Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 21A) pptx

19 Psychotropic drugs SYNOPSIS Advances in drug treatment have revolutionised the practice of psychiatry over the past six decades. Drugs provide a degree of stability and control in the lives of those suffering from schizophrenia, a chronic debilitating illness with impact so profound that it accounts for 2-3% of UK national health spending. Similarly, the impact of medication in alleviating the burden on individuals, their families and society of depression, which has a lifetime prevalence of up to I in 6 of the population, is substantial. Psychotropic drugs greatly improve the prognosis of other common conditions such as anxiety disorders, attention deficit/hyperactivity disorder and bipolar affective disorder. In this chapter the following drug groups are considered Antidepressants Antipsychotics ('neuroleptics') Mood stabilisers Drugs for anxiety and sleep disorders Drugs for Alzheimer's dementia Drugs for attention deficit/hyperactivity disorder Writing prescriptions is easy, understanding people is hard. (Franz Kafka, 1883-1924) In 1940 psychotropic medication was limited to chloral hydrate, barbiturates and amphetamine. By contrast, the modern-day formulary lists almost 100 psychotropic drugs, with efficacious treatment avail- able for the vast majority of psychiatric diagnoses and in all phases of life. Psychotropic medication has been a key factor in accelerating the closure of Victorian 'asylums' such that the psychiatric inpatient population is now a tiny fraction of its 1954 peak of 148,000 in England and Wales. DIAGNOSTIC ISSUES Older classifications of psychiatric disorder divided diseases into 'psychoses' and 'neuroses'. The term 'psychosis' is still widely used to describe a severe mental illness with the presence of hallucinations, delusions or extreme abnormalities of behaviour including marked overactivity, retardation and catatonia, usually accompanied by a lack of insight. Psychotic disorders therefore include schizophrenia, severe forms of depression and mania. Psychosis may also be due to illicit substances or organic con- ditions. Clinical features of schizophrenia may be subdivided into 'positive symptoms', which include hallucinations, delusions and thought disorder and 'negative symptoms' such as apathy, flattening of affect and poverty of speech. Disorders that would formerly have been grouped under 'neuroses' include depression in the absence of psychotic symptoms, anxiety disorders (e.g. panic disorder, generalised anxiety disorder, obsessive- compulsive disorder, phobias and post-traumatic stress disorder), eating disorders (e.g. anorexia nervosa and bulimia nervosa) and sleep disorders. 367 19 PSYCHOTROPIC DRUGS Also falling within the scope of modern psychia- tric diagnostic systems are organic mental disorders (e.g. dementia in Alzheimer's disease), disorders due to substance misuse (e.g. alcohol and opiate dependence—see Chapter 10), personality disorders, disorders of childhood and adolescence (e.g. attention deficit/hyperactivity disorder, Tourette's syndrome) and mental retardation (learning disabilities). DRUG THERAPY IN RELATION TO PSYCHOLOGICALTREATMENT No account of drug treatment strategies for psy- chiatric illness would be complete without consi- deration of psychological therapies. Psychotherapy is broad in content, ranging from simple counselling and 'supportive psychotherapy' sessions through ongoing formal psychoanalysis to newer techniques such as cognitive behavioural therapy. As a general rule, psychotic illnesses (e.g. schizo- phrenia, mania and depressive psychosis) require drugs as first-line treatment, with psychothera- peutic approaches limited to an adjunctive role, for instance in promoting drug compliance, improving family relationships and helping individuals cope with distressing symptoms. By contrast, for non- psychotic depression and anxiety disorders such as panic disorder and obsessive-compulsive disorder, forms of psychotherapy are available which provide alternative first-line treatment to medication. The choice between drugs and psychotherapy depends on treatment availability, previous history of response, patient preference and the ability of the patient to work appropriately with the chosen therapy. In many cases there is scope to use drugs and psychotherapy in combination. Taking depression as an example, an extensive evidence base exists for the efficacy of several forms of psychotherapy. These include cognitive therapy (in which individuals identify faulty views and negative automatic thoughts and attempt to replace them with ways of thinking less likely to lead to depression), interpersonal therapy (which focuses on relationships, roles and