Affective Disorders

Drugs used in affective disorders II.

Drugs used in affective disorders

Antimanic or mood stabilizing agents. Drugs used in manic depressive psychosis or bipolar illness. 1. Lithium 2. Alternative drugs: o Carbamazepine o Valproic acid o Other drugs used for mania: olanzapine, lamotrigine, risperidone, haloperidol, etc. Lithium Lithium carbonate and citrate are in use. It is a small monovalent cation. Mechanism of action- Remains unclear. Possibilities are: 1. Effect on electrolytes and ion transport: Li is closely related to Na+, can substitute for it in generation of action potential but is not a substrate for Na+ pump, hence can’t maintain membrane potential. 2. • • • 3.

Effect on neurotransmitters. Enhances some actions of 5 HT. Effects on NE and D release: may decrease NE or D turnover (antimanic effect). May augment the synthesis of ACh by increasing uptake of choline into nerve terminals. Increasing cholinergic activity reduce mania. Effect on 2nd messengers 1 2 a. IP2à IP1à inositol. Lithium inhibits step 1 and 2 i.e. it inhibits conversion of IP2 to IP1 and conversion of IP1 to inositolà depletion of PIP2 (phosphatidyl inositol 4-5 biphosphate), the membrane precursor of IP3 and DAG. Li selectively inhibits overactive circuits. b. Lithium inhibits NE sensitive adenyl cyclase. (antidepressant and antimanic effect). c. It may uncouple receptor from their G proteins (renal and thyroid action)

ADME: Absorption: oral absorption complete in 2-6 hours. Distribution: in TBW. No protein binding. Crosses placental barrier and secreted in milk. Excretion: completely through kidneys. Half life 20 hours. Therapeutic concentration: 0.6-1.4 mEq/L Monitoring done 10 hours after last dose. Adverse effects • Neurologic and psychiatric effects: – Tremor: propranolol/atenol may relieve this tremor. – Choreoathetosis, motor hyperactivity, ataxia, dysarthria and aphasia. – Psychic disturbances : mental confusion.

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Effect on thyroid: hypothyroidism- reversible. Effects on Kidney: – Polydipsia (thirst) and polyuria- nephrogenic diabetes insipidus due to inhibition of action of ADH; responds to amiloride. – Chronic interstitial nephritis, minimal change glomerulonephropathy with nephrotic syndrome. • Odema due to sodium retention, weight gain. • Cardiac adverse effects: bradycardia, T wave changes, contraindication sick sinus syndrome. • Teratogenicity: increased cardiac anomalies. • Others: – Acne – Folliculitis. – Leucocytosis. – GIT: anorexia, vomiting, and diarrhoea Lithium toxicity: increased by dehydration and diuretics. Anorexia, vomiting, diarrhoea, tremors, ECG changes, depression, inversion of T waves, generalised coarse tremors, hypertonia, hyperreflexia, epileptiform seizures, coma., death..

Treatment of acute toxicity: Mannitol Dialysis. Drug Interactions: • Renal clearance of lithium is reduced about 25% by diuretics (thiazides )-and so reduce the dose of lithium in same proportion. • NSAIDs, which block synthesis of PG, also reduce Li clearance. Contraindications • Pregnancy • Lactation Uses : i. Bipolar affective disorder: • In manic phase, because of its slow onset of action: valproate or olanzapine or haloperidol + Bz are used. After control continue with Bz and lithium and stop antipsychotic drug. • Depression : Antidepressant + Li. TCA may cause mania with rapid cycling of mood swings. SSRI + Li- may be used. • Used as prophylactic agent in preventing both mania and depression. i. Other applications: – Resistant unipolar depression – Resistant schizophrenia. – Schizoaffective disorders. – Alcoholism and bipolar illness. – Aggressive violent behavior of prisoners. Other drugs for MDP Carbamazepine: to treat acute mania and also for prophylactic therapy. Valproic acid: used for recurrent cases. ____________________________________________________________

Antidepressant drugs Types of depression 1. Unipolar- mood swings in one direction.

