CLINICAL PHARMACOLOGY 2003 (PART 21B)

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The reality is more complex since the receptor binding profile of clozapine and the newer atypical antipsychotic agents suggests that D2-receptor blockade is not essential for antipsychotic effect. The atypical drugs act on numerous receptors and modulate several interacting transmitter systems. Clozapine is a highly effective antipsychotic. It has little affinity for the D2-receptor compared with classical drugs but binds more avidly to other dopamine subtypes (e.g. D1, D3 and D4). It blocks muscarinic acetylcholine receptors, as do certain classical agents (e.g. thioridazine), a property which may reduce the experience of extrapyramidal effects. Clozapine binds more readily as an...

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19 PSYCHOTROPIC DRUGS The reality is more complex since the receptor mesolimbic system (producing antipsychotic effect) binding profile of clozapine and the newer atypical rather than the nigrostriatal system (associated with antipsychotic agents suggests that D2-receptor unwanted motor effects). In contrast to classical blockade is not essential for antipsychotic effect. antipsychotics, risperidone shares with clozapine The atypical drugs act on numerous receptors and an ability antagonise a2-adrenoceptors, a property modulate several interacting transmitter systems. which may have utility in the treatment of schizo- Clozapine is a highly effective antipsychotic. It has phrenia and is seen as an area of interest for little affinity for the D2-receptor compared with developing new drugs. classical drugs but binds more avidly to other dopamine subtypes (e.g. D1, D3 and D4). It blocks PHARMACOKINETICS muscarinic acetylcholine receptors, as do certain classical agents (e.g. thioridazine), a property which Like antidepressants, antipsychotics are well may reduce the experience of extrapyramidal effects. absorbed and distributed after oral administration. Clozapine binds more readily as an antagonist at In situations where very rapid relief of symptoms a2-adrenoceptors than the classical drugs and also or disturbed behaviour is required, faster uptake blocks histamine and serotonin receptors (5HT2 and into plasma can be achieved through the intramus- others). cular route. Again in common with antidepressants, The newer atypical psychotropics vary widely antipsychotics are mainly metabolised by cyto- in their receptor binding profiles. Olanzapine and chrome P450 isoenzymes in the liver, e.g. CYP 2D6 quetiapine bear resemblance to the profile of cloza- (zuclopenthixol, risperidone [Table 19.2a]), CYP 3A4 pine in that their therapeutic effects appear to derive (sertindole [Table 19.2b]), CYP 1A2 (olanzapine, from action on different receptors and transmitter clozapine). Metabolism of some compounds is parti- systems. All atypicals (except amisulpride) exhibit cularly complex (e.g. chlorpromazine, haloperidol), greater antagonism of 5HT2-receptors than D2- involving more than one main pathway, utilising receptors compared with the classical agents. several P450 enzymes or resulting in the production Atypical drugs that do antagonise dopamine D2- of many inactive metabolites. Antipsychotic plasma receptors appear to have affinity for those in the levels can be increased or decreased by co- prescription of drugs which are inhibitors, inducers or substrates of the same isozyme. Amisulpride is an exception to the general rule as it is eliminated by the kidneys without hepatic metabolism. Examples of plasma half-lives for antipsychotics include quetiapine 7 h, clozapine 12 h, haloperidol 18 h and olazapine 33 h. Depot intramuscular injec- tions are available from which drug is released over 2-4 weeks. EFFICACY Symptoms in schizophrenia are defined as positive and negative (Table 19.4). Whilst a classical anti- psychotic drug should provide adequate treatment of positive symptoms including hallucinations and delusions in at least 60% of cases, patients are often Fig. 19.3 Sagittal brain section illustrating dopaminergic pathways. I. Mesolimbic pathway (overactive in psychotic illness according to left with unresolved negative symptoms such as the dopamine hypothesis of schizophrenia).VTA= ventrotegmental apathy, flattening of affect and alogia. Evidence area. 2. Nigrostriatal pathway (involved in motor control, suggests that clozapine and the newer atypicals underactive in Parkinson's Disease and associated with extrapyramidal motor symptoms). 3. Tuberoinfundibular pathway have a significant advantage over classical drugs (inhibits prolactin release from the hypothalamus). against negative symptoms. Clozapine has a 382
