PA Psychopharmacology Notes

Paper A
Psychopharmacology
I. Historical overview of Psychotropic drugs ............................................................................ 2

II. Classification ..................................................................................................................................... 2
III. Concordance & Placebo response .............................................................................................. 5
IV. Rational prescribing: ................................................................................................................. 8
V. Pharmacokinetics & Pharmacodynamics ............................................................................ 11
VI. Antidepressants ....................................................................................................................... 19
VII. Antipsychotics. ......................................................................................................................... 28
VIII. Antimanic and Prophylactic drugs .................................................................................... 35
IX. Hypnotics & sedatives ................................................................................................................ 39
X. Drugs used in substance misuse disorders. ........................................................................ 41
XI. Antidementia drugs ..................................................................................................................... 45
XII. Miscellaneous topics .............................................................................................................. 47
XIII. Pharmacogenetics ................................................................................................................... 49
XIV. Summary of Pharmacological Intervention Guidance ................................................ 50
Paper A: Psychopharmacology
I. Historical overview of Psychotropic drugs

The discovery of psychotropic medications has improved well being of many people
afflicted with mental health problems, and has helped in the understanding of
neurochemical basis of psychiatric disorders. The benefits of psychotropic medications
has not been as overreaching as expected when they were discovered initially due to
the complex aetiologies involved in the development of psychiatric disorders. The 50s
is considered a golden age in psychopharmacology due to the discovery (? accidental
mostly) of psychotropic properties of many drugs used even today. The 80s and 90s
has seen emergence of drugs based on receptor profiles (SSRIs, newer antidepressants
like venlafaxine, Mirtazapine and newer antipsychotics). Some important names
involved in the discovery of the psychotropic drugs are below:
Name Year Drug
1. Ugo Cerletti & Lucio Bini 1938 ECT
2. John Cade 1949 Lithium

3. Paul Charpentier 1950 Chlorpromazine
(synthesis)
4. Delay & Deniker 1954 Chlorpromazine
(Psychosis treatment)
5. Nathan Kline 1954 Reserpine
6. Nathan Kline 1957 Monoamine inhibitors
7. Roland Kuhn 1957 Imipramine (TCA)
8. John Kane 1987 Clozapine efficacy
II. Classification
Psychotropic drugs can be classified in many ways, but the most widely used
classification is based on the disorders they act on, i.e., antidepressants,
antipsychotics, mood stabilisers, anxiolytics etc. It is important to bear in mind that
drugs from one group can be used in the treatment of other disorders, e.g.,
antipsychotics for mania.
2
Antipsychotics:
Group Drugs
Phenothiazine Chlorpromazine, Fluphenazine
Butyrophenone Haloperidol
Thioxanthine Flupenthixol
Substituted benzamides Sulpiride, Amisulpiride
Dibenzodiazepine Clozapine
Dibenzazepine Thienobenzadiazepine Olanzapine
Dibenzothiazepine Quetiapine
Benzisoxazole Risperidone
Antidepressants group Antidepressants

Tricyclic antidepressants: Tertiary Amines: Amitriptyline,
Clomipramine, Imipramine,
Lofepramine.
Secondary amines: Desipramine,
Nortriptyline, Protriptyline
SSRIs Fluoxetine, Sertraline, Fluvoxamine,
Citalopram, Paroxetine
Serotonin & Noradrenergic reuptake Venlafaxine, Duloxetine
inhibitors (SNRI)
Noradrenaline reuptake inhibitors and Mirtazapine
specific serotonin antagonist (NaSSA) Mianserin
3
Serotonin antagonist and re-uptake Trazadone

inhibitor
Selective Noradrenaline Re-uptake Reboxetine, Atomoxetine (though this is
inhibitor (NARI) not used as an antidepressant, it is used
for treating ADHD)
Anxiety and insomnia

Benzodiazepines (acting on GABA-A Lorazepam, oxazepam, Nitrazepam,
channels) Chlordiazepoxide etc
5-HT1A partial agonist Buspirone
Z Drugs (also act on GABA-A) Zopiclone, Zolpidem, Zaleplon
Anti-dementia drugs
Reversible cholinesterase inhibitors Donepezil, Rivastigmine, Galantamine
(this is also selective)
Non-competitive NMDA antagonist Memantine
Other medications
Psychostimulant (related to Methylphenidate
amphetamine)
Medications used in drug misuse • Methadone is a synthetic opioid
• Acamprosate is a GABA agonist
and glutamate antagonist
• Buprenorphine is a partial agonist
at opioid receptors
• Disulfiram blocks action of
acetylaldehyde dehydrogenase
Medication used in smoking cessation Varenicline tartrate is an a4b2 partial
agonist of nicotinic receptors
4
III. Concordance1 & Placebo response
Concordance:
Approximately 50% of people do not take their medication as prescribed and this
fiqure may rise upto 75% by 2 years2. Adherence (compliance) is the extent to which an
individual changes their health behaviour to coincide with medical advice. Non-
adherence can be intentional (i.e. patient does not wish to take medication) or non-
intentional (usually practical problems e.g. regiment is too complex). Concordance is
the degree to which clinical advice and health behaviour agrees. Concordance to
prescribed medication has been an issue in psychiatry, which leads to relapses, partial
improvement, increased hospitalisation and health services utilisation.
Three important predictors are of non-concordance are:

1. Complexity of the regimen
2. Duration of the course
3. Frequency of follow-up contact
The factors associated with poor concordance are detailed below2:
Patient factors Clinician factors Illness factors
• Concerns about the • Poor doctor–patient • Severe illness

side-effects (weight relationship • Depression or distress
gain, sexual • Poor empathy • Psychosis
dysfunction) • Poor • Cognitive impairment
• Few perceived benefits explanation/communicat • Denial of illness
• Stigma of taking ion
medication • Inadequate follow-up
• Adjustment to suit daily Perceiving clinician to be
routine authoritative and
• Concerns about dismissive
dependency
• Slips and lapses
• Misunderstanding
instructions
• Belief about illness
1
Mitchell AJ & Selmes T. Why don’t patients take their medicine? Reasons and solutions in
psychiatry. Advances in Psychiatric Treatment (2007), vol. 13, 336–346
2
Maudsley guidelines, 12th edition. p. 700-704
5
Improving patient adherence3
Improve communication with patients

• Adapt consultation style to patient needs, inc consider
problems with ability to communicate
• Open ended questions
Involve patients in decision making
• Explain condition and pros and cons of treatment
• Clarifying patient’s hopes
• Accepting that patient may have different views, has the
right to refuse medication
Involve patients in Understand patient’s perspective
decisions about
• Ask patient about their beliefs re: medication before
medicines
prescribing
• Ask re: general or specific concerns e.g. dependence
• Discuss what will happen if they don’t take medication,
non drug alternatives, reducing/stopping medication,
patient routine and choosing the right medication
Provide information
• How to use medication, benefits, side-effects, how to get
further supplies
• Check patient understands and has relevant information
• Address concerns raised in PIL (patient info leaflet)
Assess adherence
• Asking patients if they have missed any doses recently
• Non-blaming, establish habit of taking meds
Support adherence
• Use repeat prescription information
Interventions to #adherence
• Address any beliefs about medications
• Look at practicalities e.g. simplifying regimen,
alternative packaging, addressing costs
• Address side-effects
• Review at regular intervals
Review medicines • Enquire about adherence
• Has patient evaluated meds in their own way (e.g.
stopping and starting)?
Improve • Ensure you communicate with other prescribers
communication • On transfer record: diagnosis, list of medications, when
between healthcare medications were started/stopped and for what reason,
professionals how long patient needs to continue on medication,
adverse effects/allergies, any potential problems with
adherence
3
Medicines adherence (2015). NICE guideline.
6
It is important for the doctors to establish a therapeutic alliance with the patients, and
engage in shared decision making to improve concordance to medication. There are
various strategies to improve concordance or adherence including: General
strategies like identifying patient’s concerns and addressing them, taking into
account the patient’s preferences while deciding on treatment, explaining the benefits
and hazards of different treatment options; specific strategies like adjusting
medication timing and dosage for least intrusion, minimising adverse effects,
maximising effectiveness and by providing support, encouragement and follow-up.
Once the patient has started medication, it is important to evaluate concordance by
enquiring about problems with medication (side effects, missed doses,
discontinuation). It is useful to consider indirect methods to establish concordance,
including urine / plasma screens, with patient’s consent. It would be useful to involve
the GP and Pharmacists to establish that prescriptions are picked up.
The Placebo response:
A treatment that gains a response due to its therapeutic intent rather than any
specific ingredient of treatment (therapeutic effect) is termed as a Placebo. It is not
the same as no care, patients who maintain contact with services have a better
outcome than those who receive no care. The placebo response is usually higher in
milder form of illness, increases with active placebos (as compared with inert
placebos). This is due to observed side-effects with active placebo which encourages
the placebo response (expectant effect). The placebo response is usually short-lived,
but the studies are not long enough to pick up placebo relapse.
The placebo response in psychiatry can vary from 25 – 60% in depression, 53% in
Generalised anxiety disorder, 23% in Agorophobia, 21% in OCD and around 20-50
percent in chronic schizophrenia4.
In RCTs involving a placebo group, change in any placebo group occurs for three
main reasons: the encouraging effect of being in treatment, the effect of
spontaneous remission while in treatment, and because people with chronic
symptoms normally seek help when their symptoms are worst and, through natural
fluctuations in severity, are likely to be improved when next assessed5.
Clinician attention, expectation, reputation and treatment setting (injection, precise
instructions, duration of treatment, strong-tasting or foul smelling medications,
colour of medication and at times branded drugs) are some of the factors more
likely to be associated with a placebo response.
The mechanisms underlying the placebo response include: Anxiety reduction,
expectation of outcome or self efficacy expectation, Transference, ‘Meaning effects’
and Conditioning6.
4
Posternak MA, Zimmerman M, BJPsych 2007, Kane J, Neuropsychopharmacology 1996, Andrews
G, BJPsych 2001
5
Andrews G, BJPsych 2001
6
Valance AK, Something out of nothing: the placebo effect. APT, 2006; 287-296.
7
IV. Rational prescribing:

Prior to prescribing any psychotropic medication there are certain general
principles which need to be considered:
1. Indication for use: Use should be restricted to those conditions for which
clinical efficacy have been determined by controlled clinical trials. It is
important to be aware of the guidelines (NICE, Maudsley etc.) that provide
information about the most effective and evidence based interventions for
particular conditions. There may be times when the guidelines may not
provide all the information required or patient may have different preference
to what is prescribed in the guidelines. In such circumstances, one may have to
prescribe outside the guidelines, which should be done after careful discussion
with the patient, and the pharmacists. This should be clearly documented in
the notes.
2. Dosage should be kept within the range recommended in these guidelines for
the indication for which it is prescribed - lower doses are generally ineffective,
higher doses can lead to unwanted side-effects or toxic reactions. In the elderly
dose requirements are usually less. It is important to start low and go slow to
be able to identify the ‘minimum effective dose’ required for each patient.
The
3. Adequate treatment for adequate time: Treatment should be long enough
so that evaluation of efficacy could be appropriately ascertained. Usually six to
eight weeks of treatment with most psychotropics is minimum time required
before the medication could be called as ineffective.
4. Adverse events. Adverse effects or side effects are the rule with psychotropic
medication, and often lead to non concordance with prescribed medication. A
full description of the likely side effects and frank discussion of the risk of
adverse events occurring usually helps to allay concerns of patients, as well
as improves adherence to medications. People receiving treatment have an
absolute right to know the relevant information about the drugs they are
prescribed.
5. Polypharmacy is at best avoided, and if required, it is necessary to consider
whether the proposed combination of treatments is therapeutically rational
and safe. Combination drug prescription should be done after collaboration
with experts in the field, including pharmacists. Any deviation from
prescribing guidelines should be carefully considered, and documented.
6. The optimal duration of treatment needs to be considered carefully at its
onset and discussed fully with the patient. Some drugs (eg benzodiazepines)
are best given for a strictly limited period; others may need to be taken
long-term (eg lithium for bipolar disorder). Again, the guidelines (NICE etc.)
should be consulted for the optimal duration of treatment for each condition.
7. Drug interactions Before combining two psychotropic drugs, or adding
a psychotropic drug to the treatment regime of a person already
receiving drugs for another condition, it is always essential to consider
8
the possibility of an untoward drug interaction. This is particularly relevant

in the elderly, where there is use of physical health medications which
complicates psychotropic prescription. Both Pharmacokinetic and dynamic
interventions are important. The use of over the counter drugs needs to be
monitored, as these lead to adverse effects by drug interactions.
8. Prescribing in special groups*:
8a. Pregnancy: Treat only if absolutely necessary, but be mindful of the risk of
relapse when discontinuing treatment. Try to avoid all drugs in the first trimester,
and only use the lowest effective dose at all times. Polypharmacy should be avoided,
and it may be necessary to increase dosage in the third trimester as blood volume
expands by 30%. It may be necessary to arrange for foetal screening during
pregnancy.
In pregnancy there is increased hepatic metabolism, plasma volume, renal clearance
and GFR. The delay in gastric emptying during pregnancy is recently disputed. The
GFR is increased by 40-60% and renal plasma flow is increased around 70% in
pregnant women. The foetus has lower plasma protein binding, hepatic functioning
and greater BBB permeability.
The teratogeneic drugs in psychiatry are: Lithium (Ebstein’s anomaly – RR 10-20
times more than control, AR – 1:1000); Carbamazepine & Sodium valproate (Neural
tube defects, spinia bifida). Patients may take folic acid for at least a month prior to
conception to reduce the effect. Valproate is more dangerous than carbamazepine,
and should be avoided.
Some recommended psychotropics in pregnancy: Antidepressants (Nortriptyline,
Amitriptyline, Imipramine & Sertraline), Antipsychotics (Chlorpromazine,
Trifluoperazine, Haloperidol, Olanzapine), Mood stabilisers & Benzodiazepines
(best avoided)
8b. Breast Feeding: Again use the lowest effective dose, time the feeds to avoid
peak drug levels in the milk. Some medications recommend during breastfeeding
are: Antidepressants (sertraline; paroxetine, imipramine may be used,);
Antipsychotics (olanzapine); Mood stabilisers (Avoid, valproate if essential);
sedatives (Zolpidem, lorazepam)7
8c. Elderly: In the elderly there are many physiological changes which require
lower doses of psychotropic medications to be used.
Apart from these changes there may be increase in receptor sensitivity, leading to
increased effect of the drugs. In the elderly, there is reduced renal blood flow and
GFR. 35% of renal function is lost by age 65 - 50% by 80. Though liver size reduces
with age, the metabolic capacity is unaltered. In frail old people blood supply might
be compromised but this is not a physiological change. The elderly also will be
taking a concomitant physical medication, which may interact with psychotropic
medication leading to increased adverse effects.
*
The Maudsley Prescribing Guidelines, 12th edition
9
Prescribing in special groups:

Pregnancy Breastfeedi Under 18s Liver Renal Physical

ng impairme impairmen problems
nt t
st
Antidepress Amitriptyline Sertraline 1 line: Citalopram Citalopram Epilepsy :
ant Fluoxetine SSRIs
Imipramine Others can Imipramine Sertraline
(licensed) +
be used Post-
Nortriptyline CBT Paroxetine
(paroxetine, stroke;
Sertraline nortriptyline, 2nd line: SSRIs
imipramine) Sertraline
Diabetes:
and
fluoxetine
citalopram
+CBT Citalopram
has lowest
interaction
potential
Antipsychoti Most Olanzapine Aripiprazole Sulpiride Haloperidol Epilepsy:
c evidence for , haloperido
Amisulpirid Olanzapine
older olanzapine, l, sulpiride
e
antipsychotic Risperidone Avoid
Diabetes:
s Low dose Sulpiride &
Failed 2 Amisulpiri
(haloperidol, haloperidol Amisulpiride
treatments de,
chlorpromazi
of above Paliperidon aripiprazol
ne,
(including e (if depot e,
trifluoperazin
Olanzapine) required) ziprasidon
e)
, then e
Experience CLozapine
Sexual
growing with
Metabolic dysfunctio
risperidone,
side-effects n:
quetiapine &
more likely aripiprazol
aripiprazole
e
Anxiolytic Low dose Lorazepam Benzos used Short- No
Chlorpromazi only in acting: preference

ne or short-term
Lorazepam Lorazepam,
Amitriptyline
Zopiclone
Oxazepam
Promethazine
used but little Temazepa
evidence m
st
Mood Consider Avoid if 1 line: Lithium Avoid
stabalisers using possible Antipsychot Lithium
antipsychotic ics
Valproate Start at low
s,
may be used 2nd line: dose:
Lamotrigine
but can lithium,
for bipolarv Valproate,
cause valproate in
depression Carbamazepi
hepatotoxicit boys
ne
y in infant
Lamotrigine
10
V. Pharmacokinetics & Pharmacodynamics
Pharmacokinetics is concerned with the body’s effect on the drugs. Bioavailability of

a drug (amount of administered drug that reaches its target) is dependent on
absorption, distribution, metabolism and excretion of the drug.
Bioequivalence is a term in pharmacokinetics used to describe the in vivo biological
equivalence of two proprietary preparations of a drug. If two products are said to be
bioequivalent it means that they would be expected to be show comparable bio
availabilities, efficacies and safety. Bioequivalence is a term used when comparing
brand name and generic drugs.
a. Absorption
Absorption of drugs is influenced by route of administration and drug properties.
Most psychotropic drugs are lipid soluble (notable exceptions are Lithium &
Sulpiride).
The various routes of administration and their effects are below:
Route Notes
Oral Common, variable plasma concentrations (due
to absorption and first pass effect). Best
absorbed if soluble in gastric fluid, acid-
resistant, can pass through cell membranes.
Intravenous Fast (15-30 secs), 100% bioavailability. Useful in
emergencies.
Intramuscular/subcutaneous Fast (5-20 minutes) dependant on blood flow
11
to region and aqueous solubility, 100%

bioavailability
Others: Topical, Transdermal, Inhalational
First Pass Metabolism
After absorption, enterally administered drugs enter the portal circulation, and pass
through the liver where they undergo significant metabolism before entering the
systemic circulation (first pass effect or first pass metabolism). The first pass
effect reduces the amount of the orally administered drug available for systemic
circulation, which can be avoided by giving the drug through parenteral (IM / IV)
routes. This explains the differences in potency of the same drug administered by
parenteral and oral routes. Rectal and buccal administration of drugs also avoids the
first pass effect as they also enter the systemic circulation bypassing the pre
systemic metabolism in the liver.
b. Distribution.
The drugs in the plasma are distributed to various tissues depending on: Plasma
protein binding, tissue perfusion, permeability of tissue membranes and active
transport out of tissues (P-glycoprotein).
Drug distribution refers to the movement of drug to and from the blood and various
tissues of the body (for example, fat, muscle, and brain tissue) and the relative
proportions of drug in the tissues. After a drug is absorbed into the bloodstream, it
rapidly circulates through the body; the average circulation time of blood is 1
minute. As the blood recirculates, the drug moves from the bloodstream into the
body's tissues. Once absorbed, most drugs do not spread evenly throughout the
body.
Drugs that dissolve in water (water-soluble drugs), such as the antihypertensive
drug atenolol, tend to stay within the blood and the fluid that surrounds cells
(interstitial space). Drugs that dissolve in fat (fat-soluble drugs), such as the
anaesthetic drug halothane, tend to concentrate in fatty tissues. Other drugs
concentrate mainly in only one small part of the body (for example, iodine
concentrates mainly in the thyroid gland), because the tissues there have a special
attraction for and ability to retain (have high affinity for) the drug.
Drugs penetrate different tissues at different speeds, depending on the drug's ability
to cross membranes. For example, the anaesthetic thiopental, a highly fat-soluble
drug, rapidly enters the brain, but the antibiotic penicillin, a water-soluble drug,
does not. In general, fat-soluble drugs can cross cell membranes more quickly than
water-soluble drugs can. For some drugs, transport mechanisms aid movement into
or out of the tissues.
Psychotropic drugs in the plasma tend to be largely bound to proteins (90 – 95%
protein binding). The small amount of the unbound drug (free fraction) is
pharmacologically active. High protein binding means that proportionally less of
the drug is available to be distributed to the organs and tissues.
12
The Blood Brain Barrier

As the name indicates, the BBB is a barrier between the brain/CSF and Blood. It is
formed by the capillary endothelial cells (cells lining the cerebral blood vessel
walls), which are very tightly bound and function as a single continuous membrane
behaving like a lipid membrane. The BBB only allows lipid soluble molecules to
enter the brain. Non- Lipid soluble drugs will require special transport systems-
either active (L-DOPA) or passive (Lithium).
The permeability of cell membrane is proportional to drug’s Partition Coefficient (a

ratio measure of the differential solubility of the compound between the 2
immiscible solvents). Hydrophobic drugs have high partition coefficients and
distribute in hydrophobic compartments (e.g. lipid bilayers). Hydrophilic drugs
have low partition coefficients and distribute in hydrophilic compartments like the
serum. Thus the permeability of the BBB to a drug increases as its lipid solubility
(and the proportion of its unionised form) increases.
Protein binding is not directly linked to blood brain barrier permeability. Lipid
solubility and partition coefficient (ion vs. unionized fraction) determines
permeability.
Un-ionised drugs are significantly more lipid soluble than ionised drugs, so highly
ionised forms do not pass through BBB easily. Metabolites tend to be ionised and
therefore struggle to pass through the BBB. Regardless of whether it is ionised, the
presence of a metabolite will not influence the initial BBB permeability of a drug.
Dopamine does not pass through BBB, so in Parkinson’s disease (where there is
dopamine depletion) L-Dopa a precursor of dopamine (which, unlike dopamine, can
pass through BBB) is used as treatment.
Drugs given through most routes have to pass through the blood vessels and the
BBB before entering the brain. Nasal sprays, of note, come in close contact with the
olfactory epithelium which can enable direct passage via the olfactory tract to the
brain.
iii Metabolism
Most psychotropic drugs are predominantly metabolised in the liver where they are
converted from lipophilic compounds into water soluble ones in order to be
excreted by the kidneys. Metabolism can occur in the plasma, lung and kidney, but
the liver is the most important. For excretion by the kidneys, drugs need to be
converted to more polar/ionised forms. This is done through oxidation,
hydroxylation, conjugation, demethylation or sulfoxide formation.
The cytochrome P450 enzyme system

The cytochrome P450 enzyme system is located in the liver (endoplasmic reticulum
of hepatocytes), the gut wall and the brain. Cytochrome P450present in other
13
tissues of the body (e.g. mucosa of the gastrointestinal tract) plays important roles
in hormone metabolism (including oestrogen and testosterone synthesis),
cholesterol synthesis, and vitamin D metabolism. This system contains the enzymes
responsible for oxidative metabolism of most psychotropic drugs.
Some of the important isoenzymes and their metabolites are:

Cytochrome P450: Example Substrates (with notes)
1A2 Clozapine, olanzapine, zotepine, TCAs, haloperidol (inhibited
by fluvoxamine, induced by smoking)
2D6 Risperidone, clozapine, olanzapine, aripiprazole, typical

antipsychotics, TCAs, fluoxetine, paroxetine
(hydroxylation, inhibited by paroxetine, fluoxetine,
duloxetine, high-dose sertraline)
3A4 Clozapine, quetiapine, ziprasidone, sertindole, aripiprazole,
zotepine, TCAs, benzodiazepines
(inhibitors: ketoconazole, erythromycin, nefazodone,
fluvoxamine, fluoxetine, protease inhibitors, inducers:
carbamazepine)
Factors affecting drug metabolism through the cytochrome P450 system include:
metabolism include genetic variation, drug interactions, and impaired liver
function. Genetic variation of CYP450 system: 2D6: 5-10% Caucasians and only 1-2%
Asians lack this enzyme.
Some substances can induce this system, which in turn leads to increased clearance
of drugs which are substrates of these enzymes (alcohol, smoking, barbiturates,
carbamazepine, St. Johns Wort). The enzyme inducers affect the plasma
concentration of antidepressants (SSRIs), antipsychotics, valproate, &
benzodiazepines) reducing their efficacy.
Some substances inhibit this system, reducing the metabolism of drugs that are
substrate of these enzymes, leading to increased concentration and toxicity. Some of
the inhibitors are the SSRIs, chlorpromazine & grapefruit juice.
Note that the induction of inhibition can be enzyme specific – not the whole system
generally.
Below is a table summary of inducers and inhibitors with frequently asked about
interactions.
14
Substance Inducers Inhibitors

($ plasma levels of (# plasma level of drugs)8, 9
drug)8,9
Carbamazepine SSRIs
($carbamazepine,
warfarin)
Psychotropics
Barbiturates Chlorpromazine (#Valproic acid)
St John’s wort ($ OCP, Moclobemide
warfarin)
Venlafaxine
Phenytoin Fluvoxamine (#clozapine,
($carbamazepine) theophylline)
Medical drugs Omeprazole Erythromycin (# carbamazepine)

Spironolactone Cimetidine (# clozapine,
haloperidol, TCAs)
Rifampicin Ciprofloxacin
($carbamazepine)
Isoniazid
Ketoconazole
Other Alcohol Grapefruit juice
substances
Smoking ($clozapine,
haloperidol, TCAs)
iv. Excretion*:
The kidneys are the major routes through which psychotropic drugs are excreted
(excretion through other organs being negligible). Ionised and non-lipid soluble
drugs are excreted best. Reduction in renal blood flow and alterations in
reabsorption affects elimination.
Enterohepatic circulation
A small proportion of lipophilic drugs is excreted in the bile, enters the intestine
and is partly reabsorbed. This recycling of drugs between the liver and the intestines
is termed enterohepatic circulation. Not every drug undergoes EHC - Oral
contraceptives undergo marked EHC.
8
Maudsley guidelines, 12th ed, p. 646-649.
9
Easterbrook PJ, Basic sciences for MRCP Part 1. 3rd ed, p. 344
* Goodman & Gillman’s Pharmacological Basis of Therapeutics 12th edition Pg 28-30
15
The kinetics of most psychotropic drugs initially follow a first order reaction (i.e. the
rate of drug elimination depends on its plasma concentration). A constant portion
of the drug is cleared per unit of time till their clearance mechanisms (i.e. enzymes,
kidneys, and lungs) are saturated. Once the clearance systems are saturated, a
constant fraction of the drug is eliminated independent of its concentration (zero
order kinetics). Alcohol and phenytoin are good examples of drugs showing zero
order kinetics, due to rapid saturation of their enzymes.
Steady state concentration is achieved after repeated doses lead to equilibrium
between absorption and elimination. This is dependent on dose, time between
doses and elimination half lives. The half-life of a drug in plasma is the time taken
for its concentration to reduce by half. It takes 4-5 half-lives for the drug to reach
steady state concentration once the dosing begins. However, even once steady state
has been reached, plasma concentrations may still fluctuate.
Half-lives may be important clinically e.g. when considering how to swap medications.
This is especially true for antidepressants, e.g. fluoxetine has the longest half life (up to 14
days) due to its active metabolite. This means that swaps onto other serotonin increasing
medications need to be cautious and a medication free period of 4-7 days is frequently
recommended. This is increased to 5 weeks when swapping from fluoxetine onto an MOI,
due to the increased risk of serotonin syndrome10.
It is also important to consider the half-lives of different benzodiazepines and related

drugs, as this will affect the choice of medication. A summary is given below11:
Long half life Diazepam (up to 200 hrs of metabolite)
Chlordiazepoxide (up to 200hrs of active metabolite)
(>30 hrs)
Clonazepam (up to 50 hrs)
Nitrazepam (up to 38hrs)
Short half life Lorazepam
Loprazolam
( 3 – 24hrs)
Oxazepam
Temazepam
Zopiclone
Ultra-short half-life Zaleplon
Zolpidem
(<3hrs)
Shorter-acting benzodiazepines are preferred in liver impairment, as their metabolism

may be affected and longer acting benzodiazepines may lead to a higher concentration of
medication in the blood.
10
Maudsley prescribing guidelines. 12th ed.
11
Benzodiazepine equivalence table based on: Ashton Manual (BENZODIAZEPINES: HOW THEY WORK
AND HOW TO WITHDRAW) Professor C Heather Ashton DM, FRCP Revised August 2002, table
accessed online at: http://www.benzo.org.uk/bzequiv.htm
16
Therapeutic index* is a relative measure of the toxicity or safety of a drug and is

defined as the ratio of the median toxic dose to the median effective dose.
Therapeutic index = Lethal/toxic dose that would affect 50% of population

