Antidepressant drugs

Depression: is a disorder of mood rather than disturbance of thought or cognition. It is postulated that depression is due to deficiency of NA and/or 5-HT in the CNS while mania results from functional excess. Introduction

Types of depression 1.Major depressive disorder (unipolar): – Depression is autonomous and is unresponsive to changes in life. Diminished interest or pleasure. weight loss or gain. Insomnia or sleeping too much. Fatigue or loss of energy. Feelings of worthlessness or excessive guilt. – It can occur as a single episode or may be recurrent.

2.Dysthymic disorder – A mood disorder with chronic (long-term) depressive symptoms that are present most of the day, more days than not, for a period of at least two years – Low energy or fatigue. Low self-esteem. Poor concentration or difficulty making decisions. Feelings of hopelessness 3.Bipolar Episode and Bipolar Disorder (manic- depressive disorder): – less common, characterized by oscillating periods of depression and mania. There is strong hereditary origin.

Classification of antidepressant drugs 1.Monoamine oxidase inhibitors (MAOI) e.g. selegiline. 2.Tricyclic antidepressants (TCA) e.g. imipramine, amitriptyline. 3.Selective serotonin reuptake inhibitors (SSRI): e.g. fluoxetine, sertraline. 4.Other (atypical) antidepressants: e.g. maprotiline, trazodone. 5.Mood stabilizing drugs: e.g. Lithium.

1. Monoamine oxidase inhibitors (MAOIs) N.B. There are 2 isotypes of MAO enzyme: 1.MAO-A enzyme: – Present in the cytoplasm of neurons (CNS) and peripheral tissues (e.g. liver). – It acts non-specifically on NA, 5-HT, and dopamine. – Clorgyline is a specific inhibitors of MAO-A. 2.MAO-B enzyme: – Present mainly in the CNS and acts more on dopamine. – Selegiline is a specific inhibitor of MAO-B. – Pargyline is non-selective MAOI.

Mechanism of action: They inhibit MAO enzyme leading to accumulation of active monoamines (NA, 5-HT, dopamine) in the brain tissue to act on postsynaptic receptors. Most MAOIs are irreversible inhibitors. Recovery of MAO takes several weeks. Moclobemide acts as a reversible inhibitor. Therapeutic uses: Reactive depression: antidepressant action occurs after 2-3 weeks and lasts for further 2-3 weeks. They are less effective in endogenous depression. Parkinsonism: selegiline.

Adverse effects: CNS stimulation: irritability, insomnia, tremors, hyperthermia, convulsions Hepatotoxicity: occurs more with hydrazine derivatives. Orthostatic (postural) hypotension: unknown mechanism Sexual dysfunction Switch into mania (about 10% of patients with bipolar disorders)

Interactions: A. Drug-drug interactions: – Reserpine inhibit vesicular transport protein leaving the monoamines exposed for MAO destructive action. If given with MAOIs, destruction will not occur leading to elevated levels of neurotransmitter which will result in hypertension and excitement. – Toxic synergism with tricyclic antidepressants. (Serotonin syndrome)

B. Drug-food interactions: Hypertensive crisis (cheese reaction): – Tyramine is an indirect sympathomimetic present in some food and normally metabolized by MAO-A in the liver. – When the patient takes MAO-A inhibitor or non- selective MAOIs, severe hypertension can occur after eating tyramine-rich food e.g. aged cheese, yogurt

2. Tricyclic antidepressants (TCA) (Imipramine, Clomipramine, Amitriptyline, Nortriptyline) Mechanism of action: (inhibition of amine pump) TCA inhibit neuronal reuptake of both 5-HT & NA leading to accumulation of NA & 5-HT in the brain tissue. It has been suggested that improvement of the emotional symptoms is related to enhancement of 5-HT transmission while improvement of biological symptoms is related to enhancement of NA transmission. Elevation of mood in depressed patients occurs after 2-3 weeks

Adverse effects: CNS stimulation: irritability, insomnia, tremors, hyperthermia, convulsions Hepatotoxicity: cholestatic jaundice. Orthostatic (postural) hypotension: unknown mechanism Atropine-like action: dry mouth, tachycardia, urine retention, etc. Cardiac arrhythmias. Weight gain and agranulocytosis. Sexual dysfunction