ANTI PSYCHOTICS 19 further advantage over all other antipsychotics, symptoms. Conservative starting doses are also whether classical or atypical, in that it may be recommended in the elderly and for patients with effective when other antipsychotics prescribed at learning disabilities who may require antipsychotics adequate doses have failed or are not tolerated. for psychosis or severe behavioural disturbance. Schizophrenia often runs a chronic relapsing and The dose can be titrated up at intervals, until the remitting course. Less than one-quarter of patients desired effect in treating psychotic symptoms, who experience a psychotic episode and are diag- calming disturbed behaviour or effecting sedation nosed as having schizophrenia succeed in avoiding is achieved. The interval depends on the context, further episodes. Nevertheless, taking antipsychotics with the urgency of the situation and previous as prophylaxis significantly reduces the likelihood use of antipsychotics being factors which would of relapse. accelerate the upward titration. An important issue is that the longer a psychosis is left untreated the less favourable is the outcome; thus drug treatment MODE OF USE should be instigated as soon as an adequate period Since the potency (therapeutic efficacy in relation of assessment has allowed a provisional diagnosis to weight) of antipsychotic agents varies markedly to be established. between compounds, it is useful to think of the For each antipsychotic agent there is a licensed effective antipsychotic dose of classical agents in maximum dose; for example up to 1000 mg of terms of ''chlorpromazine equivalents' (see Table 19.5). chlorpromazine/day may be given under the For example, haloperidol has a relatively high anti- United Kingdom licence. Prescribing beyond the psychotic potency, such that 2-3 mg is equivalent to licensed maximum dose requires specialist consent. chlorpromazine 100 mg, whereas sulpiride 200 mg When two antipsychotics are co-prescribed, the (low potency) is required for the same antipsychotic maximum antipsychotic dose should not exceed effect. 1000 mg of chlorpromazine equivalents/day except Patients who are 'neuroleptic naive' (i.e. have under specialist supervision. For some antipsycho- never previously taken any antipsychotic agent) tics the licenced maximum dose is considerably less should start at the lowest available dosage, such as than 1000 mg of chlorpromazine equivalents/day. haloperidol 0.5 mg/day or chlorpromazine 25 mg/ For instance, the licenced maximum dose of day, in case the patient is particularly susceptible thioridazine was reduced to 600 mg/day following to adverse effects, especially extrapyramidal motor concerns about its cardiovascular toxicity. Note TABLE 19.4 Symptoms of schizophrenia Positive symptoms Negative symptoms Hallucinations, most commonly auditory (i.e. voices) in the 3rd person, Affective flattening manifest by unchanging facial expression which patients may find threatening.The voices may also give with lack of communication through expression, poor eye commands.Visual hallucinations are rare. contact, lack of responsiveness, psychomotor slowing Delusions, most commonly persecutory.'Passivity phenomena' Alogia (literally'absence of words' manifesting clinically as a include delusions of thought broadcasting, thought insertion lack of spontaneous speech (poverty of speech). or thought withdrawal, made actions, impulses or feelings. Anhedonia (inability to derive pleasure from any activity) Bizarre behaviours including agitation, sexual disinhibition, and Associality (narrowing of repertoire of interests and repetitive behaviour, wearing of striking but inappropriate impaired relationships) clothing. Apathy IAvolution involving lack of energy, lack of motivation Thought disorder manifest by failure in the organisation of speech to work, participate in activities or initiate any such that it drifts away from the point (tangentiality), never goal-directed behaviour, and poor personal hygiene. reaches the point (circumstantiality), moves from one topic to Attention problems involving an inability to focus on any the next illogically (loosened associations, knight's move thinking), one issue or engage fully with communication. breaks off abruptly only to continue on an unrelated topic (derailment) or moves from one topic to the next on the basis of a pun or words which sound similar (clang association). 383
19 PSYCHOTROPIC DRUGS that plasma electrolytes and an ECG should be for acute behavioural disturbance in schizophrenia. checked on introducing or increasing the dose of This drug is also presented as a Velotab' which thioridazine and that an ECG should be seen before dissolves rapidly on contact with the tongue allow- prescribing pimozide and sertindole. ing drug to be absorbed despite lack of cooperation from a disturbed patient. Prescription of atypical antipsychotics follows similar rules to those for classical drugs, starting at Long-acting (depot) injections low doses in neuroleptic naive patients. Whereas there is a wide range of effective doses for many Haloperidol, zudopenthixol, fluphenazine, flupentixol classical agents (e.g. chlorpromazine 25-1000 mg/ and pipothiazine are available as depot intramuscular day), much narrower ranges have been defined for injections for maintenance treatment of patients atypical