Therapeutic dose at which 50% of population would respond
The higher the therapeutic index the wider the therapeutic window i.e. the range of levels
in the blood at which the drug would be therapeutic and not toxic is wide. Penicillins and
thiazide diuretics have a high therapeutic index. A low therapeutic index indicates that
the difference between a therapeutic dose and a toxic dose is very small, so the
therapeutic window is narrow and is likely to require monitoring (e.g. Lithium).
The main reasons for monitoring plasma levels of drugs (notably psychotropics and
anticonvulsants) are:
1. To confirm concordance
2. If toxicity is suspected
3. To rule out drug interactions
4. If clinical response is difficult to assess
5. If drug has a narrow therapeutic index (lithium)
It is important to check the levels after steady state has been achieved (4-5 half
lives). Sampling time should be within 1-2 hours of that required time.**
Drug Target range Sample timing Time to steady state

Carbamazepine: >7 mg /l Trough 2 weeks
Clozapine 350-500microgm/l Trough 2-3 days
Lithium 0.6 - 1.0mmol/l 12hrs post dose 5 days
Olanzapine 20-40 microg /L 12hrs post dose 1 week
Valproate 50-100mg/l Trough 2-3 days
Of these, lithium is the one with a well-established therapeutic range. Plasma

clozapine levels can be helpful in optimising treatment, particularly in treatment
resistant cases, whereas levels may be increased to bring the plasma levels in 350-
500microgram/l range.
* Goodman & Gillman’s Pharmacological Basis of Therapeutics 12th
edition Pg 28-30
th
** The Maudsley Prescribing Guidelines, 12 edition, Page 3

17
Growing old is associated with relative metabolic impairment, often aggravated by

chronic disease. Kidneys no longer excrete so well, liver no longer metabolises as
quickly. Small doses of drugs consequently last longer, accumulate more and exert
bigger effects.
v. Physiological differences12
Pregnancy
• Absorption can be increased due to slow GI motility
• Distribution in plasma and extracellular fluid increases up to 50% hence
decreasing plasma volume.
• Renal elimination is not affected despite increased blood flow to the kidneys,
however, liver metabolism is induced by progesterone in pregnancy.
Old age
• Concentration of albumin decreases, hence less of the drug is protein bound
and a greater fraction is unbound and active.
• Volume of distribution changes as lean body mass decreases (hence more fat)
• Ability of Cyt p450 to oxidise drugs decreases in elderly males.
Pharmacodynamics
Study of drug action – ‘what the drug does to the body’. Drugs can interact with the
body via; cell membrane disruption; chemical reaction; interacting with enzymes,
ion channel, structural or carrier proteins and receptor binding.
The binding of drugs to receptors is governed by the law of mass action. The
fraction of bound receptors is known as occupancy. The relationship between
occupancy and pharmacological response tends to be non-linear (the concentration
producing 50% occupancy is typically higher than the concentration producing 50%
of the maximum response – the so called receptor reserve phenomenon).
Potency reflects the concentration of a drug necessary to produce a given response
and is dependant on affinity and efficacy. Affinity is the ability of the drug to bind to
a receptor. Efficacy reflects the relationship between receptor occupancy and the
effect/response of the drug.
Most psychotropic drugs affect the function of specific neurotransmitters either
directly or indirectly. The potency of a drug is determined by; the proportion of the
drug reaching the receptor, its affinity for the receptor and its efficacy.
12
Basic Medical Sciences for the MRCP part 1, 3rd edition (2005), p. 397-8.
18
Agonists are drugs that bind to receptors and initiate a response in neuro-effector
tissue. Drugs that produce maximum response are called full agonists, and drugs
that produce less than maximal response are called partial agonists. Drugs that do
not have any intrinsic activity, but prevent an agonist initiating a response are called
an antagonist.
Therapeutic Window
The dose range of a drug, lying between the minimum amount necessary to give an
effect and the amount that gives more adverse than desired effects.
Drug receptor interactions can be modified by changes in receptor sensitivity. When

receptor sensitivity changes, the same concentration of drug will produce a greater
or lesser physiological response.
Down regulation or desensitisation: After prolonged stimulation of cells by agonists,
the cell becomes refractory to further stimulation. Long term desensitisation may
involve negative feedback that inhibit new receptor synthesis or cause a structurally
modified receptor to be synthesised.
Supersensitivity or up-regulation: Follows prolonged blockade, and may involve
synthesis of new receptors.
VI. Antidepressants
a. Tricyclic Antidepressants:
TCAs can be classified into tertiary amines that have a terminal methyl group in the
side chain (amitriptyline (above), clomipramine, imipramine, lofepramine etc), and
secondary amines that do not have the terminal methyl groups in the side chain
(desipramine, nortriptyline, protriptyline etc.).
Pharmacokinetics: All TCAs, which are highly lipid soluble are well absorbed from
GIT, have high first pass effects with only 50-60% of oral dose reaching systemic
circulation. Plasma protein binding is high. They are metabolised by hydroxylation
and demethylation. Elimination half lives are around 20-24 hours.
19
Due to cytochrome P450 enzyme system inhibition by some drugs (e.g.

chlorpromazine), the level of TCAs can be increased. This increase is higher for
secondary amines compared to the tertiary. Concomitant use of chlorpromazine and
tricyclic antidepressants may result in increased plasma concentrations of both
drugs. The risk of neuroleptic malignant syndrome may also be increased.
TCAs increase warfarin levels, phenytoin levels; they reduce antihypertensive effects
of guanethidine and clonidine. TCA interacts with morphine, increasing
bioavailability of morphine and so, increasing analgesic effect.
Pharmacodynamics:
Mechanism of Action: TCAs inhibit the reuptake of nor-adrenaline and 5HT in the
presynaptic neurones to produce the antidepressant effects. They also act by
blocking the muscarinic receptor (anticholinergic), a1 adrenoreceptor, and H1
histamine receptor, which gives rise to the many adverse effects of TCAs. The
tertiary amines are more potent reuptake inhibitors of 5HT and more potent
blockers of M1 receptors and a1 adrenoreceptor, causing more sedation &
anticholinergic side effects than secondary amines.
All tricyclic antidepressants block the re-uptake of norepinephrine at nerve
terminals. However, the potency and selectivity for the inhibition of the uptake of
noradreline, serotonin, and dopamine vary greatly among the agents. The tertiary
amine tricyclics seem to inhibit the serotonin uptake pump, whereas the secondary
amine ones seem better in switching off the noradrenaline pump.
Clomipramine has 5HT reuptake inhibition equivalent to that of SSRIs.
Clomipramine is more selective for serotonin reuptake than any other tricyclic, but
still it does not act on 5HT receptor per se, only on reuptake channel.
Uses:
All tricyclics are licensed for use in depression. However some have other licensed
uses:
• Nocturnal enuresis in children: Imipramine is used not due to antidepressant
effect but due to autonomic effects. Nortryptiline and amitryptiline are also
licensed for this.
• Phobic and Obsessional states: Clomipramine is used as the second-line
treatment for OCD.
• Adjunctive treatment of cataplexy associated with narcolepsy: clomipramine.
• Amitriptyline is used in migraine prophylaxis and in neuropathic pain.
However these are unlicensed uses.
Adverse effects:
Adverse effects of TCAs and the receptors involved.
20
Receptor Blocked Adverse effect

M1 (anticholinergic) – Memory impairment, Confusion
central
M1 (anticholinergic) – Dry mouth, Blurred vision, Glaucoma, oesophageal
peripheral reflux, constipation, urinary retention, poorly
sustained erection, sinus tachycardia
Histaminergic - H1 Sedation, weight gain
a1 adrenoreceptor, Orthostatic hypotension (nortriptyline lower risk),
sexual dysfunction, sedation
Inhibit fast Na channels Heart block, AV block, delayed AV conduction,
Cardiac arrhythmias.
The most important adverse effect is due to the membrane stabilising effect through
inhibition of fast sodium channels (Type I antiarrhythymic effects) on the cardiac
muscles. Slight prolongation of the PR, QRS or QT intervals is seen. TCAs cause
conduction disturbance at AV node, which can present as bradyarrhythmia,
however, they also can cause a sinus tachycardia. The sinus tachycardia is not due to
changes in cardiac conduction but anticholinergic/vagolytic effects increasing the
sino-atrial rate. The TCAs can delay conduction in patients with pre-existing
conduction delay and cause heart block.
The weight gain observed is largely due to blockade of the H1 histamine receptor;
reduced basal metabolic rate may also play a part. Mirtazapine can also cause
significant weight gain.
Dry mouth is a peripheral antimuscarinic side effect.
Drug Interactions:
Pharmacodynamic: Due to the ability of TCAs to block noradrenaline reuptake,
systemically administered adrenaline or noradrenaline can lead to hypertension
(dental anaesthesia uses a cocktail of adrenaline). TCAs should not be used with
antiarrhythmic drugs particularly amiodarone. Lignocaine in anaesthetics can also
interact if systemically absorbed.
The TCAs have acute effect on amine uptake; hence it is potentially dangerous when
given with MAOIs (lead to sudden increase in catecholamine concentration leading
to potentially fatal hypertensive reaction). If these two drugs are to be used, they
should be used with caution, either by starting both the drugs at low doses, or
adding MAOIs to TCAs. (Clomipramine and Imipramine should not be used with
MAOIs).
The concomitant use of SSRIs and TCAs should be avoided due to the risk of
developing serotonin syndrome. The SSRIs, except fluvoxamine, increase levels of
TCAs by cytochrome inhibition. In spite of these potential problems, combinations
can be used under close supervision.
21
b. Specific Serotonin Reuptake Inhibitors (SSRIs):
Pharmacokinetics: All SSRIs are well absorbed, though slowly. They are well
metabolised, with fluoxetine and paroxetine inhibiting their own metabolism.
Fluoxetine has its own metabolite, norfluoxetine, which has a half-life of 4-16 days13.
This is by far the longest as other SSRIs have half lives of 22-33 hours.
Mode of action: The SSRIs inhibit the reuptake of serotonin into presynaptic
serotonergic nerve terminals. The antidepressants are equally efficacious in treating
depression; the main difference between them is with regards to their adverse
effects & toxicity. Citalopram is the most selective SSRI while paroxetine most
potent.
The main adverse effect with SSRIs is sexual dysfunction. SSRIs do not block the M1
or the H1 receptor, hence sedation, weight gain and anticholinergic side effects do
not occur with their use. Fluvoxamine, in fact, has been tried in binge-eating
disorder. Fluoxetine and sertraline have anorectic effects. Paroxetine does not share
this effect, while the others are neutral. SSRIs are known to produce SIADH with
hyponatremia.
EPSEs – Parkinsonism and akathisia is known to occur with their use.
Anticholinergic effects do occur though rarely with fluoxetine. Also, the common
side effect of sweaty palms is thought to be due to anticholinergic properties.
Paroxetine is the most anticholinergic SSRI, therefore (along with citalopram,
fluvoxamine) it has been implicated in increasing the risk of closed ankle glaucoma.
With regards to their safety in pregnancy, SSRIs have been linked with both
irritability and pulmonary hypertension in the newborn although the evidence is
weak.
Other 5HT receptors

The 5HT3 receptor is not involved in mediating antidepressant effects. It is the only
5HT receptor that is ion-gated and, thereby, fast-acting (the other 5HT receptors are
G-protein coupled and slow-acting). It is involved in emesis; hence 5HT3
antagonists like ondansetron are used as antiemetics. Other 5HT receptors which
are associated with regulation of activities include the 5-HT2c receptor which, along
with H1 is associated with weight gain, and the 5HT7 receptor which is associated
with circadian rhythm regulation.
Almost all antidepressants lead to a dose dependent prolongation of REM latency

(time to first appearance of REM sleep), and a reduction in REM sleep. So SSRIs do
increase REM latency and reduce REM sleep. The effects on REM latency are
substantial - virtually doubling the latency compared with baseline. (Kerkhofs, 1990)
13
Maudsley guidelines, 12th ed, p. 547-548
22
Drug interactions:
Pharmacodynamics: Concurrent use of SSRIs and drugs that potentiate 5HT brain
function (MAOIs, tryptophan) can lead to ‘Serotonin Syndrome’, characterised by
agitation, hyper pyrexia, rigidity, myoclonus, hypomania, coma and at times death.
Hence concurrent use of MAOIs and SSRIs should be avoided. At least 2 weeks
washout period is required before starting SSRIs after discontinuing MAOIs. At least
2 weeks washout period is required for starting MAOIs after discontinuing SSRIs
except fluoxetine, which will require a washout period of a minimum of 5 weeks
owing to its long half-life.
Pharmacokinetic: SSRIs inhibits the cytochrome P450 enzyme systems causing
decreased metabolism and increased plasma levels of the drugs require these
enzymes for their metabolism. [Hint: SSRIs will always increase (& not decrease) the
plasma levels of the concerned drugs].
Drugs whose plasma levels are increased by SSRIs include TCAs, clozapine,
risperidone, and warfarin. Fluoxetine increases plasma clozapine levels by CYP 2D6
inhibition. Fluvoxamine causes increased levels and enhanced anticoagulant action
of warfarin by CYP1A2 inhibition.
Fluoxetine may produce hypoglycaemia (as much as 30% reduction of fasting
glucose) in patients treated with oral hypoglycaemic drugs or insulin; hence dosage
reduction of insulin or oral hypoglycaemic drugs may be required.
SSRIs are known to inhibit platelet aggregation that increases the risk of GI
bleeding. This is exacerbated by concomitant use of NSAIDs and aspirin14.
SSRIs are also known to increase the effects of Lithium with Lithium toxicity
reported on concomitant use.
Uses:
All SSRIs are licensed for depression. Other licensed uses include15:
• Panic disorder: Citalopram, escitalopram, paroxetine
• GAD: Escitalopram, paroxetine
• Bulimia: Fluoxetine
• OCD: Escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline – inc.
children
• PTSD: Paroxetine, sertraline – in women only.
• Social anxiety: Escitalopram, paroxetine
Withdrawal reactions ranging from mild, transient anxiety and insomnia to severe
headache, nausea, dizziness, and "electric jolts" lasting for several months have
since been reported in up to 86 percent of patients who abruptly discontinue taking
14
Maudsley guidelines, 12th ed, p. 328
15
Maudsley guidelines, 12th ed, p. 283-285.
23
SSRIs. Therefore, gradual tapering over several weeks is strongly recommended.