losses), brief dynamic psychotherapy (a time-limited version of traditional psychoanalysis) and cognitive analytical therapy (another well structured time-limited therapy which combines the best points of cognitive therapy and traditional analysis). Finally, it must be stressed that all doctors who prescribe psychotropic drugs engage in a 'thera- peutic relationship' with their patients. A depressed person whose doctor is empathic, supportive and appears to believe in the efficacy of the drug prescribed is more likely both to take the medica- tion and to adopt a mindset that might actually make him or her feel better than if the doctor seemed aloof and ambivalent about the value of psychotropic drugs. Remembering that placebo response rates of 30-40% are common in double- blind trials of antidepressants, we should never underestimate the importance of our 'therapeutic relationship' with the patient in enhancing the pharmacological efficacy of the drugs we use. Antidepressant drugs Antidepressants can be broadly divided into four main classes (Table 19.1), tricydics (TCA, named after their three ring structure), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibi- tors (MAOIs), and novel compounds some of which are related to TCAs or SSRIs. Clinicians who wish to have a working knowledge of antidepressants would be advised to be familiar with the use of at least one drug from each of the four main categories tabulated. A more thorough knowledge base would demand awareness of differences between individual TCAs and of the distinct characteristics of the novel compounds. Since antidepressants are largely similar in their therapeutic efficacy, awareness of profiles of unwanted effects is of particular importance. An alternative categorisation of antidepressants is based solely on mechanism of action (Fig. 19.1). The majority of antidepressants, including TCAs, SSRIs and related compounds are reuptake inhibitors. Certain novel agents including trazodone and mirtazapine are receptor blockers while MAOIs are enzyme inhibitors. The first TCAs (imipramine and amitriptyline) and MAOIs appeared between 1957 and 1961 (Fig. 19.1). The MAOIs were developed from anti- tuberculosis agents which had been noted to elevate mood. Independently, imipramine was synthesised from the antipsychotic drug chlorpro- mazine and found to have antidepressant rather than antipsychotic properties. Over the next 25 368 A N Tl D E P RE SS AN T DRUGS 19 TABLE 19.1 Classification of antidepressants Tricyclics Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors Dothiepin (dosulepin) Amitriptyline Lofepramine Clomipramine Imipramine Trimipramine Doxepin Nortriptyline Protriptyline Desipramine Fluoxetine Paroxetine Sertraline Citalopram* Fluvoxamine Phenelzine Isocarboxazid Tranylcypromine Moclobemide (RIMA) Novel compounds Mainly noradrenergic Mainly serotonergic Reboxetine (NaRI) Trazodone Nefazodone Mixed Venlafaxine (SNRI) Mirtazapine (NaSSA) Milnacipran (SNRI) Within each class or subclass drugs are listed in order of frequency of prescription in the United Kingdom (1997 data). Abbreviations; RIMA—reversible inhibitor of monoamine oxidase; NaRI—noradrenaline reuptake inhibitor; SNRI—serotonin and noradrenaline reuptake inhibitor; NaSSA—noradrenaline and specific serotonergic antidepressant. * Citalopram is a racemic mixture of S and R isomers.The antidepressant activity of citalopram appears to reside in the S-isomer. Escitalopram the pure S-isomer, may offer clinical benefits over existing preparations. Trazodone, nefazodone and mirtazapine have been classed as 'receptor blocking' antidepressants based on their antagonism of postsynaptic serotonin receptors (trazodone, nefazodone) and presynaptic 2 -receptors (trazodone, mirtazapine). Nefazodone has additional weak SSRI activity. fl Not available in the United Kingdom. years the TCA class enlarged to more than 10 agents with heterogeneous pharmacological profiles and further modifications of the original three ring structure gave rise to the related (but pharmaco- logically distinct) antidepressant trazodone. In the 1980s an entirely new class of antidepres- sant arrived with the SSRIs, firstly fluvoxamine immediately followed by fluoxetine (Prozac). Within 10 years, the SSRI class accounted for half of anti- depressant prescriptions in the United Kingdom. Further developments in the evolution of the anti- depressants have been novel compounds such as venlafaxine, reboxetine, nefazodone and mirtaza- pine, and a reversible monoamine oxidase inhibitor, moclobemide. Mechanism of action The monoamine hypothesis proposes that, in depres- sion, there is deficiency of the neurotransmitters noradrenaline and serotonin in the brain which can be altered by antidepressants. Drugs