agents (Table 19.5). While classical anti- with schizophrenia and other chronic psychotic psychotics are licenced for the management of disorders. Provided the patient is willing to agree to acutely disturbed behaviour as well as for schizo- have depot injections, usually by a community phrenia, atypical agents are generally licenced only psychiatric nurse at intervals of 2-4 weeks, the need for the latter indication, although that for risperi- to take tablets two or three times a day is removed. done is broader. For most atypical agents used in Poor compliance with oral medication is the most schizophrenia, a brief period of dose titration by common cause of admission to hospital with a protocol up to a stated lowest therapeutic dose is relapse of schizophrenia. A reduced initial dose of usual, e.g. risperidone 4 mg/day, quetiapine the depot medication should be given, with a 300 mg/day. Dose increases are indicated where review for unwanted effects after 5-10 days. there is no response after 2 weeks and these may be repeated until the maximum licenced dose is achieved. Rapid tranquillisation Clozapine may be initiated only under specialist Rapid tranquillisation protocols have been devised supervision and only after two other antipsychotic for patients who are severely disturbed and violent agents have failed through lack of efficacy or or potentially violent and have not responded to adverse effects. Additionally, leucocyte count moni- nonpharmacological approaches. The risks from toring is mandatory (danger of agranulocytosis) administering psychotropic drugs (e.g. cardiac and blood pressure checking is required (for hypo- arrhythmia with high-dose antipsychotics) may tensive effect). Patients are most vulnerable to greatly outweigh the risk of leaving the patient agranulocytosis on initiation of therapy with 75% of untreated, including physical trauma and the cases occurring in the first 18 weeks. The dose consequences of over-stressing the cardiovascular titration schedule must be followed strictly, starting system. with clozapine 12.5 mg nocte and working up over A benzodiazepine, e.g. lomzepam 1-2 mg i.v. (into a period of four weeks to a target therapeutic dose a large vein) failing which i.m. (dilute with an equal of 450 mg/day. volume of water or physiological saline) is the first option if the patient is not already receiving an antipsychotic drug. Patients requiring rapid Alternative administration strategies in tranquillisation are commonly taking antipsycho- acute use of antipsychotics tics for established illness and an additional anti- Some of the antipsychotics are available as intra- psychotic may then be used if the patient has not muscular injections for patients who are unable or received an adequate dose; otherwise a benzo- unwilling to swallow tablets (as is common in diazepine should given. Haloperidol 2-10 mg i.m. is psychosis or severe behavioural disturbance). Halo- currently preferred for rapid tranquillisation, but peridol is most often used for these indications on new protocols may evolve with the development of psychiatric inpatient wards (chlorpromazine i.m. atypical antipsychotics that can be given i.m. When being restricted due to hypotension and skin i.m. antipsychotic or benzodiazepine tranquilliser is nodule formation). Olanzapine may be given i.m. given as an emergency, pulse, blood pressure, 384
A N T I P SY C H O T I C S 19 temperature and respiration should be monitored, are believed to result from a shift in favour of and pulse oximetry (oxygen saturation) if con- cholinergic rather than dopaminergic neurotrans- sciousness is lost. mission in the nigrostriatal pathway (see p. 422). When at least two doses of haloperidol i.m. Anticholinergic agents, e.g. procyclidine, orphe- fail to produce the desired result, zuclopenthixol nadrine or benztropine, restore the balance in fav- acetate i.m. is an alternative. This heavily sedating our of dopaminergic transmission but are liable to drug usually produces a calming effect within provoke antimuscarinic effects (dry mouth, urine 2 h, persisting for 2-3 days if used at appropriate retention, constipation, exacerbation of glaucoma dose. Zuclopenthixol acetate should never be and confusion) and they offer no relief for tardive prescribed to the neuroleptic naive. Patients must dyskinesia, which may even worsen. They should be observed with the utmost care following admin- be used only in response to clear dystonic or istration. Some will require a second dose within parkinsonian symptoms rather than for prophyl- 1-2 days. axis. Benzodiazepines, with their general inhibitory Amylobarbitone and paraldehyde have a role in effects, are an alternative. Thioridazine and related emergencies when antipsychotic and benzodiazepine Type 2 phenothiazines are less likely to provoke options have been exhausted. extrapyramidal effects as they also block cholinergic transmission (but patients may suffer antimusca- rinic effects). Note that confusion from anticholiner- ADVERSE EFFECTS (see Table 