Pharmacology III

(PL413)

Psychotherapeutic
drugs
Dr.Samar O.El-ganainy
Fall 2021 Pharmacology III (PL413)

By the end of this lecture, students will be able to:

1. Outline different types of psychiatric disorders.

2. Examine different pathophysiology of affective disorders and psychosis.

3. Distinguish different classes of antidepressant therapy.

4. Identify examples of mood-stabilizing drugs.

5. Distinguish different aspects of antipsychotics.

p sychiatric disorders include psychoses, such as schizophrenia, and affective

disorders, such as depression. Psychoses are disorders in which patients
exhibit gross disturbances in their comprehension of reality, as evidenced by
false perceptions (hallucinations) and false beliefs (delusions). In contrast,
affective disorders are emotional disturbances in which the mood is excessively low
(depression) or high (mania).

Affective disorders are also called mood disorders. The two most common affective
disorders are:

a. Major Depressive Disorder

• Characterized by depressed mood, loss of interest or pleasure in life, sleep

disturbances, feelings of worthlessness, diminished ability to think or
concentrate, and recurrent thoughts of suicide.

• Depressed mood lasts most of the time for at least 2 weeks or loss of interest or
pleasure in most activities, or both.

b. Bipolar disorder (previously called manic-depressive disorder)

• Is characterized by recurrent fluctuations in mood, energy, and behavior.

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Fall 2021 Pharmacology III (PL413)

• Differs from major depression in that periods of mania alternate or occur

simultaneously with depressive symptoms.

• The clinical presentation varies widely: manic phase is characterized by elevated

mood, grandiosity, increased talking (pressure of speech), racing thoughts (flight
of ideas), increased social or work activity, and decreased need for sleep.

PATHOPHYSIOLOGY OF MAJOR DEPRESSION

a) Biogenic amines theory

• The monoamine hypothesis of depression suggests that depression is related to a

deficiency in the amount or function of serotonin (5-HT), norepinephrine (NE),
and dopamine (DA).

• It is believed that impaired serotonin neurotransmission can decrease cortical

responsiveness to emotional activation, leading to affective dysfunction and
depression.

• The biogenic amine hypothesis is supported by the fact that all antidepressant
drugs act to increase serotonin, norepinephrine, and/or dopamine
neurotransmission in the brain.

• Depressed patients who respond to serotonergic antidepressants often rapidly

suffer relapse when given diets free of tryptophan.

• Depression was linked to abnormal circadian rhythms and melatonin regulation.

• Melatonin, the principal mediator of biologic rhythms, is known to suppress the

activity of serotonergic neurons.

• This hypothesis is particularly relevant to seasonal affective disorder (winter

depression).

b) neurotrophic hypothesis
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• Growth factors such as brain-derived

neurotrophic factor (BDNF) are
critical in the regulation of neural
plasticity, and neurogenesis.

• Depression is associated with the loss

of neurotrophic support and that
effective antidepressant therapies
increase neurogenesis and synaptic
connectivity.

• BDNF is thought to exert its influence on neuronal survival and growth effects.

• Stress and pain are associated with a drop in BDNF levels and loss of
neurotrophic support.

c) Neuroendocrine Factors

• Depression is associated with a number of hormonal abnormalities.

• MDD is associated with elevated cortisol levels, and chronically elevated levels
of corticotrophin-releasing hormone and (ACTH) release = indicate a
dysregulation of the stress hormone axis.

• It is known that both exogenous glucocorticoids and endogenous elevation of

cortisol are associated with mood symptoms similar to those seen in depression.

• Up to 25% of depressed patients are reported to have abnormal thyroid function

(clinical hypothyroidism)

• Sex steroids are also implicated in the pathophysiology of depression.

• Estrogen deficiency states, which occur in the postpartum and postmenopausal

periods, are thought to play a role in the etiology of depression in some women.

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Fall 2021 Pharmacology III (PL413)

• Severe testosterone deficiency in men is sometimes associated with depressive

symptoms.