Anecdotal reports suggest that the addition of benzodiazepines or trazodone for
sleep may alleviate SSRI withdrawal. (Kaplan & Sadock, 2004).
c. MAOIs:
MAOIs are third-line treatment but retain an important place in therapy. The three
compounds available are phenelzine, isocarboxazid and tranylcypromine.
Moclobomide is a new MAOI. They are useful in severe depression (especially with
lethargy and poor motivation), treatment resistance, anxiety states, OCD and
‘atypical depression’ (depression with excessive sleeping and weight gain).
Pharmacokinetics: Are readily absorbed, reach peak concentrations in 1-2 hours
and are rapidly eliminated due to complete hepatic metabolism. Phenelzine appears
to induce its own metabolism similar to carbamazepine.
Pharmacodynamics:
Mechanism of action: The MAOs are flavoproteins found on the outer membranes
of the mitochondria. They oxidise NA, 5-HT, dopamine, tyramine and other amines
that are either present in the body or taken in with food/drink/drugs. The two types
to be aware of are MAO-A & MAO-B. MAO-A metabolises NA & 5-HT, whereas both
types metabolise dopamine (preferentially B) and tyramine (preferentially A).
The MAOIs phenelzine, isocarboxazid and tranylcypromine bind irreversibly to
MAO-A & MAO-B, in contrast to the reversible MAOI, moclobemide, which binds
reversibly & selectively to MAO-A. Selegiline selectively & irreversibly inhibits the
MAO-B, but is required in such large doses to have efficacy in depression, that its
selectivity is lost. By inhibiting the MAOs, there is decreased metabolism of the
amines (NA, 5-HT & dopamine), thus increasing their availability in the synaptic
clefts.
The adverse effects of irreversible MAOIs include hypotension, dry mouth,
insomnia, constipation, peripheral neuropathy, urinary difficulties, sexual
dysfunction, and ankle oedema (not arthritis). As with other antidepressants,
MAOIs cause suppression of REM sleep. But due to amphetamine related structure
of some MAOIs, these can have an alerting effect; they are usually taken as morning
doses.
The cause for concern using these drugs is the occurrence of the potentially fatal
‘hypertensive effects’ or the ‘cheese reaction’.)
24
Cheese Reaction
Some foodstuffs contain tyramine, which is inactivated by the MAO in the gut wall
& the liver. Due to the inhibition of the MAOs by the MAOIs, tyramine is absorbed
into the system resulting in displacement of norepinephrine, leading to a
hypertensive crisis and at times death. The foodstuffs to be avoided include
fermented foodstuffs like red wine, beer, cheese (except cottage, cream & ricotta
cheese), yeast extracts, pickled or smoked fish, beef or chicken liver & fermented
sausage. The risk of a ‘cheese reaction’ with moclobemide is reduced but does occur.
There are no dietary restrictions with moclobemide unlike with the irreversible
MAOIs. If moclobomide is taken before tyramine containing food, it can be
effectively metabolised by competing with moclobomide for MAO-A sites and can
utilise MAO-B that is unoccupied and dominant form in gut.
Tyramine acts as indirect sympathomimetic; enters presynaptic neuron through
reuptake pumps and stimulates release of stored norepinephrine. Blocking the
reuptake channels e.g. when using TCAs can reduce neuronal entry and can prevent
cheese reaction to some extent. In fact TCA and MAOI combinations when used,
has lesser incidence of the hypertensive crisis. It is advisable to start TCA first in
such combinations.
Signs of Cheese reaction: occipital headache, stiff neck, nausea and vomiting,
chest pain, dilated pupils, nosebleed, elevated blood pressure.
Treatment: stop medication; give phentolamine (alpha-blockage) or
chlorpromazine (antipsychotic with hypotensive effects
Drug interactions
Patients taking MAOIs should not be given drugs that are metabolised by MAOs.
These include: adrenaline, noradrenaline, amphetamine, ephedrine, &
phenylpropanolamine, as this leads to hypertensive crises. Other drugs like
dopamine, L-Dopa, opiates, cocaine & insulin also are known to cause
hypertensive reactions.
The combination of MAOIs and salbutamol has led to isolated reports of
tachycardia and apprehension. The BNF does not list specific interactions; drug data
sheets for orally used salbutamol suggest avoiding the combination due to
potentiation of cardiovascular effects of salbutamol. MAOIs are contraindicated in
phaeochromocytoma.
A number of drugs that potentiate the 5-HT function will lead to a ‘serotonin
syndrome’ when combined with MAOIs, hence they should be avoided. These drugs
include SSRIs, clomipramine, imipramine, venlafaxine, fenfluramine & L-
tryptophan. Other TCAs have been combined with MAOIs as mentioned before.
The safest MAOI in combination with other antidepressants is phenlezine and the
most dangerous which should never be combined is tranylcypromine.
iv. Other antidepressants:
Sleep deprivation was used to treat depression, but depression returns by the next
night of sleep; this is prevented by using antidepressants.
25
Mirtazapine is a nor-adrenergic and serotonin specific antidepressant (NASSA). Its

action on the pre-synaptic alpha 2 adrenoceptor (agonist) facilitates the release of
NA and 5HT. Its blockage of the H1 receptor is responsible for the sedation.
Interestingly the sedation can be less at higher doses. The H1 blockade is also
responsible for the weight gain. Its blockage of the 5HT2 and 5HT3 receptors
mediates its effect on anxiety, but also lead to nausea and sexual dysfunction. NICE
guidelines recommend its use as a second line antidepressant but remind
prescribers to be aware of its propensity to cause sedation and weight gain.
Mianserin is also classified as a NASSA.
Venlafaxine is a selective serotonin and noradrenaline reuptake inhibitor (SNRI). It
has less anticholinergic and H1 antagonism. At lower doses (<=75mg) its actions and
side effect profile are similar to SSRIs. At higher doses it inhibits the reuptake of
5HT and NA. Although there is no longer a requirement to perform ECGs prior to
initiation, caution is recommended with using this medication with anyone who has
heart disease and it is contra-indicated in patients who have conditions associated
with a high risk of cardiac arrhythmias. It should not be used post MI. Blood
pressure should be monitored carefully when using high doses. It is recommended
that a specialist in mental health should only initiate doses above 300mg/day.
Further, there is a risk of a discontinuation syndrome on its sudden withdrawal,
which therefore should be slow.
The NICE guidelines (2009) for the treatment of depression, clearly recommend the
use of venlafaxine as a second line antidepressant after trying 2 first line choices.
STAR*D trial to some extent, confirmed the safety and (to a lesser extent) efficacy
of the combination of mirtazapine and venlafaxine.
Other side effects are similar to those of the SSRIs

Reboxetine is a selective noradrenaline reuptake inhibitor (NARI). It is a second line
antidepressant. Side effects of reboxetine are not well documented.
Duloxetine (Cymbalta) is a serotonin and noradrenaline re-uptake inhibitor (SNRI)
antidepressant introduced to the UK market by Eli Lilly in December 2004 for the
treatment of Major Depressive Disorder (MDD). It is claimed to have a more
balanced and potent effect at the serotonin and noradrenergic receptor than
venlafaxine although the clinical significance of this is unclear. Confusingly,
duloxetine is also licensed under the same brand name of Cymbalta for the
treatment of diabetic peripheral neuropathic pain and a different brand name
Yentreve for moderate to severe stress urinary incontinence in women. The
packaging, appearance, formulations, and recommended daily dosage of Yentreve in
stress urinary incontinence are different to that for Cymbalta in depression.
There is limited data on the effectiveness of duloxetine as compared to other

antidepressants. Duloxetine appears to have a similar side-effect profile to existing
SSRI antidepressants.
26
Trazodone has antagonistic properties at 5-HT2 receptors and is a weak reuptake

inhibitor of serotonin. Side effect includes excessive sedation (a1 adrenoreceptor
blockade) and priapism.
Nefazodone is similar to Trazodone except a1 adrenoreceptor blockade. It inhibits
cytochrome P450 system and elevates levels of CBZ, haloperidol, benzodiazepines
and digoxin.
St. Johns Wort is a plant (hypericum perforatum) extract. It is known to act by
weakly inhibiting monoamine oxidase enzymes (MAO) and reuptake inhibition of
5HT & noradrenaline. It has shown to be of some benefit in mild to moderate
depression.
It induces the cytochrome P450 enzyme system, causing increased metabolism of
many drugs esp. warfarin and OCPs, thus reducing their efficacy.
Since it potentiates 5-HT, it can potentially cause serotonin syndrome if used along
with SSRIs, hence it should be used with caution in people already on SSRIs. It does
not reduce the efficacy of SSRIs.
d. Prescribing in special groups16:
Use Avoid
Under 18s Only fluoxetine is licensed. Venlafaxine, TCAs and
Sertraline and citalopram paroxetine
may be used as second line
Elderly All antidepressants are likely to have side-effects. Choice
affected by profile of risk factors and regular medications.
Epilepsy SSRIs TCAs
Post-stroke SSRIs (Citalopram has lowest TCAs
interaction potential),
Mirtazapine, nortriptyline
Diabetes Fluoxetine TCAs and MAOIs (weight
gain)
Pregnancy Amitriptyline, imipramine Paroxetine
Sertraline also used
Breast feeding Sertraline; Paroxetine,
imipramine may be used
Hepatic Imipramine, paroxetine,
impairment citalopram
Renal impairment Citalopram and sertraline
16
Maudsley guidelines, 12th ed 541---.
27
VII. Antipsychotics.
c. Classification.
Group Drugs
Phenothiazine Chlorpromazine, Fluphenazine
Butyrophenone Haloperidol
Thioxanthine Flupenthixol
Substituted benzamides Sulpiride, Amisulpiride
Dibenzodiazepine Clozapine
Dibenzazepine Thienobenzadiazepine Olanzapine
Dibenzothiazepine Quetiapine
Benzisoxazole Risperidone
d. Receptor activity.
There are two groups of dopamine receptors that have been elucidated till date, the
D1 receptor group (D1 & D5) and the D2 receptor group (D2, D3 & D4). The typical
antipsychotics exert their actions by antagonism of the postsynaptic D2 receptors,
whereas the atypical drugs act by blocking the D2 receptors (in addition to 5HT2
receptors).
Clozapine has more affinity for the D4 & D1 receptors compared to the other
antipsychotics (typical & atypical). It also has the highest affinity for the 5HT2
receptors compared to other antipsychotics. At therapeutic concentrations
clozapine has D2 receptor occupancy of 50 –60% compared to the 70-80% of other
antipsychotics. We still don’t have an antipsychotic that is selective in its receptor
blockade, as all antipsychotics apart from D2 blockade also block many other
receptors (a1, M1, H1, etc). Atypical antipsychotics cause fewer EPSEs due to their
selective D2 blockade in the mesolimbic pathways.
Clozapine has a 10-fold higher affinity for the D4 dopamine receptor than other
antipsychotic agents. The D4 receptor is present in the cortex and less so in the
striatal areas. Clozapine has higher affinity for the 5HT2 receptors compared to
other antipsychotics; the only exception being olanzapine.
iii. Typical antipsychotics.
All the antipsychotics follow the ‘pharmacokinetic principles of psychotropic drugs’
i.e., lipid soluble, completely absorbed from GIT, high first pass effect, cross the BBB
easily, metabolised in the liver and excreted through the kidneys. An exception is
sulpiride, which is water soluble, poorly absorbed and has difficulty crossing the
BBB.
Patients have substantial differences in the extent to which they metabolise these
drugs, which explains the varying plasma levels of orally administered
28
antipsychotics. Although intestinal absorption is complete, the oral bioavailability is

32%±19% because of variable metabolism in the intestinal wall and liver (marked
first-pass effect).
Most antipsychotics drugs are metabolised by the cytochrome P450 enzymes.
Patients have substantial differences in the extent to which they metabolise these
drugs, which explains the varying plasma levels of orally administered
antipsychotics. Chlorpromazine has significant anticholinergic properties and when
antimuscarinics are co-administered the anticholinergic side effect can be enhanced
even though the plasma concentration is reduced.
On concomitant use of TCAs and phenothiazines, the antimuscarinic side effects
and the plasma concentration of the TCAs, are increased. SSRIs inhibit cytochrome
P450 enzymes, leading to decreased metabolism of haloperidol and increased
plasma concentration.
Smoking leads to enzyme induction and lowered plasma concentration of
antipsychotics.
Typical antipsychotics pass through the placenta. Haloperidol has not been shown
to cause congenital abnormalities in the foetus. Its use in pregnancy sometimes
leads to EPSEs in the newborn, but it has been safely used in pregnancy. It is
secreted in low concentrations in breast milk.
Side Effects of Typical Antipsychotics*