that affect depression can modify amine storage, release, or uptake (Fig. 19.2). Thus the concentration of amines in nerve endings and/or at postsynaptic receptors is enhanced. In support of the monoamine hypo- thesis are the findings that amfetamines, which release presynaptic noradrenaline and dopamine from stores and prevent their reuptake, have a weak antidepressant effect, whilst the antihypertensive agent reserpine, which prevents normal noradrena- line storage, causes depression, as does experimental depletion of the serotonin precursor tryptophan. The importance of serotonin is further illustrated by the finding that depressed patients may exhibit down-regulation of some postsynaptic serotonin receptors. Specific serotonin reuptake inhibitors, as the class name implies, act predominantly by prevent- ing serotonin reuptake and have more limited effects on noradrenaline reuptake. Tricyclic antidepressants in general inhibit noradrenaline reuptake, but effects on serotonin reuptake vary widely; desipra- mine and protriptyline have minimal potential for raising serotonin concentrations, whereas clomi- pramine possesses a greater propensity for blocking serotonin reuptake than for noradrenaline. The 369 19 PSYCHOTROPIC DRUGS Reuptake inhibitors 1950s 1960s 1970s 1980s 1990s Tricyclics Amitriptyline Imipramine Predominantly noradrenergic TCAs Desipramine Predominantly seratonergic TCAs Clomipramine SSRIs Fluoxetine Paroxetine SNRIs Venlafaxine NaRls Reboxetine Receptor blockers Mianserin Trazodone Nefazodone Mirtazapine Enzyme inhibitors Monoamine Oxidase Inhibitors Phenelzine RIMAs Moclobemide Key-Drugs classes in boxed, shaded fields represent the three major antidepressants groups, tricyclics (TCAs), selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors. Novel compounds are left unboxed. NaRI-noradrenaline reuptake inhibitor SNRI-serotonin and noradrenaline reuptake inhibitor RIMA-reversible inhibitor of monoamine oxidase *-Mianserin is rarely used due to associations with aplastic anaemia t-Nefazodone is both a reuptake inhibitor and receptor blocker Fig. 19.1 Flow chart of the evolution of antidepressant drugs and classification by mechanism of action. novel compound venlafaxine is capable of exerting powerful inhibition of reuptake of both trans- mitters, noradrenergic activity appearing at doses greater than 200 mg/day. Mirtazapine also achieves an increase in noradrenergic and serotonergic neuro- transmission, but through antagonism of presynap- tic a 2 -autoreceptors (receptors that mediate negative feedback for transmitter release, i.e. an autoinhibi- tory feedback system). Nefazodone has properties of weak serotonin reuptake inhibition but addi- tionally has complex but principally antagonist effects on postsynaptic serotonin receptors, a property it shares with trazodone. MAOIs increase the availability of noradrenaline and serotonin by preventing their destruction by the monoamine oxidase type A enzyme in the presynaptic terminal. The older MAOIs, phenelzine, tranylcypromine and isocarboxazid, bind irreversibly to monamine oxidase enzyme by forming strong (covalent) bonds. The enzyme is thus rendered permanently ineffective such that amine metabolising activity can be restored only by production of fresh enzyme, which takes weeks. These MAOI are thus called hit and run drugs as their effects greatly outlast their detectable presence in the body. But how do changes in monoamine transmitter levels produce an eventual elevation of mood? Raised neurotransmitter concentrations produce immediate alterations in postsynaptic receptor activation, leading to changes in second messenger (intracellular) systems and to gradual modifications in cellular protein expression. Antidepressants increase a cyclic AMP response-element binding (CREB) protein which in turn is involved in 370 ANTIDEPRESS ANT DRUGS 19 Physiological processes at the synapse: 1. When an electrical signal reaches the presynaptic terminal, presynaptic amine vesicles fuse with the neuronal membrane and release their contents into the synaptic cleft. 2. Amines in the synaptic cleft bind to postsynaptic receptors to produce a post synaptic response. 3. Amines may be removed from the synaptic cleft by reuptake into the presynaptic neuron. 