Therapeutic uses: Endogenous depression. Nocturnal enuresis (imipramine and amitriptyline). Chronic pain syndromes and migraine (unclear mechanism). Drug interactions: Toxic synergism with MAOIs and SSRIs (irritability and convulsions). Clonidine abolish the effect of TCA, since clonidine inhibit the release of neurotransmitter so no transmitter will be available for reuptake. Over dosage Tricyclics have a narrow therapeutic index. Manifestations include agitation, delirium, hyperpyrexia, convulsions, coma, cardiac arrhythmias, circulatory collapse

Contraindications and Precautions Seizure disorders, Parkinson’s disease Suicidal ideation Cardiac disease Glaucoma Prostatic hypertrophy Pregnancy Children Elderly (antimuscarinic effects may be greatly enhanced)

3. Selective serotonin reuptake inhibitors (SSRIs) (Fluoxetine, Paroxetine, Sertraline, Citalopram) Pharmacokinetics: They are well absorbed after oral administration. t 1/2 varies from hrs. Fluoxetine is longer acting ( hr) Paroxetine & fluoxetine inhibit hepatic metabolism of TCA Mechanism of action: They selectively block 5-HT reuptake leading to accumulation of 5-HT in brain tissue. Their effect appears after 2-3 weeks like other antidepressants.

Adverse effects: Anorexia, nausea and vomiting (usually disappear in a week). Diarrhea Sexual dysfunction, Weight gain Sleep disturbances (insomnia, more vivid and memorable dreams, morning sleepiness). Seizures, Extrapyramidal symptoms Serotonin syndrome Discontinuation syndrome: abrupt discontinuation of an SSRI or SNRI can cause a variety of symptoms that can be quite distressing. These include dizziness, nausea and vomiting, flulike symptoms, irritability and anxiety.

Drug interactions: Serotonin syndrome: patient present with hyperthermia, aqgitation, hypertension and convulsion SSRI (mainly fluoxetine and paroxetine) are inhibitors of the cytochrome P450 system and therefore can increase the effects of several drugs given concomitantly

Contraindications Seizure disorders Suicidal ideation Hepatic disease (liver clearance can be decreased) Children (about 1 out of 50 children become more suicidal) Pregnancy category C (only paroxetine is classified in FDA pregnancy risk category D)

4. Other (atypical) antidepressants 1. Trazodone: The drug is thought to act primarily as an antagonist at 5-HT2-A and 5-HT2-C presynaptic receptors It can cause pronounced sedation because it blocks H1 receptor. Used as an unlabeled hypnotic, since it is not associated with tolerance or dependence

2. Mirtazapine Mechanism of action Block presynaptic alpha-2 receptors, which results in increased release of norepinephrine. Blockade of 5-HT2A/C presynaptic receptors. Blockade of H1 receptors (which likely mediates the sedative effects)

NB: Atypical antidepressants are similar in effects to TCA but differ in: – They have faster onset of action. – They have fewer side effects (less cardiotoxic & atropine-like effects).

Mood stabilizing drugs Sodium valproate, Lithium, Carbamazepine Used in the treatment of mania Sodium valproate is the only specific antimanic agent and is the treatment of choice in the acute stages. Lithium is the drug of choice for long-term treatment to prevent relapse.

Lithium carbonate Mechanism of action: It ↓ cAMP in neuronal cells → ↓ neuronal firing. It ↓ NA release in the CNS. It interferes with Na+/K+ ATPase activity in neuronal tissues. Li+ can mimic the role of Na+ in excitable tissues. It goes across cell membranes an Na+ sodium in action potential. It is not pumped out by Na+/K+ ATPase and therefore it tends to accumulate inside the cells, displacing Na+. Ca++/Na+ exchanger is not significantly affected at therapeutic concentration

Pharmacokinetics Oral bioavailability: 100% Distribution in total body water (Vd. 45 L) No metabolism Excretion: 97% in the urine (80% is reabsorbed in the proximal tubule, some is reabsorbed in the collecting duct). Half -life: 20 hours (Accumulation can be a problem due to the long half life since it has low therapeutic index)

Therapeutic uses: Treatment of mania (valproate is the 1st choice). Treatment of manic-depressive disorder (bipolar depression). Adverse effects: – Tremor, Memory impairment, poor concentration – Ataxia, aphasia, seizures (with high doses). – Anorexia, nausea, vomiting and diarrhea. – Nephrogenic diabetes insipidus – Hypothyroidism – Hypotension and cardiac arrhythmia. – Edema, frequent during the first 5-7 days of therapy (likely due to increased Na+ in the ECF). – Teratogenicity.

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