Extrapyramidal side effects:
Acute dystonias – onset within hours of starting treatment. Intermittent or
sustained spasm of muscles. Manage by parenteral anticholinergics. Risk factors for
acute, drug induced dystonia include young age, male sex, use of cocaine, and a
history of acute dystonia. Drug induced dystonia can be prevented either by adding,
during the first four to seven days of treatment, anticholinergic drugs to treatment
with antipsychotic drugs or by starting treatment with atypical antipsychotics.
Parkinsonism – onset within days. Rigidity, bradykinesia, shuffling gait, rest tremor
(notably with zuclopenthixol). Tremors are less pronounced than the idiopathic
Parkinsonism. Treatment: anticholinergics or reduction in dosage. Antipsychotics
cause a resting tremor (infrequent and late sign of drug induced Parkinsonism).
Bradykinesia is more common, accompanied by a postural tremor. Intention tremor
is a symptom of cerebellar dysfunction.
In patients with EPS a consistent finding is high central D2-receptor occupancy (>
80%) as demonstrated with positron emission tomography (PET).
Akathisia – onset within weeks, motor restlessness and inability to sit still.
Anticholinergics not very helpful, b Blockers or Benzodiazepines need to be used or
consider reducing dosage of antipsychotics. Akathisia is caused by D2 activity
deficiency in the basal ganglia.
29
Tardive dyskinesia – Onset within months of starting neuroleptic. Involuntary

movements including lip smacking, sucking, facial grimacing, & choreoathetoid
movements occur (hyperactivity of nigrostriatal pathway). Advanced age and being
female are the two most consistent risk factors identified in tardive dyskinesia.
Other risks include:
-History of extrapyramidal adverse effects early in the course of neuroleptic
treatment
-Long duration of neuroleptic treatment
-Intermittent or interrupted neuroleptic treatment (drug holidays)
-Being Afro-caribbean
-Organic brain damage
-Having negative symptoms of psychosis or deficit states
-Having diabetes mellitus
-A history of alcohol-related or mood disorder
Anticholinergic medications and either discontinuing or reducing antipsychotics
tend to worsen TD. Management includes stopping the drug, shifting to atypical
antipsychotics, Vitamin E (not proven), or clozapine.
Concurrent administration of anticholinergic agents with neuroleptic drugs has

been blamed for increasing the risk of developing tardive dyskinesia. This
assumption has been strongly suggested by both uncontrolled (Fann & Lake, 1974;
Chouinard et al, 1979; Klawans & Rubovits, 1974; Gerlach, 1977) and controlled
(Gerlach & Thorsen, 1976; Greil et al, 1984) studies. The administration of
anticholinergic drugs to patients with tardive dyskinesia was found to lead to
exacerbation of tardive dyskinesia (Turek et al, 1972; Chouinard et al, 1979), while
withdrawal of anticholinergic medication led to a significant reduction in the
severity of tardive dyskinesia (Burnett et al, 1980; Reunanen et al, 1988).
Hyperprolactinemia
Hyperprolactinemia is caused by most typical antipsychotics and some atypical
antipsychotics (Risperidone) due to blockade of D2 receptors in the
tuberoinfundibular pathway. It is mostly asymptomatic but may cause
galactorrhoea, amenorrhoea & irregular menstrual cycles in females, gynaecomastia
in men and sexual dysfunction.
Other side effects:
Other side effects include sedation, postural hypotension (a1 adrenoreceptor
blockade), dry mouth, blurred vision, constipation, urinary hesitancy, impaired
ejaculation (anticholinergic), weight gain (5HT2c) and cardiac conduction defects.
All the typical antipsychotics tend to lower the seizure threshold, but the low
potency antipsychotics have greater propensity to do this. Clozapine also lowers the
seizure threshold at higher doses. Chlorpromazine and clozapine are considered as
the most epileptogenic antipsychotics.
The College has asked about the increased risk of neurotoxicity when
antipsychotics or lithium are combined with ECT. The mechanism underlying this
30
interaction is unclear.
Neuroleptic Malignant Syndrome

Uncommon but potentially fatal complication. Main clinical features include
hyperthermia, severe muscular rigidity, autonomic instability (tachycardia,
increased BP, tachynpnoea & increased sweating) & fluctuating consciousness.
Associated with but not the main feature is increased CPK. It occurs early in
treatment, and has occurred more with high potency antipsychotics (haloperidol,
etc.) It is twice as common in males compared to females, and tends to occur in
younger patients. Has an untreated mortality of 10 – 30%.
Management includes discontinuing antipsychotics concerned, supportive measures
(maintaining fluid balance, treating infection & fever etc). Medications that have
been used include Dantrolene, Amantadine, Bromocriptine. L-Dopa and Diazepam.
th
* The Maudsley Prescribing Guidelines, 12 edition, Page 84-88 &102
iv. Atypical antipsychotics.

The atypical antipsychotics drugs are so called due to their reduced frequency of
causing EPSEs. Over the years, questions on atypical antipsychotics are increasing in
the exams, clozapine in particular.
The atypical antipsychotics (risperidone, olanzapine, clozapine, quetiapine &
amisulpiride) have similar pharmacokinetic profile as the typical ones. They only
vary in the side effect profile, due to which they are being increasing used Though
atypical antipsychotics were being recommended as first line, the NICE
Schizophrenia update (2014)** no longer suggests this, placing an emphasis on
making individual choices as a result of a discussion of the options and side-effect
profiles with the patient and their current physical co-morbidities. This follows a
number of studies showing that atypical antipsychotics (with the exception of
clozapine) have the same efficacy as typicals.
The anticholinergic, antiadrenergic and antihistaminergic side effects are similar.
Atypicals do cause less EPSEs. Weight gain and metabolic side effects is the main
issue the atypical antipsychotics.
Risperidone and olanzapine have been associated with increased risk of stroke in
dementia patients with behavioural problems. CSM has advised against their use in
these patients.
Olanzapine, risperidone & clozapine are associated with increased incidence of
impaired glucose metabolism and even cases of diabetes. Though weight gain is
considered to be a contributing factor, the exact mechanism causing diabetes is not
clearly known. Diabetes can occur without associated weight gain.
th
** The Maudsley Prescribing Guidelines, 12 edition, Page 59-60
31
Olanzapine IM should not be combined with an IM benzodiazepine as this could

result in a rapid postural hypotension. It is advisable that there is at least 30minutes
to 1 hour gap between using Olanzapine IM and IM benzodiazepines to prevent the
rapid postural hypotension.
Thioridazine, due to its cardiotoxic effects was linked with sudden death in adult
patients taking this medication, it should not be used first line.
Clozapine
Clozapine was the first SDA to be approved. What explains its atypicality?
a. Preclinical studies in rats showed that clozapine (prototype atypical) blocks
the conditioned avoidance response, indicating that the drug has potential
antipsychotic activity. On the other hand, it did not produce catalepsy in
animals, suggesting that it is unlikely to produce extrapyramidal symptoms
in man.
b. Because its D2 receptor activity is lower than that of traditional antipsychotic
agents and its 5-HT2 receptor blockade is stronger than that of haloperidol.
Herbert Meltzer has proposed that the differential antipsychotic effect of
clozapine (atypicals) is related to its low D2 to 5-HT2 ratio. Clozapine's
affinity for the 5-HT2 receptor is among the highest for antipsychotic agents.
c. It has a selective preference for the mesolimbic dopamine system. D2-
receptor blockade in the striatum by conventional agents may interfere with
their antipsychotic effects and induce negative symptoms.
How is clozapine different from other atypicals?
• Clozapine also has a 10-fold higher affinity for the D4 dopamine
receptor than other antipsychotic agents. The D4 receptor is present
in the cortex and less so in the striatal areas. Which receptor system is
responsible for the clinical difference between conventional and novel
antipsychotic agents remains unknown.
• Using PET scans Kapur has demonstrated that clozapine occupies D2
receptor in a less tight bonding, so it stays on the receptor site for a
shorter interval – leading to lesser EPSEs than typicals. This ‘hit and
run model’ may suit quetiapine too.
Clozapine shows greater efficacy in schizophrenia, effect in treatment-resistant
patients, and low risk for extrapyramidal effects. Its adverse-effect profile keeps it
from being prescribed for first-episode patients. At this time clozapine remains the
gold standard for treatment of treatment-resistant patients. Clozapine undergoes
extensive first-pass metabolism in the liver and gut. Bioavailability after oral
administration varies from 27 to 47 percent.
Clozapine does not increase prolactin levels, has a low incidence of causing EPSEs,
but is known to cause several other side effects, including, hypersalivation (most
common), drowsiness, orthostatic hypotension, hypertension, weight gain,
hyperthermia, seizures, myocarditis, paralytic ileus, NMS and importantly
32
agranulocytosis. Clozapine is also implicated in causing significant weight gain and

glucose abnormalities including diabetes. Parkinson’s is not a contraindication for
clozapine use as it does not cause EPSE. In fact for Parkinson related psychosis,
clozapine was the preferred drug before the discovery of quetiapine.
Hypersalivation is commonly seen in clozapine treatment. It is unclear whether
clozapine increases salivation through its muscarinic M4 receptor activation and/or
blockade of alpha2-adrenoceptors, or by causing a distortion in swallowing reflex.
Agranulocytosis occurs in 1-2% of patients receiving clozapine, and hence
monitoring of the blood count is required during its use. Pancytopenia is a
reduction in all the blood cells and is not a clinically significant side effect of
clozapine, whereas agranulocytosis is reduction in the neutrophils and is a
potentially fatal side effect of clozapine use. Other haematological abnormalities
include leucopenia, leucocytosis, eosinophilia and thrombocytopenia.
Concurrent administration of clozapine and carbamazepine results in considerable
reductions in plasma clozapine concentrations. It appears that carbamazepine
reduces plasma clozapine concentrations by an average of 50%. Carbamazepine is a
potent inducer of hepatic metabolic enzymes involved in the cytochrome P450
enzyme system. While the mechanism of this interaction has not been fully
delineated, it is suspected that carbamazepine enhances the hepatic microsomal
metabolism of clozapine. Additionally, the risk of agranulocytosis may increase
during concomitant administration as both agents have been reported to induce
agranulocytosis. Concurrent treatment with clozapine and carbamazepine is not
recommended. If concurrent therapy is warranted, clozapine levels should be
monitored during initiation or withdrawal of carbamazepine therapy as clozapine
dosage adjustments may be necessary. Carbamazepine is also known to lead to
leucopenia, which will work in synergy with Clozapine's ability to reduce white cell
counts.
Aripiprazole is a highly lipid soluble quinolinone derivative that can be given in a
once-a-day dosage. Extrapyramidal adverse effects are similar to those with placebo.
Prolactin concentrations did not increase with aripiprazole at 4 weeks. The drug
stimulates dopamine autoreceptors, with a D2 antagonism at postsynaptic D2
receptors in the same dose range. It also blocks 5-HT2 and alpha1 receptors. It is
marketed as a dopamine stabiliser, due to its partial agonist effect, it increases
dopaminergic action at sites of deficiency while blocking the action at sites of
excessive availability, making it an ideal dopamine modulator in schizophrenia
where site specific alterations are seen in dopamine availability - increased in
mesolimbic (positive symptoms), reduced in mesocortical (negative symptoms) and
not disturbed nigrostriatally (more or less normal levels). Fluoxetine and paroxetine
inhibit the metabolism of aripiprazole (therefore the dose of aripiprazole may need
to be reduced if coadministered).
Comparison Table of Adverse Effects of some common atypical antipsychotics
Drug aripiprazole clozapine olanzapine quetiapine risperidone ziprasidone
anticholinergic +/- +++ + + +/- +/-
33
EPSEs + +/- + +/- ++ +/-

hyperprolactine +/- +/- +/- +/- +++ +
mia
QTc +/- + + + + ++
prolongation
Weight Gain +/- ++++ ++++ +++ ++ +/-
Metabolic +/- ++++ ++++ ++ ++ +/-
issues
Diabetes +/- ++++ ++++ ++ ++ +/-
Sedation +/- +++ ++ +++ + +/-
Hypotension + +++ + ++ + +
v. Prescribing in Special groups17

Use Avoid
Under 18s For schizophrenia and bipolar: Ziprasidone
Same as adults but metabolic
side-effects more likely
Sexual Aripiprazole
dysfunction
Epilepsy Haloperidol, sulpiride Clozapine, depots
Diabetes Amisulpiride, Aripiprazole and Risperidone,
ziprasidone quetiapine, olanzapine,
clozapine
Pregnancy Most evidence for older
medication (haloperidol,
chlorpromazine and
trifluoperazine). No evidence for
any antipsychotic being
teratogenic.
Breast Sulpiride and olanzapine
feeding
Hepatic Low dose haloperidol
impairment Sulpiride and amisulpiride
Renal Haloperidol Sulpiride and
impairment Olanzapine amisulpiride
17
Maudsley guidelines, 12th edition Pg 124, 137, 544, 633.
34
Highly anticholinergic
agents (®urinary
retention)
VIII. Antimanic and Prophylactic drugs

i. Lithium:
Lithium is the most used mood stabilizer medication, with evidence for use in acute
treatment of mania, prophylaxis in unipolar and bipolar mood disorders,
augmentation therapy in depression and in aggressive behaviour.
Lithium is the smallest solid element. It is not lipid soluble and not bound to the
plasma proteins. It is absorbed by passive diffusion, is distributed throughout the
body fluids and cells (hence doesn’t have a high lipid partition coefficient), and
secreted unchanged by the kidneys. It is also excreted in sweat, saliva, tears, breast
milk and faeces (less than 5%). As it is in the unbound form it is freely filtered by
the kidneys along with sodium and potassium. However, most of lithium is
reabsorbed in the proximal tubules in competition with sodium. This is a very
important mechanism by which much toxicity tends to occur. In dehydration and
when drugs that cause sodium depletion (e.g. diuretics) are used, more lithium is
reabsorbed by the proximal tubules leading to toxicity.
The mechanism of action of lithium is not clearly known, but it is known to inhibit
formation of cAMP and inositol monophosphatase, reducing brain inositol levels.
The other actions include membrane stabilising effects, and increasing
monoaminergic reuptake.
The adverse events including toxicity & drug interactions form the bulk of the
questions on Lithium.
Common side effects include:
• Metallic taste (this is an infrequent side effect, not usually troublesome
caused by salivary secretion), nausea, epigastric discomfort, vomiting,
constipation, weight gain (more in women)
• Polyuria & polydipsia, ¯ tubular concentrating capacity, interstitial
nephropathy
• Benign T wave changes (on ECG) & sinus node dysfunction
• Hair loss, acne, worsening of psoriasis.
• Hyperthyroidism (early & uncommon), hypothyroidism (thyroid dysfunction
secondary to lithium treatment is more frequent in women, especially above
45 years of age), hyperparathyroidism (not hypoparathyroidism -
hyperparathyroidism is clinically very rare, and may be actually due to
idiosyncratic predisposition to such parathyroid dysfunction.),
hypercalcemia, parathyroid adenoma.
• Tremor – fine & postural, memory difficulties.
• Leucocytosis.
35
Lithium induced polyuria should be initially managed with dose reduction and
change in dosage distribution. If such measures prove inadequate, potassium
supplementation may be attempted. Pharmacologic interventions included
amiloride and amiloride-hydrochlorothiazide combinations are occasionally
necessary. Indomethacin is available in cases in which immediate normalization of
polyuria is necessary.
Periodic monitoring of serum calcium levels during lithium therapy is warranted.