Drugs used in affective disorders

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i. Reactive, ii. endogenous/major depression 2. Bipolar: mood swings between mania and depression The Monoamine theory of depression: Depression results from functionally deficient monoaminergic(NE/5HT) transmission in the CNS. • Inhibitors of NE and 5HT reuptake improves mood. • Inhibition of MAO has antidepressant effect. • Reserpine which depletes monoamine stores in the nerve ending, causes depression. Classification Antidepressants 1. Inhibitors of reuptake of monoamine transmitters: I. Tricyclic antidepressants (TCA): e.g. imipramine, amitriptyline, clomipramine II. Selective serotonin reuptake inhibitors (SSRI): fluoxetine, paroxetine, fluvoxamine III. Miscellaneous uptake inhibitors, e.g. maprotiline, venlafaxine 2. MAOI • Irreversible: phenelzine, tranylcypromine • Reversible: moclobemide 3. Atypical or miscellaneous antidepressants, e.g. trazodone, bupropion, mianserine, mirtazapine. General mechanism of action: A. Action on biogenic amine neurotransmitters 1. Monoamine reuptake inhibitors: Inhibition of uptake raises the concentration of transmitter in the synaptic cleft and increases stimulation of postsynaptic receptors. The selectivity for NE and 5HT varies between the three groups and between the compounds in the same group. 2. MAOI: These inhibit MAO within nerve endings. The cytosolic NE/5HT conc increases and more leaks out into synaptic cleft.There are two isoenzyme forms of MAO (A and B). Selective MAO-A are more effective antidepressants with fewer side effects. The older MAOIs bind covalently and have a long duration of action. The newer bind reversibly (e.g moclobemide) and are safer. 3. Atypical /miscellaneous antidepressants: Some have actions of monoamine transporters and on receptors. • Trazodone has weak 5HT uptake inhibition and antagonism at 5HT receptors (5HT2A/C). • Bupropion has dopamine and NE reuptake inhibition. • Mianserine and mirtazepine have α 2 adrenoceptor antagonism- increase release of monoamines. Mirtazepine also has NE uptake inhibition. • Iprindole has dopamine reuptake inhibition B.

Receptor and Post receptor effects:

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Down regulation of beta and 5HT2 receptors. Increased serotonergic transmission and increased stimulation or responsiveness of post synaptic 5HT1A These effects follow the same delayed time course as clinical improvement in patients.

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Tricyclic antidepressants (TCA)

Pharmacological actions of TCA TCA: varying degree of selectivity for NE and 5HT, have numerous autonomic effects. Chemically related to phenothiazines, hence have similar side effects: blockade of MACh, H1 and alpha receptors. CNS: • In normal persons: Peculiar clumpsy feeling, tiredness, lightheadedness, sleepiness, difficulty in concentration and thinking, unsteady gait and anxiety. • In depressed patient: sedation, after 2-3 weeks mood is elevated, pt becomes communicative, starts taking interest. Drugs with sedative activity are good for pt with anxiety and agitation and less sedative for withdrawn pts. • They lower seizure threshold- clomipramine- high seizure potential. ANS effects • Atropine like effects • Postural hypotension: alpha blocking action. CV effects • Tachycardia-due to anticholinergic effect and NE potentiating action. • Orthostatic/postural hypotension • ECG changes and cardiac arrhythmia- T wave suppression and inversion. Tolerance and dependence: • Tolerance to anticholinergic and hypotensive effects. • Physical dependence reported, withdraw slowly. ADME Well abs. distributed to all tissues, strongly protein bound; large Vd, metabolised in liver, some have active metabolites (imipramineà desipramine) amitriptylineà nortriptyline) and undergo enterohepatic circulation. Have long half lives, may be administered daily. Unwanted/adverse effects • Atropine like effects: dry mouth, blurred vision, constipation, urinary retention.. • CNS: – Sedation- day time performance is affected by drowsiness and difficulty in concentration. – Psychiatric: aggravation of psychosis. – Some patient may switch to hypomania, mania – Neurologic: seizures- lower seizure threshold. – CNS excitation in over dose- tremors, confusion, hallucination, delirium, violence, epileptic fits in susceptible patients. • Cardiovascular: orthostatic hypotension, conduction defects, arrhythmias • Sympathomimetic: tachycardia, agitation, tremor, insomnia, sweating.

Drugs used in affective disorders

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Metabolic: endocrine ( sexual disturbances), inc appetite and weight gain Others: – Rashes – Cholestatic jaundice – Agranulocytosis Disadvantages: take 2-4 weeks, not suitable for elderly and suicidal patients Drug interactions: Additive CNS depressant effect with other CNS depressants (alcohol, Bzs, barbiturates). Reversal of antihypertensive effect of guanethidine, α methyldopa and clonidine. Acute toxicity: Symptoms: 3C: (coma, convulsions and cardiotoxicity) • CNS- excitement, delirium, convulsions, followed by coma and respiratory depression. • Atropine like effects- flushing, dry mouth and skin and inhibition of gut and bladder. • Heart- cardiac dysrhythmias are common, usually atrial or ventricular extrasystoles or sudden death from ventricular fibrillation. • Hyperpyrexia. • Acidosis Treatment: • Physostigmine controls central atropinic symptoms. • Sodium bicarbonate to treat acidosis. • Phenytoin, propranolol to treat cardiac dysrhythmia. • Diazepam to control convulsions. • Dopamine to treat hypotension. 2.