19.5) gic effects may mimic or complicate schizophrenic Active psychotic illnesses often cause patients to thought disorder. have poor insight into their condition; unwanted drug effects can compromise already fragile com- Akathisia is a state of motor and psychological pliance and lead to avoidable relapse. restlessness, in which patients exhibit persistent foot tapping, moving of legs repetitively and being unable to settle or relax. A strong association has Classical antipsychotics been noted between its presence in treated schizo- It is rare for any patient taking classical anti- phrenics and subsequent suicide. A (3-adrenoceptor psychotic agents completely to escape their adverse blocker is the best treatment, although anticholiner- effects. Thus it is essential to discuss with patients gic agents may be effective where akathisia coexists the possibility of unwanted effects and regularly to with dystonias and parkinsonian symptoms. Differ- review this aspect of their care. entiating symptoms of psychotic illness from adverse drug effects is often difficult: drug-induced Extrapyramidal symptoms. All classical anti- akathisia may be mistaken for agitation induced by psychotics are capable of producing these effects psychosis. because they act by blocking dopamine receptors in the nigrostriatal pathway. The result is that some Tardive dyskinesia affects about 25% of patients 75% of patients experience extrapyramidal symptoms taking classical antipsychotic drugs, the risk which may appear shortly after starting the drug or increasing with length of exposure. It was formerly increasing its dose (acute effects), or some time after thought to be a consequence of up-regulation or a particular dose level has been established (tardive supersensitivity of dopamine receptors. A preferred effects, see p. 387). explanation is that tardive dyskinesia is a conse- quence of oxidative damage after neuroleptic- Acute extrapyramidal symptoms. Dystonias are induced increases in glutamate transmission. Patients manifest as abnormal movements of the tongue display a spectrum of abnormal movements from and facial muscles with fixed postures and spasm, minor tongue protusion, lip-smacking, rotational including torticollis and bizarre eye movements tongue movements and facial grimacing, choreo- ('oculogyric crisis'). Parkinsonian symptoms result athetoid movements of the head and neck and even in the classical triad of bradykinesia, rigidity and to twisting and gyrating of the whole body. It is less tremor. Both dystonias and parkinsonian symptoms likely to remit on stopping the causative agent than 385
19 PSYCHOTROPIC DRUGS TABLE 19.5 Relative frequency of selected adverse effects of antipsychotic drugs Drug CPZ Equiv Max dose Structure Dose (/day) Classical Chlorpromazine 100mg 1 000 mg Type 1 Phenothiazine ++ ++ +++ ++ + + +++ Thioridazine 50 mg 300 mg* Type 2 Phenothiazine + +++ +++ +++ +++ + +++ Trifluoperazine 5mg 50 mg Type 3 Phenothiazine +++ + +++ ++ + + + Haloperidol 3 mg 30 mg Butyrophenone +++ + +++ ++ + + + Sulpiride 200 mg 2400 mg Substituted benzamide + + +++ + + Zuclopenthixol 25 mg 150mg Thioxanthene ++ ++ +++ ++ + + ++ Min eff. Max dose dose (/day) (/day) Atypical Clozapine** 300 mg 900 mg Dibenzodiazepine +++ +++ + +++ +++ Olanzapine 5-1 0 mg 20 mg Theinobenzodiazepine ++ + +++ + ++ Quetiapine 300 mg 750 mg Dibenzothiazepine + + + +++ Risperidone 4mg I6mg Benzisoxazole + + ++ + + + Amisulpride 800 mg 1 200 mg Substituted benzamide + ++ + + Key: CPZ equiv dose = Chlorpromazine equivalent dose.This concept is of value in comparing the potency of classical antipsychotics. Dose ranges are not specified as they are extremely wide and drugs are normally titrated up from low starting doses (e.g. Chlorpromazine 25 mg or equivalent) until an adequate antipsychotic effect is achieved or the maximum dose reached.The Chlorpromazine equivalent dose concept is of less value for atypical antipsychotics since minimum effective doses (Min. eff. dose) and narrower therapeutic ranges have been defined. Maximum dose (Max. dose) can be exceeded only under specialist supervision. * The maximum recommended dose of thioradazine was reduced to 300 mg/day (or 600 mg/day in hospitalised patients) following concerns about QT prolongation and risk of fatal cardiac arrhythmias at higher doses. ** A dose of clozapine 50 mg is considered equivalent to Chlorpromazine 100 mg. 1f Lower doses of amisulpride (e.g. 100 mg/day) are indicated for patients with negative symptoms of schizophrenia only. are simple dystonias and parkinsonian symptoms. tetrabenazine. Clozapine, which does not appear to Any anticholinergic agent should be withdrawn cause tardive dyskinesia, may be used in severe immediately. Reduction of the dose of classical anti- cases where continuing antipsychotic treatment is psychotic is often advised but psychotic symptoms required and symptoms have not responded to may then worsen or be 'unmasked'. Alternatively, other medication strategies. an atypical antipsychotic can provide