Hypercalcemia should be considered in any patient who becomes delirious or who
develops any of the symptoms noted above. Hypercalcemia should also be
considered in any patient who becomes refractory to lithium after an initial
response. Any patient who is noted to be hypercalcemic or to have
hyperparathyroidism prior to initiation of mood stabilizer therapy should not
receive lithium, and patients who develop lithium-induced parathyroid dysfunction
should be switched to an alternate mood stabilizer. After discontinuation of lithium
therapy, PTH levels may remain elevated for months but in most cases the
hyperparathyroid state is reversible and should not prompt premature surgical
intervention.
Lithium hypothyroidism is more common in middle aged women. Some reports

have described prevalence in this group as high as 20%
For women who need a mood stabilizer during pregnancy, lithium is the safest
option; however, when used during the first trimester, it carries a 0.1% risk of a
cardiac malformation called Ebstein's anomaly. Ebstein's anomaly is a heart defect
in which the tricuspid valve is abnormally formed. The tricuspid valve normally has
three "flaps" or leaflets. In Ebstein's anomaly, one or two of the three leaflets are
stuck to the wall of the heart and don't move normally. Often there is also an atrial
septal defect. Lithium is contraindicated during breast-feeding.
Lithium toxicity can occur due to excessive intake, reduced excretion (renal disease,
low sodium diet, drug interaction – diuretics, ACEIs & anti-inflammatory drugs),
reduced volume (dehydration) and increased sensitivity (elderly). The signs include
ataxia, coarse tremor, dysarthria, confusion, seizures, coma & death. Treatment is
directed at removal of lithium by forced alkaline diuresis or haemodialysis.
Coarsening of tremor may also be simply due to ageing of the patient.
NMS has been associated with lithium use.
Drug interactions: Pharmacokinetic
Diuretics increase serum lithium levels due to reasons mentioned above. Similarly
most NSAIDs reduce lithium clearance and increase its concentration. These drugs
include indomethacin, ibuprofen, diclofenac etc. Aspirin is an exception.
One of the actions of lithium is potentiating 5-HT function, so when it is used with
SSRIs a serotonin syndrome has been described.
36
Neurotoxicity has been described with co-administration of lithium & CBZ, but they
can be used together with caution. There is also increased risk of neurotoxicity with
co-administration of lithium and antipsychotics (note however, that lithium does
not increase haloperidol levels).
The antipsychotics are as effective as lithium in treatment of acute manic episode,
however only lithium, valproate and olanzapine are licensed for use in prophylaxis
of bipolar disorders. Lithium efficacy as prophylaxis of unipolar depressive disorder
is established as being equal to that of antidepressants.
ii. Anticonvulsants:
The evidence for use of anticonvulsants in treatment of mood disorders has been
present for some time now, however it was only recently that valproic acid (not
sodium valproate) was granted the license for use in acute manic episodes and in
prophylaxis of bipolar disorders. Carbamazepine has been licensed for use in
prophylaxis of bipolar disorder in patients unresponsive to lithium. CBZ is also
considered more effective than lithium in treatment of rapid cyclers and mixed
affective states.
The rate of neural tube defects in the newborn offspring of women taking sodium
valproate has been estimated at between 1-5%. This is greater than the risk with
carbamazepine (0.5-1%). Women in the reproductive age group on either of these
medications should be taking high dose folate (5mg/day) prior to conception to
reduce the risk of neural tube defects.
Agranulocytosis is a rare, but serious, side effect of carbamazepine. It is due to
idiosyncratic marrow suppression; also lupus like syndrome, Steven Johnson
syndrome and hepatotoxicity are reported.
Carbamazepine induces its own metabolism as an inducer of the cytochrome p450
system. Patients on oral contraceptives will have a failure of contraceptive effect if
continued on same dose following carbamazepine treatment. Carbamazepine
reduces levels of sodium valproate, but by inducing its metabolism via CYP450
instead of mitochondrial beta-oxidation, carbamazepine increases the production
of potentially toxic metabolites, leading to fatal hepatic necrosis at times.
Carbamazepine reduces the effects of various calcium channel blockers including
felodipine and isradipine; other Ca-Channel Blockers like verapamil, diltiazem can
reduce carbamazepine metabolism via CYP3A4 leading to toxicity. Carbamazepine
can cause hyponatraemia due to inappropriate ADH secretion - leading to oedema;
hypocalcemia is also noted.
Weight gain is problematic with valproate. Whether this is causally linked to
occurrence of polycystic ovary syndrome in epileptic patients taking valproate is
unclear. Except topiramate, which causes weight loss, most antiepileptics cause
weight gain. Sodium valproate increases carbamazepine, clomipramine,
phenobarbitone and lamotrigine levels. This may mean increased incidence of
toxicity due to lamotrigine.
37
Phenytoin is a prototype anticonvulsant with no proven psychiatric use. Its adverse

effects are sedation, ataxia, diplopia, acne, gingival overgrowth, hirsutism,
osteomalacia, hematotoxicity (granulocytopenia, megaloblastic anaemia).
Recently there have been a couple of questions concerning topiramate. This mood
stabiliser is mentioned in the Maudsley guidelines as being useful in acute manic
states. It is not used for prophylaxis. 1.5% of people taking this drug develop renal
calculi, which is 10 times the rate of placebo. The BNF therefore advises all patients
prescribed this medication to maintain adequate hydration.
The mechanism of action of the anticonvulsants is frequently asked, a table for easy
reference is provided.
Drug Mechanism of Notable side effects Drug Interactions

action
Sodium valproate Potentiates GI effects, weight gain, Doesn’t not induce /
GABA function alopecia, tremor, inhibit Cyt P450.
sedation, PCOD Increases CBZ levels and
lamotrigine levels
Carbamazepine Block sodium Dizziness, drowsiness, Induces Cyt P450.
channels ataxia, agranulocytosis Induces own metabolism,
(rare), cardiac reduces levels of OCP,
conduction defects, warfarin, valproate,
hyponatremia, rash antidepressants etc.
etc.
Lamotrigine Block sodium A rash is commonly Inhibit Cyt P450.
channels. Also, seen in lamotrigine use CBZ reduces levels.
it indirectly - rarely this can
inhibits the develop into Stevens-
presynaptic Johnson's syndrome.
release of
glutamate and
aspartate;
reduces calcium
entry through
voltage-
sensitive
calcium
channels.
Phenytoin Blocks sodium Nystagmus, ataxia, Induces Cyt P450.
channels dizziness, dyskinesias, Antacid/Calcium impairs
polyneuropathy, SJS GI absorption
Gabapentin GABA Sedation, dizziness Doesn’t not induce /
potentiation ataxia inhibit Cyt P450.
Topiramate Both block Psychomotor slowing, CBZ & Valproate lower its
sodium drowsiness concentration
channels &
GABA
potentiation.
38
Vigabatrin and valproate inhibit GABA transaminase. Vi + gaba + transaminase +

inhibitor = vigabatrin.
iii. Prescribing in special groups18
Use Avoid
Under 18s Lithium, valproate (in boys) Valproate in girls (as it
increases risk of developing
polycystic ovary syndrome and
is teratogenic)
Pregnancy Antipsychotics if possible All anticonvulsants
Lithium in 1st trimester of
pregnancy
Breast feeding Antipsychotics best
Can use valproate but may
cause hepatotoxicity in
infant
Hepatic Lithium
impairment
Renal impairment Valproate, carbamazepine, Lithium
lamotrigine starting at low
dose
IX. Hypnotics & sedatives

Benzodiazepines
Benzodiazepines act as agonists at the a subunit of the GABA A receptor complex.
They potentiate the GABA inhibitory effects on the CNS by increasing the number
and frequency of chloride channels opened, rather than prolonging the duration of
open state of a few. Caffeine is known to counteract the effects of benzodiazepines,
but the exact mechanism is still unclear. Uncoupling of BDZ-GABA interaction is
suspected.
BDZs suppress REM sleep. They also increase slow wave sleep especially phase 2.
Sudden withdrawal of benzodiazepines can cause REM rebound - the suppressed
REM bounces back with vengeance!
All benzodiazepines are lipophilic except clorazepate. This quality makes them
effective as inducing agents in anaesthesia where rapid crossing of lipid membranes
is needed. Flurazepam is 10% more lipid soluble than diazepam, while temazepam
and lorazepam are only 50% as lipid soluble as diazepam. Midazolam is 50% more
soluble than diazepam, making is a suitable anaesthetic agent.
18
Maudsley guidelines, 12th edition Pg 551, 569-570, 578, 594
39
The benzodiazepines are metabolised in the liver (mostly by CYP3A4) but do not
induce or inhibit the liver enzymes. Some inhibitors of the enzymes like cimetidine
decrease their metabolism, leading to increase plasma levels. Benzodiazepines can
have a significant interaction with methadone, leading to increased levels of
methadone and potential accidental overdose.
Apart from dependence, they cause drowsiness, ataxia and impairment in new
learning and anterograde amnesia. It can also cause respiratory depression when
used in the parenteral form. Flumazenil is a benzodiazepine antagonist that can be
used to reverse its effects. Withdrawal symptoms include anxiety, irritability,
dizziness, depersonalisation / derealisation, increased sensory perception &
abnormal perception.
Half Lives and equivalent dosages of common benzodiazepines#

T1/2 (hours)[active metabolite] Equivalent oral dose (mg)
Alprazolam 6-12 0.5
Oxazepam 4-15 15
Lorazepam 10-20 1
Diazepam 20-100 [36-200] 5
Chlordiazepoxide 5-30 [36-200] 25
Clonazepam 18-50 0.25
Temazepam 8-22 15
# Comprehensive Textbook of Psychiatry, 9th Ed Page 3053
Z drugs
Zaloplon, zolpidem and zopiclone are non-benzodiazepine hypnotics, but they act
at the benzodiazepine receptor and are also reversed by flumenazil. Zolpidem, an
imidazopyridine, acts selectively at benzodiazepine receptors w1; zopiclone, a
cyclopyrrolone, also interacts with GABA A complex, but slightly different in its
allosteric positive modulation of chloride channels. Zopiclone, the now popular
hypnotic also mediates its action via the same receptor complex as benzodiazepine.
It is considered to be less dependence producing than the benzodiazepines, but still
retains dependence potential.
Zaloplon offers the shortest t1/2 (1 hour), zolpidem (2.4) and zolpiclone (5).
Older drugs:
• Chloral hydrate acts on GABA receptors and was previously used in children.
It is still licensed for use in insomnia in adults.
• Barbiturates also act on GABA –A but at a different site to benzodiazepines.
They create a stronger sense of euphoria and tranquillity.
40
Other Drugs:
• Buspirone is a 5HT 1A partial agonist used in the treatment of generalised
anxiety disorder. It is not known to cause tolerance or dependence (till
now!). It cannot be used for treating acute anxiety, as the anxiolytic effects
takes time (10-14 days) to develop.
• Phenobarbitones are used to treat epilepsy but may be sedative in adults,
although they can cause paradoxical excitement, restlessness and confusion
in the elderly and hyperkinesia in children.
• Propranolol is an b adrenergic blocker, which is lipid soluble, and hence
easily crosses the BBB. In contrast some b adrenergic blocker like atenolol
and nadolol are not that lipid soluble, hence cross the BBB poorly.
Propranolol is used for treatment of performance anxiety, lithium induced
tremor and akathisia.
• Hydroxyzine, a first-generation antihistamine has an anxiolytic effect, along
with sedative hypnotic and tranquilizing. It has little of abuse, dependence
and addiction potential of the benzodiazepines. It can cause dizziness, GI
upset, hypotension and antimuscarinic side effects.
• SSRIs, although also used to treat anxiety, are not classed as anxiolytics (see
above).
Prescribing in special groups19
Use
Under 18s Benzodiazepines are used to alleviate acute
anxiety but are not recommended for long-term
use.
Melatonin is usually used for sleep problems
Pregnancy Benzodiazepines probably safe
Promethazine used, but little evidence
Breast feeding Lorazepam
Zolpidem for sleep
Hepatic Short half-life medication – lorazepam, oxazepam,
impairment temazepam. Sedatives can precipitate hepatic
encephalopathy
Renal impairment No specific data that one agent is preferable.
X. Drugs used in substance misuse disorders.

1. Alcohol:
19
Maudsley guidelines, 12th ed.
41
Pharmacological management of alcohol dependence can be divided into

detoxification, maintenance and relapse prevention.
Detoxification
The treatment of withdrawal is with long acting benzodiazepines like
chlordiazepoxide, given in decreasing doses for 5-7 days. For patients with hepatic
impairment, shorter acting benzodiazepine such as oxazepam or lorazepam is
preferred20. For patients with previous history of seizures, carbamazepine can be
started prior to detox. Other medications including parenteral/oral thiamine,
multivitamins, antiemetics etc. need to be used. Studies show that lower overall
doses of benzodiazepines can be used if the dose is continually adjusted to the
severity of symptoms – for example by calculating clinical need over the first 24
hours, and then introducing a 5-day reducing regime using this as a baseline. 21
Although outpatient detoxification is less expensive and almost as effective, it is not
a viable option in those with severe withdrawal reactions (including fits or
delirium), those lacking a stable home environment or supportive partner/friend,
those at risk of serious self-harm and those unable to travel to the outpatient unit.
Chlomethiazole is also licensed to be used in alcohol withdrawal. However, due to
its interaction with alcohol it poses a danger in patients who may continue to drink
and is rarely used22.
Wernicke’s encephalopathy may present in patients undergoing detoxification. The
classic triad is opthalmoplegia, ataxia and confusion, but this is rarely present.
However clinicians are encouraged to have a high level of suspicion. Wernicke’s
encephalopathy should be treated with 4 ampoules of high potency B complex
vitamins three times a day for 2 days23.
Maintenance
The pharmacological treatments for maintenance include disulfiram, acamprosate
and naltrexone. Disulfiram acts as an aversive agent, by negative reinforcement,
through blocking the aldehyde dehydrogenase enzyme that normally metabolises
acetaldehyde – this leads to accumulation of acetaldehyde and unpleasant side
effects such as flushing, headache, palpitations, nausea and vomiting, even with
small intake of alcohol. Larger alcohol intake can lead to hypotension and collapse.
Disulfiram should only be prescribed to patients who are physically healthy and
understand the possible adverse effects of drinking whilst on the drug.
Acamprosate enhances GABA transmission and appears to restore normal NMDA
receptor tone in glutamatergic systems. The drug works by reducing craving for
alcohol. It has been shown in meta-analyses to reduce alcohol relapse if given early
in the course of alcohol detoxification. Studies of acamprosate have excluded the
elderly, so there is no good evidence in this age group yet. 24
20
Maudsley guidelines, 12th edition, Pages 415-418
21
Saitz. 1998. Alcohol Health and Research World 22(1): 5-12
22
BNF 60 (September 2010) http://bnf.org/bnf/bnf/current/3163.htm
23
Maudsley guidelines, 12th edition, Pages 415-418
24
Tempesta et al. 2000. Alcohol & Alcoholism 35(2): 202-209
42
Naltrexone is an opioid antagonist. The use of naltrexone can reduce relapse in