4. The monoamine oxidase enzyme breaks down presynaptic amines. Effects of antidepressants: A. Tricyclics prevent presynaptic reuptake of the amines nonadrenaline and serotonin B. SSRIs predominantly block reuptake of serotonin. C. MAOIs reduce the activity of monoamine oxidase in breaking down presynaptic amines (leaving more available for release into the presynaptic cleft). D. Some antidepressants (e.g. nefazodone) block postsynaptic receptors directly. Fig. 19.2 Mechanism of action of antidepressant drugs at the synapse. regulating the transcription of genes that influence survival of other proteins including brain derived neurotrophic factor (BDNF) which exerts effects on neuronal growth. The role of BDNF in depression is supported by the observation that stress both reduces its expression and impairs neurogenesis. While the monoamine hypothesis of depression is conceptually straightforward, it is in reality it is an oversimplification of a complicated picture. Other systems that are implicated in the aetiology of depression (and which provide potential targets for drug therapy) include the hypothalamopituitary- thyroid axis and the hypothalamopituitary-adrenal axis (HPA). The finding that 50% of depressed patients have elevated plasma cortisol concentra- tions constitutes evidence that depression may be associated with increased HPA drive. Drugs with similar modes of action to antidepres- sants find other uses in medicine. Amfebutamone/ buproprion inhibits reuptake of both dopamine and noradrenaline and was originally developed and used as an antidepressant; it is now used to assist smoking cessation (see p. 178). Sibutramine, licenced as an anorectic agent, is a serotonin and noradrenaline reuptake inhibitor (see p. 697). Despite its similarity of action to venlafaxine and evidence of an anti- depressant effect from animal studies, sibutramine has yet to be recognised as effective for depression. PHARMACOKINETICS The antidepressants listed in Table 19.1 are generally well absorbed after oral administration. Steady-state plasma concentrations of TCAs show great individual variation but correlate with thera- peutic effect. Measurement of plasma concentration can be useful especially where there is apparent failure of response (though it is often not available). 371 19 PSYCHOTROPIC DRUGS Antidepressants in general are inactivated princi- pally by metabolism by hepatic cytochrome P450 enzymes (see p. 112). Of the many isoenzymes iden- tified, the most important in antidepressant metabolism are Cytochrome P450 (CYP) 2D6 (Table 19.2a) and CYP 3A4 (Table 19.2b). Other important P450 enzymes are CYP 1A2 (inhibited by the SSRI fluvoxamine, induced by cigarette smoking, sub- strates include caffeine and the atypical antipsychotics clozapine and olanzapine) and the CYP 2C group (inhibition by fluvoxamine and fluoxetine, involved in breakdown of moclobemide). Sometimes several CYP enzymes are capable of mediating the same metabolic step. For example at least six isoenzymes, including CYP 2D6, 3A4 and 2C9 can mediate the desmethylation of the SSRI sertraline to its major metabolite. Several of these drugs produce active meta- bolites which prolong their action (e.g. fluoxetine is TABLE 1 9.2A Psychotropic (and selected other) drugs known to be CYP 2D6 substrates and inhibitors CYP 2D6 inhibitors Antidepressants Paroxetine Fluoxetine CYP 2D6 substrates Antidepressants Paroxetine Fluoxetine Citalopram Sertraline Venlafaxine* Amitriptyline Clomipramine Desipramine Imipramine Nortriptyline Antipsychotics Chlorpromazine Haloperidol Thioridazine Zuclopenthixol Perphenazine Risperidone Miscellaneous Dexfenfluramine Opioids Codeine Hydrocodeine Dihydrocodeine Tramadolol Ethyl Morphine Tenamfetamine ('Ecstasy') Bupropion -blockers Propanolol Metoprolol Timolol Bufaralol A substrate is a substance that is acted upon and changed by an enzyme. An enzyme inducer accelerates metabolism of co-prescribed drugs which are substrates of the same enzyme, reducing their effect. An enzyme inhibitor retards metabolism of co-prescribed drugs, increasing their effects (see Chapter 7, Metabolism). Competition between drugs that are substrates for the same enzyme may retard their metabolism, increase plasma concentration and lead to enhanced therapeutic or adverse effects. *CYP 2D6 is involved only in the breakdown of venlafaxine to its active metabolite and implications of 2D6 interactions are of limited significance. metabolised to norfluoxetine, t 1 / 2 200 h). The meta- bolic products of certain TCAs are antidepressants in their own right, e.g. nortriptyline (from ami- triptyline), desipramine (from lofepramine) and imipramine (from clomipramine). Half-lives of TCAs lie generally in the range of 15 h (imipramine) to 100 h (protriptyline) and those for SSRIs from 15 h (fluvoxamine) to 72 h (fluoxetine). Around 7% of the Caucasian population have very limited CYP 2D6 enzyme activity. Such 'poor metabolisers' may find standard doses of tricyclic antidepressants intolerable and it is often worth starting at a very low dose. If the drug is then tolerated, plasma concentration assay may to confirm the suspicion that the patient is a poor metaboliser. TABLE I9.2B Psychotropic (and selected