Pharmacology - An Illustrated Review
10. Antidepressant and Antimanic Drugs
Antidepressant and antimanic drugs are used to treat the affective disorders. These include major depression, mania, and manic depression. These disorders may be bipolar (cycling back and forth between mania and depression) or unipolar (mania or depression only). Table 10.1 lists symptoms of depression and mania.
Table 10.1 Symptoms of Depression and Mania
Intense sadness and despair; fatigue, musculoskeletal complaints, sleep disorders, feeling of worthlessness, and loss of joy in living
Abnormally elevated mood, feelings of grandiosity, decreased sleep, increased talkativeness, and increased activity or agitation
Antidepressant drugs block the reuptake of the biogenic monoamines norepinephrine and serotonin. Their selectivity for different uptake mechanisms varies.
10.1 First-generation Antidepressant Drugs
Amitriptyline, Nortriptyline, Imipramine, and Desipramine
Tricyclic antidepressants are structurally related to phenothiazines (antipsychotic drugs—see page 100) but have different pharmacological effects.
Mechanism of action. These agents block the reuptake of the biogenic monoamines norepinephrine and seratonin. They also interact with many other receptor types, including muscarinic (M1), histamine (H1), and adrenergic (α1) (Fig. 10.1).
– Desipramine is the most potent inhibitor of norepinephrine reuptake. It is 1000 times less potent on serotonin reuptake.
– Amitriptyline blocks both norepinephrine and serotonin reuptake equally.
– Tricyclics also block muscarinic, serotonergic, histaminic, and α-adrenergic receptors. These actions are thought to be related to their side effects.
– Acute effects include drowsiness and decreased blood pressure, but with sustained use will cause an elevation of mood
– Suppression of rapid eye movement (REM) sleep
– Sleep promotion
– Anticholinergic: dry mouth, blurred vision, urinary retention, and constipation
– Antiadrenergic: orthostatic hypotension and delayed cardiac conduction
– Weight gain
– Mania, confusion, and delirium
Acute poisoning with tricyclic antidepressants
Accidental and deliberate overdose of tri-cyclic antidepresssants occurs frequently and constitutes a serious medical emergency that may result in death. Signs may include excitement, seizures, coma with depressed respiration, hypoxia, hypothermia, and hypotension. Anticholinergic effects are also evident. Because no antagonists are available, treatment includes supportive measures in an intensive care unit setting.
Fig. 10.1 Antidepressants.
Activity profiles of selected first-generation antidepressants (tricyclic antidepressants) and third-generation antidepressants (selective serotonin reuptake inhibitors), including the neurotransmitter affected.
Drug interactions. When tricyclic antidepressants are taken with other drugs, their effects or side effects can be potentiated.
– When they are taken with alcohol, this leads to additive sedation.
– When taken with other anticholinergic drugs, additive anticholinergic effects occur.
– When they are taken with monoamine oxidase inhibitors (MAOIs), severe central nervous system (CNS) toxicity can occur, but this is rare.
Monoamine Oxidase Inhibitors (MAOIs)
Tranylcypromine, Phenelzine, and Isocarboxazid
Mechanism of action. MAOIs inhibit both monoamine oxidase A and B (MAO-A and MAO-B).
– Phenelzine and isocarboxazid are “suicide” inhibitors of the enzyme. This means that once an MAO molecule binds to one of these drugs, its activity cannot be restored. Restoration of MAO activity depends on synthesis of new enzyme molecules. The exception to this is tranylcypromine, which is reversible.
– MAOIs interfere with hepatic metabolism of many drugs and are not selective for MAO-A or MAO-B.
– The effects of MAOIs take 2 to 3 weeks to become apparent.
Uses. MAOIs are used to treat depression when tricyclic antidepressants are ineffective.
– Cardiovascular system: postural (orthostatic) hypotension
– Suppression of REM sleep
– Hepatotoxicity and CNS stimulation
Note: Acute poisoning causes agitation, hallucinations, hyperreflexia, and convulsions. Treatment is by maintaining vital functions in the hospital setting for approximately 1 week.
– MAOIs interact with sympathomimetic drugs, leading to hypertensive crisis.
– MAOIs taken with meperidine (an opioid analgesic) can lead to fever, delirium, and hypertension.
Hypertensive crisis with monoamine oxidase inhibitors
Hypertensive crisis may occur within hours of ingestion of tyramine-containing foods, including cheese, certain meats (liver and fermented or cured meats), cured or pickled fish, overripe fruits and vegetables, Chianti wine, and some beers. Hypertensive crisis is characterized by headache, palpitation, neck pain or stiffness, nausea, vomiting, sweating (sometimes with fever or cold, clammy skin), photophobia, tachycardia or bradycardia, constricting chest pain, and dilated pupils. Potentially fatal intra-cranial bleeding may result from this crisis. Patients should avoid tyramine-containing foods while taking MAOIs and for 2 weeks after treatment with MAOIs is discontinued to avoid precipitating this condition. If hypertensive crisis does occur, then treatment is with intravenous (IV) phentolamine (a non-selective α antagonist agent).