Integration of Hypotheses:

• It is evident that the monoamine, neuroendocrine, and neurotrophic systems are

interrelated.

• Steroid abnormalities may contribute to suppression of transcription of the BDNF

gene.

• The chronic activation of monoamine receptors by antidepressants appears to

have the opposite effect of stress and results in an increase in BDNF transcription.

• Activation of monoamine receptors appears to down-regulate the HPA axis and

may normalize HPA function.

ANTIDEPRESSANT DRUGS

• All currently available antidepressants enhance monoamine neurotransmission

by one of several mechanisms. The most common mechanism is inhibition of the
activity of serotonin transporter (SERT), norepinephrine transporter (NET), or
both monoamine transporters.

• Another mechanism for increasing the availability of monoamines is inhibition

of their enzymatic degradation (by the MAOIs).

• Additional strategies for enhancing monoamine tone include binding presynaptic

autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT2
antagonists and mirtazapine).

• The increased availability of monoamines for binding in the synaptic cleft results
in a cascade of events that enhance the transcription of some proteins including
BDNF, glucocorticoid receptors, β adrenoceptors, and others.
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Fall 2021 Pharmacology III (PL413)

• Maximum beneficial effects of most antidepressants are not seen for many weeks.
This delayed effect could be explained by:

o Most antidepressant drugs increase the synaptic concentration of

serotonin, and this leads to down-regulation of presynaptic autoreceptors.
& increases the firing rate of serotonergic neurons

o The time required to synthesize neurotrophic factors has been proposed as

an explanation for this delay of antidepressant effects.

Indications

• Antidepressants have been used to treat all forms of depression and to treat
several other conditions.

• They are also effective in the treatment of certain anxiety disorders, such as panic
disorder, phobic disorders, and obsessive-compulsive disorder.

• Clomipramine is particularly effective in treating patients with obsessive-

compulsive behavior.

• Some antidepressants are beneficial in the management of certain sleep

disorders.

• The newer SSRIs and SNRIs are used to treat depression, eating disorders (e.g.,
bulimia nervosa and anorexia nervosa), and anxiety disorders.

1. Tricyclic Antidepressants

• Include amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline.

• Are highly effective in the treatment of depression.

Pharmacokinetics:

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o The TCAs are incompletely absorbed after oral administration and are
extensively metabolized to active and inactive metabolites in the liver.

o Several of these metabolites are available as drugs. For example,

amitriptyline is converted to nortriptyline,,and imipramine is metabolized
to desipramine.

Mechanism of Action

• All TCAs block the neuronal reuptake of norepinephrine and serotonin (blockade
of the reuptake transporters, called the norepinephrine transporter [NET] and
serotonin transporter [SERT]), but with differing degrees.

Adverse Effects

• The TCAs produce autonomic side effects by blocking muscarinic (constipation,

dry mouth) and α- adrenoceptors (orthostatic hypotension).

• Some of the TCAs also produce marked sedation owing to H1 blockade.

• They are often administered at bedtime when their sedative effects can have the
added benefit of promoting sleep.

• An overdose of a TCA can cause life-threatening cardiac dysrhythmia.

2. Selective Serotonin Reuptake Inhibitors

• Includes fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram,

escitalopram.
• Have become the most widely used drugs for the treatment of depression and
certain anxiety disorders.
• They are as effective as the TCAs but cause fewer autonomic side effects and
less sedation.

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Fall 2021 Pharmacology III (PL413)

Pharmacokinetics

• Fluoxetine, which has a longer half-life than the other drugs in this class, is
converted to an active metabolite that has an even longer half-life.
• The metabolites of other SSRIs have little or no pharmacologic activity.

Mechanism of Action

• Block the neuronal reuptake of serotonin and have much less effect on the
reuptake of norepinephrine.
• Allosterically inhibit the transporter by binding the serotonin transporter receptor
at a site other than the serotonin binding site.
• At therapeutic doses, about 80% of the activity of the transporter is inhibited.

