initially well maintained, later anoxia

flushing. Bag-mask ventilation until naloxone has been given can often obviate the need for intubation in mild to moderate cases. Repeat if necessary at 2-3 min intervals in the event of return of respiratory depression or coma. salivation. fever and hypertension. arrhythmias and convulsions may require additional specific pharmacological treatment. Part of the action involves binding to 5HT receptors and inhibition of serotonergic neurotransmission.4mg ( I ampoule) stat is a reasonable start. Agitation. convulsions. 10 LYSERGIC ACID DIETHYLAMIDE (LSD) LSD is an indoleamine structurally related to serotonin. Minimally effective dose is about 25ug with hallucinogenesis over 100ug. Hypotension. For respiratory and CVS depression and coma give Naloxone IV. Also nausea. Assess and maintain airway. Oxygen and assisted ventilation may be necessary. Symptoms and Findings Sympathomimetic effects are seen first. . Maximum dose about 10mg.2mg/kg but in adults 0. pilo-erection. Doses may range from 0.01mg/kg -0. . including mydriasis. vomiting. Hypothermia and pulmonary oedema are risks.may cause hypotension. hyperreflexia. Activated charcoal (preceded by gastric lavage in obtunded patients seen early) when the patient is stabilised. or arrhythmias are more likely with meperidine or propoxyphene. tremor.

early presentations should receive activated charcoal. Fatalities can occur secondary to effects on behaviour. but hallucinogen intoxication may be aggravated. Observation and reassurance in a quiet setting. eg. plus visual illusions with changed perceptions of colours. and there may be profound hypotension. Haloperidol has been suggested in non-responders.weakness and ataxia. In severe toxicity. Acute panic reactions and impaired judgement. monitor for hypotension. Peak effects typically at around 4 hours persisting for 12 hours or so. convulsions. increasing the risk of trauma. Some of the most effective antagonists to both the psychic and autonomic effects of LSD are the phenothiazines. Hallucinogenic effects are bizarre and highly variable. muscle injury or associated trauma. along with coma. respiratory depression and hypotension in massive overdose. usually developing within 30-90 minutes. . Convulsions have occurred rarely. Cooling measures for fever. Diazepam may therefore be the treatment of choice. hyperthermia. Complete loss of reality contact (derealisation) and loss of body image. shapes and distances. Treatment Although the typical doses ingested are well under the estimated toxicologically lethal dose.