AFFECTIVE DISORDERS Affective disorders involve a disturbance of mood (cognitive/emotional symptoms) associated with changes in behaviour, energy, appetite

and sleep (biological symptoms). Affective disorders can be thought of as pathological extremes of the normal continuum of human moods, from extreme excitement and elation (mania) to severe depressive states. There are two types of affective disorder: Unipolar affective disorders and bipolar affective disorders. Unipolar affective disorders A common unipolar affective disorder is depression, which is characterized by misery, malaise, despair, guilt,apathy, indecisiveness, low energy and fatigue, changes in sleeping pattern, loss of appetite and suicidal thoughts. classify depression as either reactive or endogenous in origin. Reactive depression is where there is a clear psychological cause, less-severe symptoms and less likelihood of biological disturbance. it is more common in females. Endogenous depression is where there is no clear cause and more severe symptoms, e.g. suicidal thoughts, and a greater likelihood of biological disturbance, The distinction between reactive and endogenous depression is of importance since there is some evidence that depressions with endogenous features tend to respond better to drug therapy. TCAs and related drugs TCAs nclude amitriptyline, imipramine, dosulepin (dothiepin) and lofepramine. Mechanism of actionTCAs act by blocking 5-HT and noradrenaline uptake into the presynaptic terminal from the synaptic cleft . They also have a certain affinity for H1 and muscarinic receptors, and for a1- and a2-receptors. ContraindicationsTCAs and related drugs should not be used in: Recent myocardial infarction or arrhythmias (especially heart block) since TCAs increase the risk of conduction abnormalities Manic phase Severe liver disease Epilepsy, where TCAs lower the seizure threshold Patients taking other anticholinergic drugs, alcohol and adrenaline as TCAs potentiate the effects of these. Lidocaine is contraindicated in combination with TCAs, owing to a potentially fatal drug interaction. Adverse effectsAlthough TCAs are an effective therapy for depression, their adverse effects can reduce patient compliance and acceptability. Side-effects include: Muscarinic blocking effects such as a dry mouth,blurred vision, constipation a-Adrenergic blocking effects causing postural hypotension Noradrenaline uptake block in the heart, increasing the risk of arrhythmias Histamine-blocking effects leading to sedation Weight gain. TCAs are relatively dangerous in overdose. Patients present with confusion, mania, and potentially fatal arrhythmias due to the cardiotoxic nature of the drug. Therapeutic notesNo individual TCA has superior antidepressant activity, and the choice of drug is usually determined by the most acceptable or desired side effects. For example, drugs with sedative actions, such as amitriptyline or trimipramine, are the TCAs of choice for patients in agitated or anxious states. The most recent TCA is lofepramine, which causes fewer antimuscarinic sideeffects, and is less dangerous if taken in overdose.Therapeutic effects take 2 3 weeks to develop. TCArelated antidepressants should be withdrawn slowly.

Selective serotonin reuptake inhibitors (SSRIs) Mechanism of actionSSRIs act with a high specificity for potent inhibition of serotonin reuptake into nerve terminals from the synaptic cleft, while having only minimal effects on noradrenaline .They block serotonin transporters, which belong to a class of Na+/Cl-coupled transporters. ContraindicationsSSRIs should not be used with MAO inhibitors as the combination can cause a potentially fatal serotonergic syndrome of hyperthermia and cardiovascular collapse. Adverse effectsThe side-effect profile of SSRIs is much better than that of TCAs and MAO inhibitors as there are no amine interactions, anticholinergic actions,adrenergic blockade or toxic effects in overdose. Therapeutic notesSSRIs have a similar efficacy to that of TCAs. It is their clinical advantages and lack of side-effects that have led to their popularity. SSRIs are now the most widely prescribed antidepressants. Serotonin-noradrenaline reuptake inhibitors Venlafaxine is the most commonly used serotonin-noradrenalinereuptake inhibitor(SNRI)-typeantidepressant. Mechanism of actionSNRIs cause potentiation of neurotransmitter activity in the CNS, by blocking the norepinephrine and serotonin reuptake transporter . ContraindicationsThe drug interactions of SNRIs are much like those of SSRIs; however, extra care must be taken with hypertensive patients as venlafaxine raises blood pressure. Adverse effectsThe adverse effects of SNRIs are similar to those of SSRIs, but they occur with lower frequency.

