Depression is a common psychiatric disorder and
could be:             

• Reactive: Due to distressing circumstances in
  life
• Endogenous: Major depression due to a biochemical abnormality in brain.
• Bipolar mood disorder: Mania and depression occur alternately causing cyclic mood
  swings.

Antidepressants

Classification

1. Tricyclic antidepressants (TCA)—Imipramine, desipramine, amitriptyline, nortriptyline
   doxepin
2. Selective serotonin (5-HT) reuptake inhibitors (SSRI)—Fluoxetine, fluoxamine, paroxetine,
   citalopram, sertraline, venlafaxine.
3. Monoamine oxidase (MAO) inhibitors— Phenelzine, tranylcypromine.
4. Atypical antidepressants—Trazodone, nefazodone, bupropion, mianserine.

Tricyclic Antidepressants

Pharmacological Actions

• • CNS:

In normal subject, TCA cause dizziness, drowsiness, confusion and difficulty in thinking. In depressed patients, after 2-3 weeks of treatment, elevation of mood occurs; the patient shows more interest in the surroundings and the sleep pattern become normal.

• • CVS :

Postural hypotension and tachycardia (due to blockade of α1 adrenergic and muscarinic receptors) can be severe in
overdosage.

• • ANS:

TCAs have anticholinergic properties and cause dry mouth, blurred vision, constipation and urinary retention.

Pharmacokinetics

TCAs are rapidly absorbed, highly protein bound and metabolized in liver. They have a long t½ and can be given once daily

Adverse Effects

Sedation, postural hypotension, tachycardia, sweating and anticholinergic side effects like dry mouth, constipation, blurred vision and urinary retention are relatively common. TCA may precipitate convulsions in epileptics; may cause hallucinations and mania in some patients. Many TCAs may also cause weight gain due to increased appetite.

Treatment

Physostigmine is given to overcome atropine-like effects; sodium bicarbonate for acidosis, phenytoin for seizures and arrhythmias—with other supportive measure.

Drug Interactions

• Tricyclics potentiate sympathomimetics— even small amount of adrenaline used with local anesthetics can cause serious hypertension.
• Highly protein bound drugs like phenytoin, aspirin and phenylbutazone displace TCAs from binding site resulting in toxicity.
• TCAs potentiate the effects of alcohol and other
  CNS depressants.

Atypical antidepressants:

Trazodone, bupropion, mianserin.

Advantages

• Fewer side effects—particularly sedation and anticholinergic effects.
• Safer in overdose.
• Effective in patients not responding to TCA.

Uses of Antidepressants

• Endogenous depression: Antidepressants are used over a long period. The response appears after 2-3 weeks of treatment. The choice of the antidepressant depends on the side effects and patient factors like age. In severe depression with suicidal tendencies, electroconvulsive
  therapy (ECT) is given.
• Panic attacks: Post-traumatic stress disorders and other anxiety disorders—all respond to antidepressants (acute episodes of anxiety are
  known as panic attacks).
• Obsessive compulsive disorders: SSRIs and clomipramine are effective.
• Nocturnal enuresis in children may be treated with antidepressants only when other measures fail and drugs are to be given.
• Psychosomatic disorders: Newer antidepressant are tried in fibromyalgia, irritable bowel syndrome, chronic fatigue, tics, migraine and sleep apnea.
• Other indications: Attention deficit hyperactivity disorder, chronic pain and chronic alcoholism—may result in depression— antidepressant are tried.

MOOD STABILIZERS

Lithium is a monovalent cation. On prophylactic use in bipolar mood disorder (manic-depressive illness), lithium acts as mood stabilizer. It prevents swings of mood and thus reduces both the depressive and manic phases of the illness. Given in acute mania, it gradually suppresses the
episode over weeks.

The Mechanism of Action

The mechanism of actions of lithium is complex and not fully understood. It inhibits the synthesis of second messengers IP3 and DAG and thereby blocks the respective receptor-mediated effects. This is the most accepted mechanism of action.

Pharmacokinetics

Lithium is small ion and mimics role of sodium in excitable tissue. Given orally it is well absorbed. It is filtered at the glomerulus but reabsorbed like sodium. Steady state concentration is reached in 5-6 days. Since safety margin is narrow, plasma lithium concentration needs to
be monitored.

Adverse Effects

Lithium is drug of low therapeutic index and side effects are common. Nausea, vomiting, mild diarrhea, thirst and polyuria occur initially in most patients. As the plasma concentration rises, hypothyroidism, CNS effects like coarse tremors, drowsiness, giddiness, confusion, ataxia, blurred
vision and nystagmus are seen. In severe over dosage, delirium, muscle twitching’s, convulsions, arrhythmias and renal failure develop.

Precautions

• Minimum effective dose should be used.
• Patients should always use the same formulation.
• Patients should be aware of first symptom of toxicity
• Lithium is contraindicated in pregnancy

Drug Interactions

1. Diuretics enhance Na+ loss and lithium absorption from the kidney. This increase plasma lithium levels resulting in toxicity.
2. NSAIDs ↓ lithium elimination and enhance toxicity.

Uses

1. Acute mania—since response to lithium is slow, neuroleptics are preferred.
2. Prophylaxis of bipolar mood disorder— episodes of mania and depression are reduced
3. Other uses—lithium is tried in recurrent
   neuropsychiatric disorders, hyperthyroidism and inappropriate ADH secretion syndrome