rapid improvement whilst retaining control of psychotic Cardiovascular effects. Postural hypotension may symptoms. result from blockade of oc-adrenoceptors; it is Atypical drugs, particularly at high doses, can dose-related. Prolongation of the QT interval in the yet cause extrapyramidal effects and this strategy cardiac cycle may rarely lead to ventricular arrhyth- is not always helpful. If the classical antipsychotic mias and sudden death (but particular warnings is simply continued, tardive dyskinesia remits and constraints apply to the use of thioridazine and spontaneously in around 30% of patients within a pimozide). year but since the condition is difficult to tolerate, patients may be keen to try other medications, even Prolactin elevation. Classical antipsychotics raise where evidence suggests that the success rates for plasma prolactin concentrations by their blocking remission are limited. These include vitamin E, action on dopamine receptors in the tuberoinfundi- benzodiazepines, (3-blockers, bromocriptine and bular pathway (Fig. 19.3 and p. 711) and can cause 386
A N T I P S Y C H OTI CS 19 gynaecomastia and galactorrhoea in both sexes, and Clozapine and olanzapine are the most likely of menstrual disturbances. A change to an atypical the atypical agents to cause anticholinergic (anti- agent such as quetiapine or olanzapine (but not muscarinic) effects. They are more likely than other risperidone or amisulpride) should minimise these atypicals to cause weight gain (glucose tolerance effects. If continuation of the existing classical may be impaired and should be monitored in antipsychotic is obligatory, a dopamine agonist susceptible individuals) and are second only to such as bromocriptine or amantadine may be quetiapine in their sedative effects. Sexual dysfunction beneficial. and skin problems are rare with atypical anti- psychotics. Risperidone and amisulpride are as Sedation. In the acute treatment of psychotic likely as classical antipsychotics to raise prolactin illness this may be a highly desirable property but it concentrations and cause galactorrhoea. may be unwelcome as the patient seeks to resume Clozapine warrants further mention, given its work, study or relationships. value for patients with treatment-resistant schizo- Classical antipsychotics may also be associated phrenia or severe treatment-related extrapyramidal with: symptoms. It may cause postural hypotension and tachycardia, and provoke seizures in 3-5% of • weight gain (a problem with almost all classical patients at doses above 600 mg/day. Most important antipsychotics with the exception of loxapine, is the risk of agranulocytosis in up to 2% of patients most pronounced with fluphenazine and (compared with 0.2% in classical antipsychotics). flupentixol) When clozapine was first licenced without require- • seizures (chlorpromazine and thioridazine are ments for regular white count monitoring, the especially likely to lower the convulsion threshold) haematological problems caused appreciable morta- • interference with temperature regulation lity. Thanks to strict monitoring, there have been no (hypothermia or hyperthermia, especially in the recorded deaths from agranulocytosis since clozapine elderly) was reintroduced in the United Kingdom, and • skin problems (phenothiazines, particularly internationally the death rate among the small chlorpromazine, may provoke photosensitivity minority who develop agranulocytosis is now less necessitating advice about limiting exposure to than 1 in 1000. sunlight. Rashes and urticaria may also occur) • sexual dysfunction (ejaculatory problems through a-adrenoceptor blockade) Neuroleptic malignant syndrome • retinal pigmentation (chlorpromazine, thioridazine, The syndrome may develop in up to 1% of patients vision is affected if dose is prolonged and high) using antipsychotics and is more prevalent at • corneal and lens opacities high doses. The elderly, and those with organic • blood dyscmsias (agranulocytosis and leucopenia) brain disease, hyperthyroidism or dehydration are • osteoporosis (associated with prolactin elevation) thought to be most susceptible. Clinical features • jaundice (including cholestatic). include: Atypical antipsychotics • fever • confusion or fluctuating consciousness Atypical drugs can provoke a range of adverse • rigidity of muscles which may become severe effects that is similar to that of the classical anti- • autonomic instability manifest by labile blood psychotics but is generally lesser in degree (with pressure exceptions). The following are the main differences. • tachycardia Atypical antpipsychotics provoke fewer extra- • urinary incontinence or retention. pyramidal effects (less blockade of dopamine D2- receptors in the nigrostriatal pathway). Neverthe- Raised plasma creatine kinase concentration and less, extrapyramidal effects are seen, notably with white cell count are suggestive (but not conclusive) high dose of risperidone (8-12 mg per day) and of neuroleptic malignant syndrome. There is some olanzapine (> 20 mg/day). clinical overlap with the 'serotonin syndrome' (see 387