Adverse Effects

• The SSRIs produce fewer sedative, autonomic, and cardiovascular side effects
than the TCAs.
• Unlike the TCAs, the SSRIs are usually administered in the morning, because
they tend to increase alertness in patients.
• Prescribed with caution in patients with seizure disorders, hepatic disorders,
diabetes, or bipolar disorder.
3. Serotonin and Norepinephrine Reuptake Inhibitor
• New drugs are selective for both NE and serotonin reuptake transporters, but not
other receptors (unlike TCAs).
• Duloxetine and venlafaxine are structurally unique antidepressants that strongly
inhibit the reuptake of both norepinephrine and serotonin.
• Indicated for major depressive disorder, diabetic peripheral neuropathic pain, and
generalized anxiety disorder.

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• Both have a side effect profile similar to that of the SSRIs. These agents do not
antagonize other receptors.
4. MAO inhibitors
• Have many potentially serious interactions with other drugs and with food, they
are not considered drugs of choice in the treatment of depression.
• They are generally used as alternative therapy when patients have failed to
respond adequately to other drugs.
• Bind irreversibly to an enzyme, monoamine oxidase (MAO), responsible for the
degradation of the biogenic amine neurotransmitters, norepinephrine, dopamine
and serotonin.
• The MAOIs are classified according to their selectivity for the two main types of
MAO.MAO-A preferentially oxidizes serotonin but will also metabolize
norepinephrine and dopamine, MAO-B preferentially metabolizes dopamine.
• The inhibition of MAO-A is believed to be responsible for the antidepressant
effects of most of the MAOIs.
5. 5-HT Receptor Modulators
• nefazodone and trazodone appears to be blockade of the 5-HT2A receptor.
• Inhibition of this receptor is associated with antianxiety, antipsychotic, and
antidepressant effects.
6. Tetracyclic and unicyclic antdepressants
• Bupropion is modest to moderate inhibitors of norepinephrine and dopamine and
substantially increase the presynaptic availability of NE.
• Mirtazapine has a complex pharmacology. It is an antagonist of the presynaptic
α2 autoreceptor and enhances the release of both norepinephrine and 5-HT.
• In addition, mirtazapine is an antagonist of 5-HT2 and 5-HT3.

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Serotonin syndrome

• Life threatening condition caused by overstimulation of 5-HT receptors.

• Caused by a combination of MAOIs with serotonergic agents including SSRIs,
SNRIs, and most TCAs along with some analgesic agents such as meperidine.
• Symptoms range from mild to lethal and include a triad of cognitive (delirium,
coma), autonomic (hypertension, tachycardia,), and somatic (, tremor) effects.
• Most serotonergic antidepressants should be discontinued at least 2 weeks before
starting an MAOI.
• Fluoxetine, because of its long half-life, should be discontinued for 4–5 weeks
before an MAOI is initiated.

Treatment Considerations

• Primary treatment for patients with depression is drug therapy, but psychotherapy
enhances the response to pharmacologic treatment and increases patient
compliance with medication.

• Electroconvulsive therapy is sometimes used as an alternative when

antidepressants have been ineffective or are not tolerated.

• The initial drug used in the treatment of depression is usually either a TCA or an
SSRI.

• If TCAs or SSRIs are not effective or well tolerated, the choice would be SNRIs
and other antidepressants.

• To prevent relapse, antidepressants are usually continued for 4 to 9 months after

remission of depressive symptoms.

MOOD-STABILIZING DRUGS

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Fall 2021 Pharmacology III (PL413)

Mood-stabilizing drugs act to normalize the swings in bipolar disorder. They

reduce both manic and depressive symptoms and thereby tends to normalize the
mood in patients with bipolar disorder. But, they have greater activity against manic
symptoms than it does against depression, and it is primarily used to treat or prevent
the manic phase of bipolar disorder.

1. Lithium
• Lithium produces a calming effect in manic patients, but the maximal response
to lithium often requires several days or weeks of treatment.

Mechanism of action

• The mechanisms by which lithium produces its mood stabilizing effects are not
well understood.
• The drug appears to act by suppressing the formation of inositol triphosphate
(IP3).
• By reducing IP3 formation, lithium reduces multiple pathways markedly
increased during a manic episode.