other) drugs known to be CYP 3A4 substrates, inhibitors and inducers CYP 3A4 inhibitors Antidepressants Nefazodone Fluoxetine CYP 3A4 substrates Antidepressants Anxiolytics, hypnotics and antipsychotics Fluoxetine Sertraline Amitriptyline Imipramine Nortriptyline Trazodone* Alprazolam Buspirone Diazepam Midazolam Triazolam Zopiclone Haloperidol Quetiapine Sertindole CYP 3A4 inducers Antidepressant St. John's Wort Other drugs Cimetidine Erythromycin Ketoconazole (and grapefruit juice) Miscellaneous Buprenorphine Carbamazepine Cortisol Dexamethasone Methadone Testosterone Calcium channel blockers Diltiazem Nifedipine Amlodipine Other drugs Amiodarone Omeprazole Oral contraceptives Simvastatin Miscellaneous Carbamazepine Phenobarbital Phenytoin * mCPP, the active metabolite of trazodone, is a CYP 2D6 substrate; observe for unwanted effects when trazodone is co- administered with the 2D6 inhibitors fluoxetine or paroxetine. 372 19 THERAPEUTIC EFFICACY Provided antidepressant drugs are prescribed at an adequate dose and taken regularly, 60-70% of patients with moderate or severe depression should respond within 3-4 weeks. Meta-analyses have shown little evidence that any particular drug or class of antidepressant is more efficacious than others, but there are four possible exceptions to this general statement. • Small trials have suggested that the SNRI agent venlafaxine, in high dose (> 150 mg/day) may have greater efficacy than other antidepressants. • Amitriptyline appears to be slightly more effective than other TCAs and also SSRIs but this advantage is compromised by its poor tolerability relative to more modern agents. • The older MAOIs (e.g. phenelzine) may be more effective than other classes in 'atypical' depression, a form of depressive illness where mood reactivity is preserved, lack of energy may be extreme and biological features are the opposite of the normal syndrome i.e. excess sleep and appetite with weight gain. • Evidence suggests that in patients hospitalised with severe depression, TCAs as a class (also venlafaxine) may be slightly more effective than either SSRIs or MAOIs. SELECTION An antidepressant should be selected to match individual patients' requirements, such as the need or otherwise for a sedative effect or the avoidance of antimuscarinic effects (especially in the elderly). In the absence of special factors the choice rests on tolerability, safety in overdose and likelihood of an effective dose being reached. SSRIs, lofepramine, mirtazapine, nefazodone, reboxetine and venlafaxine are highlighted as best fulfilling these needs. MODE OF USE The action of TCAs in ameliorating mood is usually absent in the first 2 weeks of therapy and at least 4 weeks must elapse to constitute an adequate trial. Where a minimal response is noted in this period, it is reasonable to extend the trial to 6 weeks to see ANTIDEPRESSANT DRUGS if further benefit is achieved. By contrast, patients may experience unwanted drug effects imme- diately on starting treatment (and they should be warned), but such symptoms often diminish with time. Titrating from a generally tolerable starting dose, e.g. amitriptyline 30-75 mg/day (25-50 mg/ day for imipramine), with weekly increments to a recognised 'minimum therapeutic' dose, usually around 125 mg/day (140 mg/day for lofepramine) lessens the impact of adverse symptoms before a degree of tolerance (and therapeutic benefit) develops. Low starting doses are particularly important for elderly patients. Only when the drug has reached the minimum therapeutic dose and been taken for at least 4 weeks can the test of response or nonresponse be considered adequate. Some patients do achieve response or remission at subtherapeutic doses, for reasons of drug kinetics and individual metabolism, the self-limiting nature of depression or by a placebo effect (reinforced by the experience of side effects suggesting that the drug must be having some action). TCAs are given either in divided doses or, for the more sedative compounds, as a single evening dose. SSRIs have advantages over tricyclics in simplicity of introduction and use. Dose titration is often unnecessary since the minimum therapeutic dose can usually be tolerated as a starting dose. Divided doses are not required and administration is by a single morning or evening dose. Evidence suggests that patients commencing treatment on SSRIs are more likely to reach an effective dose than those starting on TCAs. The novel compounds nefazodone and trazodone usually require titration to a minimum therapeutic dose of at least 200 mg/day. Response to reboxetine, venlafaxine and mirtazapine may occur at the starting dose but some dose titration is commonly required. Venlafaxine is licensed for treatment-resistant de- pression by gradual titration from 75 to 375 mg/day. There is some need for dose titration when using MAOIs although recommended starting doses (e.g. phenelzine 15 mg t.d.s.) may be effective. Unlike other drug classes, reduction to a lower maintenance dose is recommended after a response is achieved. 