alcohol dependence. A meta-analysis of naltrexone showed that in the short term at
least, it significantly decreases relapse in alcohol-dependent patients (Srisurapanont
et al).25 Any two of these three medications for relapse prevention can be used in
combination in severe cases, with an additive effect. 26
2. Opioids
Opioids include heroin, morphine, codeine, methadone and pethidine (last two are
synthetic analogues, while the others are naturally occurring substances). Heroin is
the most abused opiate. Heroin is around three times more potent than morphine,
and causes euphoriant effects within seconds – minutes of usage. Side effects of
acute intoxication include nausea/vomiting, constipation, pupillary constriction,
drowsiness and respiratory depression. Overdose can be treated by Naloxone – an
opioid antagonist with a short half-life.
The concerns with opioid dependence include overdose (which can be fatal),
infections (Hep B, HIV, Hep C), other medical complications including
endocarditis, septicaemia, pulmonary oedema etc. There are huge social and
psychological consequences common to other forms of drug dependence, though
psychosis is not associated with opiates.
The rate of stillbirths is increased in heroin addiction, but there is no increase in
congenital abnormalities. The neonate can undergo opiate withdrawal with
irritability, high-pitched cry, tremors, hypertonicity, diarrhoea and vomiting,
tachypnoea.
Withdrawal - Peaks 32-36 hrs after last dose and subsides by 5 days. They are
unpleasant but not life-threatening. Symptoms include restlessness, lacrimation,
rhinorrhea, yawning, sweating, piloerection, muscle cramps, nausea, vomiting,
diarrhoea.
Treatment
In direct treatment of withdrawal: methadone is the mainstay of treatment. This is
a synthetic opiate with a long half-life. Initial dose established by titrating it
against withdrawal symptoms (30mg is a typical effective dose). Dose can be
reduced over 2-3 weeks or continued as maintenance for as long as needed.
Buprenorphine (a partial agonist) can also be used for withdrawal, but can actually
precipitate a withdrawal (due to its relatively high affinity it can displace other
opiates).
Lofexidine or clonidine which are centrally acting alpha 2 agonists along with other
medications to decrease effect of withdrawal symptoms are used in conjunction in
the initial week of treatment. Buprenorphine or Methadone can be used as
substitutes. Loperamide may be used for diarrhoea.
Methadone and buprenorphine can both be used in maintenance therapy and have
been shown to reduce the rate of relapse. They both require strict monitoring in
25
Srisurapanont et al. 2005. Int J Neuropsychopharmacol 8(2): 267-280
26
Wilde et al. 1997. Drugs 53(6): 1038-1053
43
specialised programs. Naltrexone (a longer acting opioid antagonist) can also be

used in relapse prevention, though not if the person continues opioid use, as this
precipitates a withdrawal state. It can also be used for rapid detox.
3. Stimulants:
Amphetamine: acute use may lead to euphoria, excitement, hyperalertness,
irritability & psychotic experiences including paranoia, delusions and
hallucinations. Chronic use may lead to depression, lethargy, tolerance and
psychological dependence in the long term. Amphetamines act by increasing
release, blocking uptake and reducing storage of dopamine. It does not produce
physical dependence but a withdrawal syndrome for amphetamine has been
reported.
The medical use now is restricted to narcolepsy and hyperactivity disorders in
childhood. The treatment of acute overdose is supportive. Longer term treatment
should involve a number of agencies, as well as a variety of techniques (advice,
counselling, harm reduction, motivation interviewing, CBT, group therapy).
Khat is a plant found in tropical East Africa which produces an alkaloid with an
amphetamine-like effect.
Cocaine is a stimulant that is mainly inhaled. It causes increased energy, increased
confidence, euphoria, and diminished need for sleep. Its effects can be analogous to
mania. Cocaine acts by blocking the reuptake of dopamine into presynaptic
dopamine terminals. Hallucinations and psychotic states (usually short lived,
occasionally up to a month) are known to occur with its use. Dysphoria follows the
high usually. Crack cocaine is produced by alkalinisation (‘free-basing’) and is more
potent than cocaine. Does not produce dependence syndrome but causes a strong
psychological dependence. PET studies suggest altered blood flow in anterior
cingulate and amygdala in cocaine users when subjected to drug-related cues.27
There is no association between somatisation and cocaine use.
Treatment of withdrawal has been attempted with dopamine analogues, but with
limited success. Desipramine is a tricyclic antidepressant that has some efficacy in
treating the depressive symptoms following withdrawal as well as shortening the
period of craving after withdrawal.28
Other drugs that increase extracellular dopamine by stimulating dopamine release
(dexamfetamine), inhibiting dopamine reuptake (bupropion and modafinil), or
inhibiting dopamine metabolism (disulfiram) have been tried. However the results
are inconclusive and most of these medications have substantial side-effects.#
Ecstasy (MDMA) acts as an agonist at the serotonin 2A receptor29, and is both a

stimulant and a hallucinogenic. Chronic use is associated with neurotoxicity,
hepatotoxicity and cognitive impairment.30 It does not produce dependence.
# The Maudsley Prescribing Guidelines, 12th edition, Page 463

28
Cornish et al. 2005. Psychopharmacology Jan: 29
29
Stahl’s essential psychopharmocology, 3rd edition, p. 992
44
Toxicity is idiosyncratic. Adverse effects include hyperthermia, seizures,

arrhythmias, hyponatraemia, bruxism and depression and psychosis.
LSD also acts on serotonin 2A receptors and is hallucinogenic. Its actions are
situation and expectation dependent. There is mild euphoria, a sense of
detachment, a sense of novelty, synaesthesia. It causes papillary dilation.
Dependence does not occur. Bad trips – Dissociations, frightening perceptions do
occur. Panic and avoidance states are well-described in LSD. The hallucinogenic
ingredient in magic mushrooms is psilocybin.
PCP Phenylcyclidine is similar to ketamine (NMDA blocker), leads to confusion,
sensory distortion, aggression and sudden violence.
4. Other Substances:
Cannabis Active ingredient is delta-9-tetrahydrocannabinol (THC). Immediate
effects include mild euphoria, subjective sense of enhanced sensation, relaxation
and increased appetite. This may be associated with mild paranoia, panic attacks
and delayed reaction time. Chronic effects include amotivational syndrome,
psychosis and anxiety or depression.
Nicotine increases the dopamine levels in the mesolimbic areas, which acts on the
reward pathway in the brain.31 Smoking is seen in about 28% of people in the UK.
Nicotine withdrawal involves irritability, anxiety and headaches. Despite the fact
nicotine is a stimulant a smoker may feel calmer after smoking, due to relief from
nicotine withdrawal. Nicotine reaches the brain in 5-6 seconds after inhalation.
Rate of smoking in schizophrenia is 1.6 times the rest of the population.
Bupropion is a noradrenaline and dopamine re-uptake inhibitor and it is
recommended as an adjunct to nicotine replacement therapy in the NICE
guidelines. It reduces craving during nicotine withdrawal. Trials show 1-year
abstinence rates of 30% with bupropion, 16% with nicotine patches and 15% for
placebo. Combination of bupropion and nicotine patches increased abstinence rate
to 35%. 32 It can also be used as an adjunct for treating refractory depression. There
is, however, a 1 in 1000 risk of seizures33.
Varenicline Tartrate (also known as Champix) is a selective a4, b2 nicotinic
acetylcholine partial agonist and now appears in the NICE guidelines for smoking
cessation. Depression and suicidality have been noted as its side-effects34.
XI. Antidementia drugs

Anticholinesterases are the main drugs used in the treatment of Alzheimer’s
dementia. These drugs inhibit acteylcholinesterase, an enzyme that degrades
acetylcholine, thus leading to increased availability of acetylcholine. In trials all
30
Burgess et al. 2000. European Psychiatry 15(5): 287-294
31
Griesar et al. 2002 Nicotine & Tobacco Research 4(2): 185-194
32
Kendler et al 1999. Psychological Medicine 29: 299-308
33
Maudsley guidelines, 12th edition, p. 460
34
Maudsley guidelines, 12th edition, p. 461
45
anticholinesterases showed similar efficacy with ⅓ of patients improving over 6

months and a further ⅓ not showing deterioration in 6 months.
Donepezil and galantamine are selective inhibitors of acteylcholinesterase, while
rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase. They
have similar efficacy in treating cognitive symptoms. Rivastigmine and galantamine
require twice daily dosing as against donezepil, which is given once a day. NICE has
provided guidance about their usage which we have summarised below. Studies
have shown that anticholinesterases are also effective in the treatment of Lewy
Body dementia (which has marked acetylcholine depletion).
Memantine is a NMDA receptor inhibitor, and is considered to be neuroprotective
and disease modifying. Though there are trials of its benefit in vascular dementia, it
is not licensed to be used in vascular dementia.
The main pharmacological properties of these medications are summarised below:#
Drug Type Site of Side effects

metabolism and
half life
Donepezil Reversible cholinesterase Liver Dose related nausea
inhibitor. High specificity for and diarrhoea, rarer
Long half life (70
acetylcholinesterase over side effects include
hours). Once
butrylcholinesterase which ulcers, cardiac
daily dosing
may reduce peripheral side conduction blocks,
effects TIAs
Rivastigmine Reversible cholinesterase Non-hepatic, As above ( more
inhibitor short half life peripheral side effects)
(less than 2
hours). Twice
daily dosing.
Least likely to
have interactions
Galantamine Tertiary Alkaloid Liver GI effects, rarer-
arrhythmias, fainting,
Selective and reversible Short half life
urinary difficulties, GI
cholinesterase inhibitor
bleeds.
Memantine Non competitive NMDA Primarily non- Hallucinations,
antagonist hepatic confusion
60-80 hours
# Gelder, M et al (2nd ed) New Oxford Textbook of Psychiatry, 2011 Page 1290-91
The three acetylcholinesterase inhibitors donepezil, galantamine and rivastigmine

are recommended as options in the management of people with Alzheimer’s disease
of moderate severity only (MMSE score of between 10 and 20 points) and these
should be initiated by a mental health specialist. Memantine is not recommended
46
as a treatment option for people with moderately severe to severe Alzheimer’s

disease except as part of well-designed clinical studies.
Patients who continue on the drug should be reviewed every 6 months by MMSE
score and global, functional and behavioural assessment. Carers’ views on the
patient’s condition at follow-up should be sought. The drug should only be
continued while the patient’s MMSE score remains at or above 10 points and their
global, functional and behavioural condition remains at a level where the drug is
considered to be having a worthwhile effect.
Any review involving MMSE assessment should be undertaken by an appropriate
specialist team, unless there are locally agreed protocols for shared care. In some
cases it will be acceptable to commence treatment in those with a score greater
than 20 e.g., those who have moderate dementia as judged by significant
impairments in functional ability and personal and social function compared with
premorbid ability.
For people with learning disabilities, tools used to assess the severity of dementia
should be sensitive to their level of competence. Options include Cambridge
Cognitive Examination (CAMCOG), Modified Cambridge Examination for Mental
Disorders of the Elderly (CAMDEX) or the Dementia Scale for Down Syndrome
(DSDS) which can be useful in diagnosis of dementia in people with learning
disability with or without Downs Syndrome.
Pharmacological interventions for the cognitive symptoms of non-Alzheimer
dementias and MCI:
• For people with vascular dementia, acetylcholinesterase inhibitors and
memantine should not be prescribed for the treatment of cognitive decline,
except as part of properly constructed clinical studies.
• For people with mild cognitive impairment, acetylcholinesterase inhibitors
should not be prescribed, except as part of properly constructed clinical
studies.
• Rivastigmine is licensed for treatment of dementia associated with
Parkinson’s disease
As per recent advice by CSM, risperidone and olanzapine should not be used to
treat behavioural problems in elderly patients with dementia. However they can be
used to treat acute psychotic conditions and schizophrenia in the elderly. Comorbid
psychosis, depression and anxiety can be treated as indicated with caution for
adverse effects especially with atypicals ( SSRIs, SNRIs and valproate may be
adjunctive).
Monitoring for risk factors for stroke in this population is advised. Aspirin and
clopidogrel and indicated in vascular dementia.
XII. Miscellaneous topics