Pharmacokinetics

• About 95% to 100% of the administered dose is absorbed from the gut.
• Widely distributed throughout the body, with the highest concentrations found in
the thyroid gland, bone, and some areas of the brain.
• The drug is not metabolized. It has a half-life of about 24 hours.

Adverse Effects

• Lithium has a relatively narrow therapeutic index. Elevated lithium levels can
cause neurotoxicity and cardiac toxicity leading to dysrhythmia.
• Nausea with vomiting can be one of the earliest signs of lithium overdose.

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• Common side effects include drowsiness, weight gain, a fine hand tremor, and
polyuria.
• Lithium causes polyuria because it interferes with the action of antidiuretic
hormone
• In some patients, lithium causes hypothyroidism by blocking thyroid hormone
synthesis and release.
2. Other Mood-Stabilizing Drugs
• Other drugs have been found to have equal or greater efficacy and may be better
tolerated by some patients.
• These include antiepileptic drugs such as carbamazepine and valproate.
SCHIZOPHRENIA

S chizophrenia, the most common form of psychosis, affects about 1% of the

world’s population. Its hallmarks are delusions, hallucinations, disorganized
thinking, and emotional abnormalities. Several forms of the disease, including
paranoid, disorganized, and catatonic forms, are differentiated on the basis of
symptoms.
Symptoms
a. The positive symptoms, which include delusions and
hallucinations, probably result from excessive neuronal
activity in mesolimbic neuronal pathways. These
symptoms are usually the primary manifestations of
acute psychotic episodes.

b. The negative symptoms, which include apathy,

withdrawal, and lack of motivation and pleasure,
probably result from insufficient activity in
mesocortical neuronal pathways. The negative

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symptoms generally are more difficult to treat, often persist after positive symptoms
resolve, and are associated with a poor prognosis.

Pathophysiology

✓ Dopamine Hypothesis

• According to this hypothesis, schizophrenia results from abnormalities in

dopamine neurotransmission in mesolimbic and mesocortical neuronal pathways.

• Several lines of evidence suggest that excessive limbic dopaminergic activity

plays a role in psychosis:

o Many antipsychotic drugs strongly block postsynaptic D2 receptors in

the central nervous system.

o Drugs that increase dopaminergic activity, such as levodopa, aggravate

schizophrenia psychosis.

o Dopamine-receptor density has been found postmortem to be increased

in the brains of schizophrenics.

✓ Serotonin hypothesis

• Several hallucinogens such as LSD was found to be agonist on serotonin receptor.

• 5-HT2A-receptor and possibly 5-HT2C stimulation was found to play a role in

the hallucination of schizophrenics.

• Second-generation antipsychotic drugs are inverse agonists of the 5-HT2A

receptor; that is, they block the constitutive activity of these receptors.

• These receptors modulate the release of dopamine, norepinephrine, glutamate,

GABA, and acetylcholine.

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Fall 2021 Pharmacology III (PL413)

• Stimulation of 5-HT2C receptors leads to inhibition of cortical and limbic

dopamine release. = mechanism of many atypical antipsychotic.

ANTIPSYCHOTIC DRUGS
Antipsychotic drugs are agents that reduce psychotic symptoms and improve the
behavior of schizophrenic patients. Antipsychotic drugs were also called neuroleptic
drugs because they suppress motor activity and emotional expression.

1. Typical antipsychotic drugs (first-generation antipsychotic agents):

• E.g.chlorpromazine, fluphenazine and haloperidol.

• Chlorpromazine is considered low potency agents, fluphenazine has a slightly

greater potency, and haloperidol is a high-potency antipsychotic agent.

Mechanism of action and Pharmacologic Effects

• An equal or greater affinity for D2 receptors than for 5-HT2 receptors.

• Antagonism of D2 receptors in mesolimbic pathways is thought to repress the

positive symptoms of schizophrenia.