373 19 PSYCHOTROPIC DRUGS CHANGING AND STOPPING ANTIDEPRESSANTS When an antidepressant fails through lack of efficacy despite an adequate trial or due to unacceptable side effects, it is generally advisable to change to a drug of a different class. For a patient who does not respond to an SSRI it is logical to try a TCA or a novel compound such as venlafaxine, reboxetine or mirtazapine. Any of these options may offer a greater increase in synaptic noradrenaline than the ineffective SSRI. There is also evidence to suggest that patients failing on one SSRI may respond to a different drug within the class, an approach which is particularly useful where other antidepressant classes have been un- successful previously, are contraindicated, or have characteristics which the patient or doctor feel are undesirable. For example, a patient who is keen to avoid putting on weight may prefer to try a second SSRI after an initial failure than to switch to a TCA or MAOI since both of these classes commonly cause weight gain. Awareness of differences between drugs within a class may also be helpful, e.g. the greater serotonergic enhancing effects of clomipramine compared to other tricyclics may be advantageous in a patient who cannot tolerate any other drug class. When changing between SSRIs and/or TCAs doses should be reduced progressively over 2-4 weeks. Where a new drug is to be introduced it should be 'cross-tapered' i.e. the dose gradually increased as that of the substituted drug is reduced. Changes to or from MAOIs must be handled with great caution due to the dangers of interactions between anti- depressant classes (see below). Therefore MAOIs cannot safely be introduced within 2 weeks of stop- ping paroxetine, sertraline or tricyclics (3 weeks for imipramine and clomipramine; combination of the latter with tranylcypramine is particularly dangerous), and not until 5 weeks after stopping fluoxetine, the active metabolite of which has a very long t l / 2 (9 days). Similarly, TCAs and SSRIs should not be introduced until 2-3 weeks have elapsed from discontinuation of MAOI (as these are irreversible inhibitors, see p. 370). No washout period is required when using the reversible monoamine oxidase inhibitor moclobemide. When a patient achieves remission, the antidepres- sant should be continued for at least 9 months at the dose which returned mood to normal. Premature dose reduction or withdrawal is associated with increased risk of relapse. In cases where three or more depressive episodes have occurred, evidence suggests that long-term continuation of an anti- depressant offers protection, as further relapse is almost inevitable in the next three years. When ceasing use of an antidepressant, the dose should be reduced over at least 6 weeks to avoid a discontinuation syndrome (symptoms include anxiety, agitation, nausea and mood swings). Dis- continuation of SSRIs and venlafaxine are asso- ciated additionally with dizziness, electric shock- like sensations and paraesthesia. Short-acting drugs that do not produce active metabolites are most likely to cause such problems. Paroxetine in particular is associated with severe withdrawal symptoms including bad dreams, paraesthesia and dizziness (which can be misdiagnosed as labyrinthitis). AUGMENTATION Augmentation, i.e. the addition of another drug, is used to enhance the effects of standard antidepres- sants when two or more have successively failed to alleviate depressive symptoms despite treatment at an adequate dose for an adequate time. The therapeutic efficacy of new agents, e.g. venlafaxine, has provided clinicians with further options which now tend to be employed before augmentation but the following may be used. The most common is augmentation is with the mood stabiliser lithium carbonate. Indeed, lithium may be effective as monotherapy for depression but is not preferred because of its adverse effect profile and need for plasma concentration monitoring. Its prescription in combination with antidepressants that have failed to produce remission is more usual and evidence suggests that up to 50% of patients who have not: responded to standard antidepressants can respond after lithium augmentation. Addition of lithium requires careful titration of the plasma concentration up to the therapeutic range, with periodic checks thereafter and monitoring for toxicity (see p. 389). Thyroid hormones also aid antidepressant action. Guidance points to the combination