Therapeutic notesThe pharmacological effects of venlafaxine are similar to those of the TCAs, but adverse effects are reduced because it has little affinity for cholinergic and histaminergic receptors or a-adrenoreceptors. MAO inhibitors Examples of irreversible MAO inhibitors include phenelzine, tranylcypromine and isocarboxazid, example of reversible inhibitors of MAOA (RIMAs) is moclobemide. Mechanism of actionMAO inhibitors block the action of MAOA and MAOB, which are neuron enzymes that metabolize the monoamines (noradrenaline, 5-HT and dopamine) . two main isoforms,MAOA and MAOB. Inhibition of the MAOA form correlates best with antidepressant efficacy. Adverse effectsDietary interactions may occur, such as the cheese reaction. MAO in the gut wall and liver normally breaks down ingested tyramine. When the enzyme is inhibited, tyramine reaches the circulation and this causes the release of noradrenaline from sympathetic nerve terminals; this can lead to a severe and potentially fatal rise in blood pressure. Preparations containing sympathomimetic amines (e.g.cough mixtures and nasal decongestants) should also be avoided. MAO inhibitors are not specific, and they reduce the metabolism of barbiturates, opioids and alcohol. Therapeutic notesResponse to treatment may be delayed for 3 weeks or more. Because of the dietary and drug restrictions outlined above, MAO inhibitors are largely reserved for depression refractory to other antidepressants and treatment. Atypical antidepressants Examples of atypical antidepressants include reboxetine, mirtazapine and tryptophan. Mechanism of actionReboxetine is a selective inhibitor of noradrenaline reuptake, increasing the concentration of this mediator in the synaptic cleft. Mirtazapine has a2-adrenoreceptor-blocking activity, which, by acting on inhibitory a2-autoreceptors on central noradrenergic nerve endings, may increase the amount of noradrenaline in the synaptic cleft. Tryptophan is an amino acid precursor for serotonin. ContraindicationsThe contraindications for atypical antidepressants are similar to those for TCAs. Adverse effectsAtypical antidepressants generally cause less autonomic side-effects and are less dangerous in overdose, owing to their lower cardiotoxicity compared with TCAs. mirtazapine may cause agranulocytosis. Tryptophan is associated with eosinophilas Myalgia syndrome. Therapeutic notesMirtazapine is sedative, and it is, therefore, used in depression when a degree of sedation is desirable. Neither reboxetine nor mirtazapine are currently first-line drugs for the treatment of depression. Tryptophan requires specialist supervision due to the stated adverse affect. Bipolar affective disorder Bipolar affective disorder presents with mood and behavior oscillating between depression and mania, and it is, therefore, also known as manic-depressive disorder. HINTS AND TIPS Mania hardly ever exists in isolation from depression,which is why it is referred to as bipolar affective disorder. Treatment of bipolar affective disorders Bipolar affective disorder is treated with a combination of mood stabilizers and antidepressants, and sometimes antipsychotics. Mood stabilizers include lithium and carbamazepine. Lithium Lithium is administered as lithium carbonate, and it is the most widely used mood stabilizer, with antimanic and antidepressant activity. Mechanism of actionThe mechanism of action of lithium is unclear, but it probably involves modulation of secondary-messenger pathways of cAMP and inositol triphosphate (IP3). It is known that lithium inhibits the pathway for recapturing inositol for the resynthesis of polyphosphoinositides. It may exert its effect by reducing the concentrations of lipids important in secondary signal transduction in the brain. IndicationsLithium salts are mainly used in the prophylaxis and treatment of bipolar affective disorder, but also in the prophylaxis and treatment of acute mania and in the prophylaxis of resistant recurrent depression. ContraindicationsSome drugs may interact, causing a rise in plasma lithium concentration and so should be avoided. Such drugs include antipsychotics, non-steroidal anti-inflammatory drugs (NSAIDs), diuretics and cardioactive drugs. Lithium is excreted via the kidney, and caution should be employed in patients with renal impairment. Adverse effectsLithium has a long plasma half-life and a narrow therapeutic window; Early side-effects include thirst, polyuria nausea,diarrhoea, tremor and; late side-effects include weight gain, edema, acne, nephrogenic diabetes insipidus and hypothyroidism. Toxicity/overdose (serum level >23 mmol/L) effects include vomiting, diarrhoea, tremor, ataxia, confusion and coma. Therapeutic notesCareful monitoring after initiation of treatment is essential. Carbamazepine Carbamazepine is as effective as lithium in the prophylaxis of bipolar affective disorder and acute mania, particularly in rapidly alternating bipolar affective disorder. Mechanism of actionCarbamazepine is a GABA agonist, and this may be the basis of its antimanic properties. The relevance of its effect in stabilizing neuronal sodium, and on calcium channels, is unclear. Adverse effectsDrowsiness, diplopia, nausea, ataxia, rashes and headache; blood disorders such as agranulocytosis and leucopenia; and drug interactions with lithium, antipsychotics, TCAs and MAO inhibitors. Many other drugs can be affected by the effect of carbamazepine on inducing hepatic enzymes. Diplopia, ataxia, clonus, tremor and sedation are associated with acute carbamazepine toxicity. Therapeutic notesAt the start of treatment with carbamazepine, plasma concentrations should be monitored to establish a maintenance dose.