§ Medications used in ADHD
47
Methylphenidate is the most commonly used stimulant in treating ADHD. It blocks

noradrenaline transporters in the frontal cortex and the dopamine transporters in
the nucleus accumbens increasing the levels of dopamine and noradrenaline35.
Atomoxetine is another treatment option, which is recommended if the patient has
co-morbid tics, or if methylphenidate has been poorly tolerated. It is selective
noradrenaline re-uptake inhibitor (NRI) and is similar to the antidepressant
Reboxetine36.
§ Modafinil
Used in the treatment of narcolepsy, but can also be used in depression. Most likely
it acts as weak inhibitor on dopamine transporters, causing decreased dopamine
re-uptake and increased dopamine levels. This in turn leads to activation of the
lateral hypothalamus that releases orexins to promote wakefulness37
§ Rimonabant
Is an antagonist of the cannabinoid 1 receptor. It is approved in some countries for
weight-loss and has been trialled as an antipsychotic but with little effect. Trials to
use it in antipsychotic-induced weight-gain are ongoing38.
§ Cyproterone acetate
Is an androgen receptor antagonist which suppresses the effects of testosterone and
can be used to treat hypersexuality in males. However results are uncertain and
side-effects include gynaecomastia and depression.
§ Miscellaneous
• GABA and the amino acid Glycine are the major inhibitory neurotransmitters.
Glutamate, aspartate, cysteic acid & homocysteic acid are the excitatory
neurotransmitters.
• L-tyrosineàL-DopaàDopamineàNoradrenaline. All the monoamines
(dopamine, Noradrenaline and serotonin) are metabolised by the monoamine
oxidase enzymes.
• Amphetamines act by increasing the synaptic activity of dopamine and
noradrenaline. It increases dopamine by stimulating rapid release, blocking
uptake, and inhibiting its storage. It however does not stimulate the dopamine
receptors.
• 5HT2 antagonists such as trazodone, mirtazapine reduce the impact of
inhibitory effect of serotonin on sexual function.
• All the monoamines (dopamine, noradrenaline and serotonin) are metabolised
by the monoamine oxidase enzymes. Dopamine is metabolised by both MAO
(esp.B) and COMT. HVA - homovanillic acid is the end product.
35
Stahl’s essential psychopharmocology, 3rd edition, p. 887-8
36
Stahl’s essential psychopharmacology, 3rd edition, p. 557
37
Stahl’s essential psychopharmacology. 3rd edition. p. 857
38
Stahl’s essential psychopharmocology, 3rd edition, p. 449
48
• Glutamate, aspartate, cysteic acid and homocysteic acid are the major excitatory
neurotransmitters. Glycine and GABA are major inhibitory ones. GABA is the
most prevalent brain chemical in transmission, occupying about 40% synapses.
GABA is purely brain-only transmitter.
• For the treatment of periodic limb movement in sleep or restless leg syndrome
Dopaminergic agents are currently used as first-line treatments. Newer-
generation dopaminergic agents such as pramipexole and ropinirole have been
used successfully.
• Acetazolamide (250 mg twice daily) can prevent or reduce symptoms of acute
mountain sickness and improve sleep at high altitudes.
XIII. Pharmacogenetics
Pharmacogenetics is a relatively new and exciting field which attempts to integrate
knowledge from both pharmacology and genetic research. Research has
demonstrated that people respond to medication depending upon the type of
variant they have of the enzymes which are responsible for drug metabolism.
Drugs whose principal metabolic pathways are under polymorphic genetic

regulation may show considerable inter-individual pharmacokinetic variability.
This could lead to clinically significant differences in the pharmacological responses
of some patients and so might lead the pharmaceutical industry to stop
development of the drug. This can be prevented and there are several measures that
can be taken to avoid such premature termination of development. They include
studies in vitro with human liver samples, and clinical pharmacological experiments
designed specifically to examine possible genetic polymorphism in the disposition
of the drug.
Deficient metabolic enzymes have been related to drug accumulation and toxic
events. Allelic variants of dopaminergic and serotonergic receptors have been
associated with clinical outcome and adverse events such as movement disorders.
In the future this field hopes to explain variations in treatment outcomes on the
basis of genomic profiles. Below we have reproduced a table (Staddon, 2002) which
illustrates some of the polymorphisms and their associations.
Polymorphisms
Associated with Reference
in
CYP1A2 Movement disorders Basile et al. (2000)
Tardive dyskinesia Kapitany et al. (1998)
CYP2D6
Extra-pyramidal side-effects Scordo et al. (2000)
CYP2C19 Mephenytoin blood levels Ferguson et al. (1998)
D2 Short-term neuroleptic response Malhotra et al. (1999)
49
Polymorphisms
Associated with Reference
in
Schafer et al. (2001)
Clozapine response Scharfetter et al. (1998)
Steen et al. (1997)
D3 Kapitany et al. (1998)
Tardive dyskinesia
Segman et al. (2000)
Ozdemir et al. (2001)
D4 Clozapine response Shaikh et al. (1993)
Arranz et al. (1995,
5-HT2A Clozapine response
1998b)
Clozapine response Sodhi et al. (1995)
5-HT2C
Tardive dyskinesia Segman et al. (2000)
5-HT6 Clozapine response Yu et al. (1999)
Smeraldi et al. (1998)
5-HTT Response to SSRIs
Kim et al. (2000)
5-HTs, 5-HTT, H2 Clozapine response prediction Arranz et al. (2000)
Alzheimer's disease treatment
APOE, PS1 and PS2 Cacabelos et al. (2000)
response
For cytochrome P450 2D6, poor metabolizer status is inherited as an autosomal

recessive trait.
XIV. Summary of Pharmacological Intervention Guidance
50
Disorder NICE guidance Additional Influential studies

guidance from
the Maudsley
• Typical or atypical In resistant cases: CUtLASS Study
oral medication first
• Amisulpiride • found that first
depending on patient
and generation and
profile, and choice
Schizophrenia haloperidol second generation
39 • Avoid combinations
show some antipsychotics have
• Relapse risk greatest effect for similar efficacies
for 1-2 years after clozapine and little difference
stopping meds augmentation in side-effects
• Found clozapine to
be the only
• In resistant cases:
antipsychotic which
• If have not
is more effective
responded to 2
antipsychotics, one CATIE Study
of which is atypical – • No difference in
consider clozapine efficacy of typical
and atypical
antipsychotics
• EPSEs as common
in atypicals
• Patients stayed
longest on
risperidone
• Generic SSRI first In resistant cases: STAR*D

• Another SSRI or
• SSRI + • 28% of patients
Mirtazapine can be
Buproprion responded to 1st line
second line
• Or treatment
• Continue for at least
Depression40 SSRI/venlafax • Augmentation
6 months after
ine with buspirone and
remission
+Mianserin/ Bupropion could be
mirtazapine worthwhile
• In resistant cases:
• T3
• Consider another augmentation and
class of drug (e.g. Post stroke: Nortriptyline
TCA, venlafaxine) augmentation both had
• Augment with • SSRI
(citalopram better results than Li
Lithium / augmentation
antipsychotic/mirtaz has lowest
apine/mianserin interaction
• Don’t augment with potential)
benzodiazepines (<2
weeks), buspirone,
pindolol, valproate,
Lamotrigine, thyroid
39
Psychosis & schizophrenia in adults: treatment and management (2014). NICE Guideline
40
Depression in adults. The treatment and management of depression in adults (2014). NICE Guideline
51
harmones,
Carbamazepine.
Disease NICE guidance Additional guidance

from the Maudsley
Acute Mania • Topiramate may be used
for acute manic state, but
• Haloperidone, Olanzapine, not for prophylaxis
risperidone or quetiapine
• Stop antidepressants if they are • Lamotrigine may be
Bipolar 41
taking it useful in treatment of
• If no response to 1st depression
antipsychotic, offer second one • Li may be less effective in
from above rapid cycling bipolar
• If no response, consider adding disorder
Lithium
• If lithium not tolerated, add
Valproate
• If person is one Lithium,
Valproate, increase dose to max
BNF, if no response consider
adding one of the above
antipsychotics.
Bipolar depression
If person is not taking any medication,
then offer
• Fluoxetine combined with
Olanzapine or Quetiapine on its own,
• If the person prefers, consider either
olanzapine (without fluoxetine) or
lamotrigine on its own.
• If there is no response to fluoxetine
combined with olanzapine, or
quetiapine, consider lamotrigine on
its own.
If the person is on Lithium or valproate,
increase dose to max BNF (or plasma
level). If no response, follow the same as
above
Prophylaxis
• Offer lithium as a first-line,
41
Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people
in primary and secondary care (2014). NICE guideline.
52
long-term pharmacological treatment

for bipolar disorder
• if lithium is ineffective, consider

adding valproate
• if lithium is poorly tolerated, or is not

suitable, consider valproate or
olanzapine instead or, if it has been
effective during an episode of mania
or bipolar depression, quetiapine.
Generalised Anxiety Disorder42 • Alternatives(with a

weaker evidence base)
• Benzodiazepines should not be include buspirone and
prescribed beyond 4 weeks hydroxyzine for GAD
• SSRI (esp. sertraline) should be
considered for 1st line treatment.
• SSRI / SNRI – second line
Anxiety • Paroxetine and slow release
venlafaxine have a license for
disorders
treatment of GAD
• If SSRI/SNRI unsuccessful
consider pregabalin
Panic disorder
• SSRI licensed for panic disorder
• If not successful consider
imipramine/clomipramine.
• Antipsychotics may be
OCD43
used for SSRI
• SSRI is appropriate for patients
augmentation in OCD
with moderate or severe
impairment
• If no response to adequate trial
clomipramine may be considered
• Medication should not be first • Antipsychotic may be

line treatment used as augmentation
PTSD44 • You can use
paroxetine/mirtazapine or
amitryptiline/phenelzine, the
latter only under
42
Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults: Management in
primary, secondary, and community care (2014). NICE Guideline
43
Obsessive-compulsive disorder: Core interventions in the treatment of obsessive-compulsive disorder and
body dysmorphic disorder (2014). NICE Guideline
44
PTSD: The management of PTSD in adults and children in primary and secondary care (2014). NICE
guideline.
53
specialist supervision
Cognitive symptoms of Alzheimer’s CATIE-AD Trial

• Donepezil, Galantamine and • Minor advantages of
Rivastigmine are recommended olanzapine and
in patients who have moderate risperidone over placebo
Alzheimer’s disease (i.e. MMSE in controlling behavioural
of 10-20) and aggressive symptoms
Dementia45 • Memantine can be considered for • Sedation, confusion and
those intolerant of AChE EPS main side-effects-
inhibitors or with severe poorly tolerated
Alzheimer’s.
Other evidence
Non-cognitive symptoms • Cochrane review says
• Antipsychotics should only be risperidone and
considered for severe non- olanzapine should not be
cognitive symptoms. Important routinely used
to consider risk. • #mortality in dementia
• Acetylcholinesterase inhibitors patients on antipsychotics
may help, but should not be used
in vascular dementia
Anorexia Anorexia
• Medication should not be used, • Some poor evidence that
Eating
unless treating comorbidity olanzapine may reduce
disorders46 agitation and improve
Bulimia weight gain
• SSRIs are the medication of
choice. In particular fluoxetine Bulimia
60mg may be used. • Some evidence that
topiramate may reduce
frequency of binges
REFERENCES:
§ Companion to Psychiatric Studies – Eight edition. Churchill Livingstone.
2010.
§ Gelder, M., Mayou, R., & Cowen, P. (2001). Shorter Oxford Textbook of
psychiatry. Oxford university press. Oxford.
§ Gelder, M et al (2nd ed) New Oxford Textbook of Psychiatry, 2011
§ Goodman & Gillman’s Pharmacological Basis of Therapeutics 12th edition
45
Dementia: Supporting people with dementia and their carers in health and social care (2006). NICE
guideline
46
Eating disorders: Core interventions in the treatment and management of anorexia nervosa, bulimia
nervosa and related eating disorders (2014) Eating disorders. NICE guideline
54
§ King, D. J. (1999). Seminars in clinical psychopharmacology. The Royal

College of Psychiatrists, London.
§ Kohen , D. (2004) Psychotropic medications in pregnancy.Advances in
Psychiatric Treatment, 10, 59-66.
§ The Maudsley Prescribing Guidelines, 12th edition
§ Sadock, B.J., & Sadock, V.A. (1999). Comprehensive textbook of psychiatry.
Lippincott Williams & Wilkins, London.
§ Staddon, S (2002) Psychopharmacology- Clinical applications of
pharmacognetics in psychiatry,162:18-23
§ Stahl, S.M. (2013). Essential psychopharmacology - Neuroscientific basis and
practical applications. 4th edition. Cambridge University Press, Cambridge.
§ Taylor, D., Paton, C., and Kapur, S. (2015). The South London and Maudsley
NHS trust 2012 prescribing guidelines. 12th edition.
55

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Paper A

I. Historical overview of Psychotropic drugs ............................................................................ 2

I. Historical overview of Psychotropic drugs

2. John Cade 1949 Lithium

Antidepressants group Antidepressants

Serotonin antagonist and re-uptake Trazadone

Anxiety and insomnia

III. Concordance1 & Placebo response

Three important predictors are of non-concordance are:

The factors associated with poor concordance are detailed below2:

Patient factors Clinician factors Illness factors

• Concerns about the • Poor doctor–patient • Severe illness

Improving patient adherence3

Improve communication with patients

IV. Rational prescribing:

the possibility of an untoward drug interaction. This is particularly relevant

Prescribing in special groups:

Pregnancy Breastfeedi Under 18s Liver Renal Physical

V. Pharmacokinetics & Pharmacodynamics

Pharmacokinetics is concerned with the body’s effect on the drugs. Bioavailability of

to region and aqueous solubility, 100%

The Blood Brain Barrier

The permeability of cell membrane is proportional to drug’s Partition Coefficient (a

The cytochrome P450 enzyme system

Some of the important isoenzymes and their metabolites are:

2D6 Risperidone, clozapine, olanzapine, aripiprazole, typical

Substance Inducers Inhibitors

Medical drugs Omeprazole Erythromycin (# carbamazepine)

It is also important to consider the half-lives of different benzodiazepines and related

Shorter-acting benzodiazepines are preferred in liver impairment, as their metabolism

Therapeutic index* is a relative measure of the toxicity or safety of a drug and is

Therapeutic index = Lethal/toxic dose that would affect 50% of population

Drug Target range Sample timing Time to steady state

Of these, lithium is the one with a well-established therapeutic range. Plasma

Growing old is associated with relative metabolic impairment, often aggravated by

Drug receptor interactions can be modified by changes in receptor sensitivity. When

Due to cytochrome P450 enzyme system inhibition by some drugs (e.g.

Receptor Blocked Adverse effect

b. Specific Serotonin Reuptake Inhibitors (SSRIs):

Other 5HT receptors

Almost all antidepressants lead to a dose dependent prolongation of REM latency

SSRIs. Therefore, gradual tapering over several weeks is strongly recommended.

Mirtazapine is a nor-adrenergic and serotonin specific antidepressant (NASSA). Its

Other side effects are similar to those of the SSRIs

There is limited data on the effectiveness of duloxetine as compared to other

Trazodone has antagonistic properties at 5-HT2 receptors and is a weak reuptake

antipsychotics. Although intestinal absorption is complete, the oral bioavailability is

Side Effects of Typical Antipsychotics*

Tardive dyskinesia – Onset within months of starting neuroleptic. Involuntary

Concurrent administration of anticholinergic agents with neuroleptic drugs has

Neuroleptic Malignant Syndrome

iv. Atypical antipsychotics.

Olanzapine IM should not be combined with an IM benzodiazepine as this could

agranulocytosis. Clozapine is also implicated in causing significant weight gain and

anticholinergic +/- +++ + + +/- +/-

EPSEs + +/- + +/- ++ +/-

v. Prescribing in Special groups17

VIII. Antimanic and Prophylactic drugs

Periodic monitoring of serum calcium levels during lithium therapy is warranted.

Lithium hypothyroidism is more common in middle aged women. Some reports

Phenytoin is a prototype anticonvulsant with no proven psychiatric use. Its adverse

Drug Mechanism of Notable side effects Drug Interactions

Vigabatrin and valproate inhibit GABA transaminase. Vi + gaba + transaminase +

IX. Hypnotics & sedatives