of tri- iodotyronine (T 3 ) and TCAs as being most effective 374 19 (but effects of lofepramine may be augmented by levothyroxine to the extent that co-administration should be avoided). The amino acid isomer L- tryptophan, a precursor of serotonin, may also augment but such use is restricted to hospital specialists who must monitor haematological function (it is associated with an eosinophilia/ myalgia syndrome though this may have been due to an impurity rather than the L-tryptophan itself). The (3-adrenoceptor blocker pindolol can augment the action of SSRIs. Pindolol may act by binding to a serotonin autoreceptor and thus interfere with a homeostatic mechanism which acts to reduce sero- tonin concentrations after the initial elevation by SSRI action. None of these augmentation strategies is ideal, since they either require plasma monitoring (lithium, tryptophan, tri-iodothyronine), expose the patient to potential toxicity (lithium, tryptophan) or have only a moderate evidence base for efficacy (tri- iodothyronine, pindolol). OTHER INDICATIONS FOR ANTIDEPRESSANTS Antidepressants may benefit most forms of anxiety disorder, including panic disorder, generalised anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder and social phobia (see p. 393). SSRIs are effective in milder cases of the eating disorder bulimia nervosa, particularly fluoxetine (in higher doses than are required for depression). This effect is independent of that on depression (which may co-exist) and may therefore involve action on transmitter systems other than those involved in modulating depression. Antidepressants appear to be ineffective in anorexia nervosa. ADVERSE EFFECTS As most antidepressants have similar therapeutic efficacy, the decision regarding which drug to select often rests on adverse effect profiles and potential to cause toxicity. Tricyclic antidepressants The commonest unwanted effects are those of the antimuscarinic action, i.e. dry mouth (predisposing ANTI DEPRESSANT DRUGS to tooth decay), blurred vision and difficulty with accommodation, raised intraocular pressure (glaucoma may be precipitated), bladder neck obstruction (may lead to urinary retention in older males). Patients may also experience: postural hypo- tension (through inhibition of a-adrenoceptors) which is often a limiting factor in their utility in the elderly, interference with sexual function, weight gain (through blockade of histamine H 1 receptors), prolongation of the QT interval of the ECG which predisposes to cardiac arrhythmias especially in overdose (use of TCAs after myocardial infarction is contraindicated). Some TCAs (especially trimipramine and ami- triptyline) are heavily sedating through a combination of antihistaminergic and a-adrenergic blocking actions. This presents special problems to those whose lives involve driving vehicles or performing skilled tasks. In selected patients, sedation may be beneficial, e.g. a severely depressed person who has a disrupted sleep pattern or marked agitation. It is essential to remember that there is great heterogeneity in adverse effect profiles between TCAs. Imipramine and lofepramine cause relatively little sedation and lofepramine is associated with milder antimuscarinic effects (but is contraindicated in patients with severe liver disease). Overdose. Depression is a risk factor for both parasuicide and completed suicide, and TCAs are commonly taken by those who deliberately self- harm. Dothiepin (dosulepin) and amitriptyline are particularly toxic in overdose, being responsible for up to 300 deaths per year in the UK despite the many alternative antidepressants that are available. Lofepramine is at least 15 times less likely to cause death from overdose; clomipramine and imipramine occupy intermediate positions. Clinical features of overdose reflect the pharma- cology of TCAs. Antimuscarinic effects result in warm, dry skin from vasodilatation and inhibition of sweating, blurred vision from paralysis of accom- modation, pupillary dilatation and urinary retention. Consciousness is commonly dulled and respira- tion depression and hypothermia may develop. Neurological signs include hyperreflexia, myo- clonus and divergent strabismus. Extensor plantar responses may accompany lesser degrees of impaired 375 19 PSYCHOTROPIC DRUGS consciousness and provide scope for diagnostic confusion, e.g. with structural brain damage. Con- vulsions occur in a proportion of patients. Halluci- nations and delirium occur during recovery of consciousness, often accompanied by a character- istic plucking at bedclothes. Sinus tachycardia (due to vagal blockade) is a common feature but abnormalities of cardiac conduction accompany moderate to severe intoxi- cation and may proceed to dangerous