Selective serotonin reuptake inhibitors (SSRI) • More effective than previous group. First choice for depression. • Currently the most prescribed group. • Patient acceptance high. • Lack toxicities of TCA. o Produce little or no sedation. o Less risk of switching over to hypomania o No anticholinergic side effects. o No alpha adrenergic blockade- no postural hypotension- suitable for elderly o No seizure producing activity. o No overdose cardiac arrhythmia o No weight gain. o Acute toxicity is less than MAOI or TCA so over dose risk is reduced. o No interaction with food Fluoxetine Takes 2-4 weeks to act clinically. Longest acting. Half life 2 days. Active metabolite half life-7-10 days. Adverse effects: • Nausea, anorexia, diarrhea

Drugs used in affective disorders •

Sexual dysfunction: loss of libido and orgasm- interference with ejaculation or orgasm. • Nervousness, restlessness, insomnia, headache, dyskinesia. • Increased aggression. • Serotonin syndrome with MAOI- tremor, hyperthermia, seizures, coma, CV collapse and death. Uses: • First choice for depression. • Other indications: OCD, panic disorder, social phobia, eating disorders (bulimia), post traumatic stress disorder, anxiety disorder, compulsive lying, kleptomania 3. MAOIs: Pharmacological actions Psychological effects: antidepressant action with elevation of mood occurs in 2-3 weeks and action lasts for a few weeks on stopping drug. In normal subjects, MAOI causes an immediate increase in motor activity, and euphoria and excitement develop over the course of a few days (in contrast to TCA which cause sedation and confusion). CVS: hypotension Unwanted effects • Hypotension. • Excessive central stimulation may cause tremors, excitement, hyperthermia, insomnia and convulsions. • Weight gain (due to increased appetite). • Atropine like side effects -dry mouth, blurred vision etc. • Hepatotoxicity: hydrazine type • Optic nerve damage. Interactions • Hypertensive crisis with : – Food containing tyramine: (mature cheeses, conc.yeast products such as marmite, wines, etc).. – Indirectly acting sympathomimetic amines (ephedrine, amphetamine). • Toxic synergism with TCA: excitement and hyperactivity. • Serotonin syndrome with SSRI • Inhibition of drug metabolising enzymes- potentiate actions of barbiturates, meperidine, sulfonylurea. Uses: Reactive depression responds better than endogenous, phobic disorders. ii.

Reversible inhibitor of monoamine oxidase A (RIMA) Moclobemide: Short acting • Action lasts 1-2 days. • No dietary restriction of tyramine. • No anticholinergic, sedative, cognitive, psychomotor, and cardiovascular adverse effects of typical TCAs; and is safe in overdose. • Particularly useful in elderly and in patient with heart disease. Adverse effects:

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Nausea, dizziness, headache, insomnia, rarely excitement and liver damage. • Interactions with alcohol, meperidine, SSRI and TCA, are less. Uses: mild to moderate depression and social phobia. 2. Atypical or miscellaneous antidepressants. • Fewer side effects (sedation, anticholinergic effects) than TCAs. • Lower acute toxicity in overdose. • Action with less delay e.g. mirtazapine • Efficacy in patients non-responsive to TCA and MAOI. • Atypical can be used with SSRI in treatment resistant cases. Uses of antidepressants. SSRI and TCA are used primarily, MAOI are less effective and are 2nd line drugs. • Depression- major depression. • Depressed phase of MDP: along with lithium. TCA may cause switch to mania, prefer SSRI. • Panic disorder: imipramine, as good as MAOI and Bzs for acute anxiety manifested as panic attacks. SSRI takes weeks to be effective. • Obsessive compulsive disorders: SSRI, clomipramine (5HT and NE reuptake inhibitor). • Enuresis in elderly- imipramine • Chronic pain: trigeminal neuralgia, migraine- TCA, not SSRI • Other indications: – Eating disorders: anorexia nervosa (TCA); bulimia (fluoxetine) – ADHD: atomoxetine (selective NE reuptake inh.), imipramine – Social phobia: SSRI preferred – Sleep apnea: imipramine – Generalised anxiety disorder: TCA Role of ECT in psychiatry Involves stimulation through electrodes placed on either side of the head, with the patient lightly anaesthetized, paralyzed with NMB drug, so as to avoid physical injury and artificially ventilated. It is as effective as antidepressant drugs with response ranking between 60-80%. It is most effective in patients with severe suicidal depression. Disadvantages- Confusion and memory loss lasting for a few days or weeks. Biochemical effect: Down regulation of beta receptors

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Anxiety disorders

Neurones involved : adrenergic, serotonergic, gabaergic. Anxiolytic drugs: Bzs, azapirons (buspiron) Drugs with anxiolytic effects: antidepressants (imipramine, SSRI, venlafaxine, moclobemide); beta blockers. Generalised anxiety disorders: • Bzs (diazepam, lorazepam): immediate effect; not more than 3-4 weeks, gradual withdrawal • Buspiron: 5HT1A agonist; effect starts after 3 weeks, no cross tolerance with Bz. • Antidepressant drugs- contd for 6-12 months.

Drugs used in affective disorders •

Propranolol

Phobic disorders: • Bzs (diazepam, lorazepam) • Antidepressants: SSRI, MAOI- contd for 6-12 months • Beta blockers- propranolol. Panic disorders: • Bzs: alprazolam, clonazepam • Antidepressant drugs: imipramine, SSRI, moclobemide Obsessive compulsive disorder: • SSRI • Clomipramine Used up to 12 weeks

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