10.2 Second-generation Antidepressant Drugs
Second-generation antidepressant drugs were developed in an attempt to eliminate some of the troublesome side effects seen with tricyclic antidepressants, such as cardiac manifestations, orthostatic hypotension, drowsiness, and weight gain.
Bupropion, Mirtazapine, Duloxetine, Amoxapine, Maprotiline, and Trazadone
Mechanism of action. These agents are pharmacologically very similar to tricyclics. They may act as serotonin and norepinephrine reuptake inhibitors.
– Anticholinergic: dry mouth, blurred vision, urinary retention, and constipation
– Antiadrenergic: postural (orthostatic) hypotension and delayed cardiac conduction
– Antihistaminergic: sedation
– Weight gain
Side effects. This generation of antidepressants generally has fewer side effects than tri-cyclic antidepressants. Exceptions include
– Bupropion: seizures and cardiac arrhythmias
– Amoxapine: extrapyramidal side effects
– Maprotiline: rashes and seizures
10.3 Third-generation Antidepressant Drugs
Third-generation antidepressants may be safer than tricyclics in overdose situations. Selective serotonin reuptake inhibitors (SSRIs) are not as effective in treating severe depression as first- or second-generation agents.
Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Citalopram, and Venlafaxine
Mechanisms of action
– Fluoxetine (see also Fig. 7.3, page 70), paroxetine, sertraline, and fluvoxamine and citalopram are SSRIs.
– Venlafaxine affects serotonin and norepinephrine reuptake and weakly inhibits dopamine reuptake.
– Completely absorbed from the gastrointestinal (GI) tract and extensively metabolized in the liver
– Eliminated in the urine and feces
– The therapeutic effect takes 10 to 14 days to develop.
– Long half-life (days)
– Obsessive-compulsive disorder (fuvoxamine and fluoxetine)
Side effects. Fewer anticholinergic and sedative effects are seen than with tricyclics (they do not interfere with cardiac conduction or cause orthostatic hypotension). Side effects do include the following:
– Headache, tremor, insomnia, diarrhea, and nausea. Diarrhea and nausea diminish or resolve over time.
– They also stimulate the CNS, with agitation the most frequent adverse effect.
– Psychotic reactions may be exacerbated in depressed schizophrenics.
– Liver enzymes are inhibited by fluoxetine and paroxetine but not affected by sertraline.
– Sexual dysfunction and anorgasmia occur in both men and women.
– Generally less weight gain than seen with other classes
– Altered sleep
– Akathisia (a movement disorder charaterized by motor restlessness)
Acute intoxication with third-generation antidepressants can cause serotonin syndrome when given with MAOIs. The effects of the syndrome include hyperthermia, rigidity, myoclonus (quick, involuntary muscle jerks), confusion, delirium, and coma.
10.4 Antimanic Drug
Lithium is an alkali metal ion used to treat mania, manic-depressive illness, and unipolar depression. It has no effects on healthy individuals unless toxic levels are reached. With acute mania, 70 to 80% of patients improve when given lithium.
Mechanism of action. The mechanism of action for lithium salts is unknown.
– Completely absorbed from the GI tract
– Eliminated in the urine
– Narrow therapeutic index, so frequent monitoring of serum or urine levels is required to prevent toxicity. This is performed daily during treatment of acute mania.
– There is a lag of 10 to 14 days before treatment becomes effective.
– Acute mania
– Bipolar manic-depressive illness
– Unipolar depression
– Neurologic effects can range from mild side effects such as tremor to muscle twitches or fasciculations, ataxia, and confusion. Severe side effects such as seizures, hallucinations, and delirium may also occur.
– Cardiac effects: flattened or inverted T waves (benign), arrhythmias, and sudden death
– Polydipsia (excessive thirst) and polyuria (excessive urination) are seen, possibly from the inhibition of antidiuretic hormone (ADH) by lithium. This may be disturbing to the patient. Mild polyuria usually occurs early in treatment. Polyuria appearing late may indicate impaired renal function.
– Nephrogenic diabetes insipidus (see p. 189)
– Thyroid enlargement
Note: Acute intoxication is characterized by nausea, vomiting, profuse diarrhea, tremor, coma, and convulsions. Treatment is supportive.
10.5 Obsessive-Compulsive Disorder
Obsessive-compulsive disorder is characterized by obsessive thoughts and compulsive behaviors. Obsessions are unwanted thoughts that run repeatedly through the patient's mind. Compulsions are irresistible urges to perform ritualistic behaviors.
Clomipramine, Fluvoxamine, and Fluoxetine
– Clomipramine is a tricyclic antidepressant agent.
– Fluvoxamine and fluoxetine are SSRIs.
Treatment with these drugs may take up to 10 weeks for a full response. About half of all patients treated with these drugs respond favorably.