tachy- or bradyarrhythmias. Hypotension may result from a combination of cardiac arrhythmia, reduced myocardial contractility and dilatation of venous capacitance vessels. Supportive treatment suffices for the majority of cases. Activated charcoal by mouth is indicated to prevent further absorption from the alimentary tract and may be given to the conscious patient in the home prior to transfer to hospital. Convulsions are less likely if unnecessary stimuli are avoided but severe or frequent seizures often preceed cardiac arrhythmias and arrest, and their suppression with diazepam is important. The temptation to treat cardiac arrhythmias ought to be resisted if cardiac output and tissue perfusion are adequate. Correc- tion of hypoxia with oxygen and acidosis by i.v. infusion of sodium bicarbonate are reasonable first measures and usually suffice. Reboxetine is not structurally related to tricyclic agents and acts predominantly by noradrenergic reuptake inhibition. Antimuscarinic effects trouble only a minority of patients, postural hypotension may occur and impotence in males. It is relatively safe in overdose. Selective serotonin reuptake inhibitors SSRIs have a range of unwanted effects including nausea, anorexia, dizziness, gastrointestinal disturb- ance, agitation, akathisia (motor restlessness) and anorgasmia (failure to experience an orgasm). They lack direct sedative effect, an advantage in patients who need to drive vehicles. SSRIs can disrupt the pattern of sleep with increased awakenings, transient reduction in the amount of REM and in- creased REM latency but eventually sleep improves due to elevation of mood. This class of antidepres- sant does not cause the problems of postural hypo- tension, antimuscarinic or antihistaminergic effects seen with TCAs. Their use is not associated with weight gain and conversely they may induce weight loss through their anorectic effects. SSRIs are relatively safe in overdose. The serotonin syndrome is a rare but dangerous complication of SSRIs and features restlessness, tremor, shivering and myoclonus possibly leading on to convulsions, coma and death. Risk is increased by co-administration with drugs that enhance serotonin transmission, especially MAOIs, the anti- migraine drug sumatriptan and St. John's Wort. Note. When SSRIs are compared with TCAs for patients who discontinue therapy (a surrogate end- point for tolerability), most meta-analyses show a slight benefit in favour of SSRIs. Comparisons which exclude TCAs with the most prominent anti- muscarinic effects (amitriptyline and imipramine) show either marginal benefits in favour of SSRIs or no difference between the groups. It is noteworthy that despite their pronounced adverse effects, amitriptyline and imipramine tend to be selected as 'standard' TCAs against which SSRIs are compared. Lofepramine, the second most prescribed TCA in the UK and the one TCA which causes little sedation, has few antimuscarinic effects and is as safe as SSRIs in overdose is; it under-represented in meta-analyses Novel compounds Venlafaxine produces some unwanted effects that resemble those of SSRIs with a higher incidence of nausea. Sustained hypertension (due to blockade of noradrenaline reuptake) is a problem in a small percentage of patients at high dose and blood pressure should be monitored when > 200 mg/day is taken. Nefazodone lacks antimuscarinic effects but may cause postural hypotension and abdominal discom- fort. It appears to improve sleep quality and seems not to interfere with sexual function. Mirtazapine also has benefits in rarely being asso- ciated with sexual dysfunction and in improving 376 [...]... motor symptoms in rats) and adverse effect profiles Categorisation of atypical agents by their chemical structure is of limited value clinically as they are very heterogenous A classification by receptor binding profiles is likely to emerge with growing evidence on the clinical importance of their actions on inter-related transmitter systems INDICATIONS Antipsychotic drugs are used for the prophylaxis... state, for instance the severely depressed patient who has stopped eating or drinking Modern-day ECT is a safe and effective alternative to pharmacological treatment and remains a firstline option in clinical circumstances where rapid, response is desired, when it can be life-saving Antipsychotics CLASSIFICATION Originally tested as an antihistamine and then proposed as a drug for combating helminth . Psychosis may also be due to illicit substances or organic con- ditions. Clinical features of schizophrenia may be subdivided into 'positive. to reside in the S-isomer. Escitalopram the pure S-isomer, may offer clinical benefits over existing preparations. Trazodone, nefazodone and mirtazapine