e.g. interpersonal difficulties or other life stresses (including physical illness), antidepressant drugs may be useful. Drugs used in the initial treatment of depression include TCAs and related drugs, SSRIs and SNRIs. Although clinical experience is most extensive with the TCAs, the side-effect profile of the SSRIs is usually less troublesome, and these drugs are safer in overdose. Therefore many psychiatrists and general practitioners use SSRIs rather than TCAs as first-line treatment for depression. SSRIs are more expensive than TCAs. The relative side effects of the different antidepressant drugs are summarized in Table 20.1. In refractory depression, other drug treatment or electroconvulsive therapy (ECT) are considered. Alternative drug strategies include (1) adding lithium to a tricyclic to give a lithium blood level of 0.6–0.8 mmol/L; (2) combining antidepressants; (3) augmenting with T3 (or T4), a mood stabilizer such as lamotrigine, buspirone or estradiol; (4) MAOIs, usually prescribed only by psychiatrists; (5) MAOI plus a TCA – but only in expert psychiatric hands; or (6) small doses of flupentixol (for short-term treatment only). Figures 20.1 and 20.2 show a treatment algorithm for management of depressive illness. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) These drugs are safer in overdose than the tricyclic group. Selective serotonin reuptake inhibitors (SSRIs) do not stimulate Table 20.1: Relative antidepressant side effects DEPRESSIVE ILLNESSES AND ANTIDEPRESSANTS 117 appetite and have much fewer antimuscarinic side effects than the tricyclics and other catecholamine-uptake inhibitors. They are also well tolerated in the elderly. Examples include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram. Uses These include the following: 1. in depression (they have similar efficacy to tricyclics, but are much more expensive); 2. in chronic anxiety, and as prophylaxis for panic attacks; 3. obsessive-compulsive states; 4. bulimia nervosa; 5. seasonal affective disorder, especially if accompanied by carbohydrate craving and weight gain; 6. possibly effective as prophylactic agents in recurrent depression. Adverse effects 1. The most common adverse reactions to SSRIs are nausea, dyspepsia, diarrhoea, dry mouth, headache, insomnia and dizziness. Sweating, erectile dysfunction and delayed orgasm are well-recognized associations. These tend to become less severe after one to two months of treatment. 2. They have less anticholinergic and cardiotoxic actions than tricyclic drugs. Drug Anticholinergic Cardiac Nausea Sedation Overdose Pro-convulsant Tyramine Tricyclics and related antidepressants effects effects risk interaction Amitriptyline ��� ��� � ��� �� �� � Clomipramine ��� �� � �� � �� � Dothiepin �� �� � ��� ��� �� � Imipramine �� �� � � �� �� � Lofepramine �� � � � � � � Trazodone Selective serotonin reuptake inhibitors � � �� �� � � � Citalopram � � �� � � � � Fluoxetine � � �� � � ? � Paroxetine � � �� � � ? � Sertraline Monoamine oxidase inhibitors � � �� � � ? � Phenelzine � � �� � � � ��� Moclobemide Others � � � � � ? � Venlafaxine � �� �� � ? � � �, little or nothing reported; �, mild; ��, moderate; ���, high; ?, insufficient information available.
118 MOOD DISORDERS 3. Epilepsy can be precipitated. 4. They are usually non-sedating, but may cause insomnia and do not usually cause orthostatic hypotension. 5. All antidepressants can cause hyponatraemia, probably due to induction of inappropriate antidiuretic hormone secretion, but it is reported more frequently with SSRIs than with other antidepressants. Contraindications These include the following: • hepatic and renal failure; • epilepsy; • manic phase. Psychotherapy Significant symptoms persist after 6 weeks Add medication Continue same treatment Diagnosis of unipolar depression Psychotherapy and medication Evaluate response to medication after 3–4 weeks Evaluate response to medication after 6–8 weeks Medication Partial response No response Advance dose as tolerated Symptoms resolving Symptoms persist Go to second phase of treatment Figure 20.1: General algorithm for the initial phase of treatment of depression. When symptoms persist after first-line treatment, re-evaluate the accuracy of the diagnosis, the adequacy of the dose and the duration of treatment before moving to the second phase of treatment. (Redrawn with permission from Aronson SC and Ayres VE. ‘Depression: A Treatment Algorithm for the Family Physician’, Hospital Physician Vol 36 No 7, 2000. Copyright 2000 Turner White Communications, Inc.) Drug interactions • Combinations of SSRI with lithium, tryptophan or MAOIs may enhance efficacy, but are currently contraindicated because they increase the severity of 5HT-related toxicity. In the worst reactions, the life-threatening 5HT syndrome develops. This consists of hyperthermia, restlessness, tremor, myoclonus, hyperreflexia, coma and fits. After using MAOIs, it is recommended that two weeks should elapse before starting SSRIs. Avoid fluoxetine for at least five weeks before using MAOI because of its particularly long halflife (about two days). • The action of warfarin is probably enhanced by fluoxetine and paroxetine. • There is antagonism of anticonvulsants. • Fluoxetine raises blood concentrations of haloperidol. SEROTONIN-NORADRENALINE REUPTAKE INHIBITORS AND RELATED ANTIDEPRESSANTS Venlafaxine: A potent 5HT and NA uptake inhibitor that appears to be as effective as TCAs, but without anticholinergic effects. It may have a more rapid onset of therapeutic action than other antidepressants, but this has yet to be confirmed. It is associated with more cardiac toxicity than the SSRIs. Duloxetine inhibits NA and 5HT reuptake. TRICYCLICS AND RELATED ANTIDEPRESSANTS (TCAs) Uses These include the following: 1. depressive illnesses, especially major depressive episodes and melancholic depression; 2. atypical oral and facial pain; 3. prophylaxis of panic attacks; 4. phobic anxiety; 5. obsessive–compulsive disorders; 6. imipramine has some efficacy in nocturnal enuresis. Although these drugs share many properties, their profiles vary in some respects, and this may alter their use in different patients. The more sedative drugs include amitriptyline, dosulepin and doxepin. These are more appropriate for agitated or anxious patients than for withdrawn or apathetic patients, for whom imipramine or nortriptyline, which are less sedative, are preferred. Protriptyline is usually stimulant. Only 70% of depressed patients respond adequately to TCAs. One of the factors involved may be the wide variation in individual plasma concentrations of these drugs that is obtained with a given dose. However, the relationship between plasma concentration and response is not well defined. A multicentre collaborative study organized by the World Health Organization failed to demonstrate any relationship whatsoever between plasma amitriptyline concentration and clinical effect.