• Typical antipsychotic drugs can have some effect on negative symptoms, but it
is usually less pronounced than the effect of atypical antipsychotic drugs.

Adverse effects

• Blockade of D2 receptors in the basal ganglia is believed to be responsible for

extrapyramidal effects: including motor restlessness, pseudoparkinsonism, and
dystonias.

• Those extrapyramidal effects often occur early in the course of treatment with
antipsychotic drugs.

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• Tardive dyskinesia is a disorder that usually develops after months or years of

treatment due to long-term dopamine receptor antagonism.

• Typical antipsychotic agents can increase serum prolactin levels by blocking

dopamine receptors in hypothalamus / pituitary pathway and thereby cause
gynecomastia in men and menstrual irregularities in women.

Treatment of adverse effects

• Acute extrapyramidal effects caused by typical antipsychotic drugs can be

managed by lowering the drug dosage, changing to an atypical antipsychotic
drug, or administering an additional drug to counteract the adverse effects.

• Drugs that counteract the effects include benztropine, an anticholinergic drug;

diphenhydramine.

• Tardive dyskinesia is not easily managed and does not necessarily decrease if
drug is discontinued.

• To prevent tardive dyskinesia, antipsychotic drugs should be used in the lowest

doses for the shortest period of time required to control symptoms of
schizophrenia.

• The drugs should be discontinued periodically to assess the need for continued
treatment and possibly to reduce the development of dopamine supersensitivity.

2. Atypical antipsychotic drugs (second-generation antipsychotic agents)

• Clozapine, olanzapine, and a number of newer agents are atypical antipsychotics

that produce fewer extrapyramidal effects than do older antipsychotic drugs.

• Some members of this class are approved for the treatment of acute manic
episodes associated with bipolar disorder.

• This class has a greater affinity for 5-HT receptors than for D2 receptors.
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i. Clozapine

• First of a new generation of atypical antipsychotic drugs that cause significantly

fewer extrapyramidal.
• Therapeutic effects result from blockade of D4 receptors and 5-HT2 receptors.

• Both of these actions may contribute to its greater efficacy against the negative
symptoms of schizophrenia.

Adverse effects

• Clozapine is associated with significant sedation and autonomic side effects.

These adverse reactions are caused by antagonism of histamine, muscarinic, and
α1-adrenoceptors.

• The use of clozapine is also associated with fatal agranulocytosis.

ii. Olanzapine

• Its pharmacologic properties are similar to those of clozapine, but olanzapine

causes fewer autonomic side effects and has not been reported to cause
agranulocytosis.

• Has about twice the affinity for 5-HT2 receptors as it does for D2 receptors.

• Olanzapine is as effective as haloperidol in alleviating the positive symptoms of

schizophrenia, is superior to haloperidol in alleviating the negative symptoms.

iii. Risperidone
• ts pharmacologic properties are similar to those of olanzapine, but it appears to
cause less sedation and a higher incidence of extrapyramidal effects.
• It also can predispose patients to cardiac dysrhythmias.
• Its effects on treating both the positive and negative symptoms of schizophrenia
are caused by antagonism at both D2 and serotonin (5-HT2A) receptors.
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Treatment Considerations

• All typical antipsychotic drugs appear to be equally effective.

• The choice of drug is primarily based on the need to minimize autonomic or

extrapyramidal effects.

• Low-dose regimens are as effective as high-dose regimens and produce fewer

side effects.

• Atypical antipsychotic drugs may become the drugs of choice for treating most
forms of psychosis.

• In comparison with the typical drugs, the atypical drugs produce a lower
incidence of extrapyramidal effects and appear to be more effective against the
negative symptoms.

• Patient show alleviation of symptoms in 2 weeks but maximal response need 6

weeks.

• Antipsychotic medication is usually continued with low dose for at least 12

months after the remission of acute psychotic symptoms.

Adjunct Use of Atypical Antipsychotics in Treating Depression:

• Newer antipsychotics are used as “augmentation therapy,” or adjunct

medications to treat depression that hasn’t responded adequately to standard
antidepressant= treatment-resistant depression.

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