19 PSYCHOTROPIC DRUGS p. 376) and concomitant use of SSRI antidepressants tinaemia (with gynaecomastia and galactorrhoea), (or possibly TCAs) with antipsychotics may increase although these latter remain common with risperi- risk. done and amisulpride. Improved tolerance is reflected It is essential to discontinue the antipsychotic in better compliance with taking atypical agents, so when the syndrome is suspected and to be ready to lessening the chance of psychosis being untreated transfer the patient to a medical ward for rehydra- with the likelihood of relapse once remission has tion. Benzodiazepines are indicated for sedation been achieved. Secondly, atypical antipsychotics are and their transquillising effect may be useful where more efficacious against the negative symptoms of active psychosis has to be left untreated. Dopamine schizophrenia which are particularly debilitating in agonists (bromocriptine, dantrolene) are beneficial chronic illness. in some cases. There is also evidence to support Thirdly, clozapine (but not the newer atypicals) a role for electroconvulsive therapy in treatment is more effective than classical agents for resistant of neuroleptic malignant syndrome. Even when schizophrenia. recognised and treated, the condition carries a Atypical antipsychotics are significantly more mortality of 12-15%, through cardiac arrhythmia, expensive than classical drugs. In some countries rhabdomyolysis or respiratory failure. The condition this will be the overriding argument for retaining usually lasts for 5-7 days after the antipsychotic classical agents as first choice drugs in schizoph- is stopped but may continue longer when a depot renia. Additionally, if a patient is successfully main- preparation has been used. Fortunately those who tained on a classical antipsychotic, transfer to an survive tend to have no long lasting physical effects atypical agent is difficult to justify. Where a classical from their ordeal. antipsychotic is not achieving optimal results or causes unwanted effects, a more persuasive case for change to an atypical can be made. CLASSICAL VERSUS ATYPICAL But economic analysis must take into account ANTIPSYCHOTICS factors beyond the crude cost of drugs. If atypical As atypical antipsychotics have become established antipsychotics truly cause fewer distressing extra- as alternatives to classical agents, clinicians are pyramidal symptoms and improve compliance, presented with the dilemma as to which should be they may prevent relapse of psychotic illness and their first choice in patients with schizophrenia and protect patients against lasting damage from psychotic illnesses, and indeed whether there is periods of untreated psychosis. Greater effective- sufficient justification to transfer a patient stabilised ness in treating negative symptoms would afford on a classical agent over to an atypical. patients with schizophrenia more opportunity of Atypical antipsychotics may have advantages in re-integrating into the community and to make three areas. First, they appear to be better tolerated,2 positive contributions to society rather than the in particular being less likely than classical agents alternative of long-term institutionalisation. Such to induce extrapyramidal effects and hyperprolac- factors alleviate the cost burden of psychotic illness on society, and must form part of the overall accounting between classical and atypical drugs as first line treatment. 2 Whilst the advantages of atypicals over classical antipsychotics may seem clear cut, one analysis using only trials where doses of classical antipsychotics were at or below a dose of haloperidol 12 mg/day or equivalent (now regarded as the upper limit for optimised use of these Mood stabilisers agents) produced rather different results. Although the atypicals retained their advantage in causing extrapyramidal In bipolar affective disorder patients suffer episodes side effects less frequently, overall tolerability and efficacy of mania, hypomania and depression, classically appeared to be similar. Geddes J et al 2000 Atypical antipsychotics in the treatment of schizophrenia: systematic with periods of normal mood in between. Manic overview and meta-regression analysis. British Medical episodes involve greatly elevated mood, often Journal 321: 1371-1376. interspersed with periods of irritability or undue 388
MOOD S T A B I L I S E R S 11 excitement, accompanied by biological symptoms sitides. These intracellular molecules are part of the (increased energy, restlessness, decreased need for transmembrane signalling system that is important sleep, increased sex drive), loss of social inhibitions, in regulating intracellullar calcium ion concentra- irresponsible behaviour and grandiosity. Psychotic tion, which subsequently affects neurotransmitter features may be present, particularly disordered release. Other putative mechanisms involve the thinking manifested by grandiose delusions and cyclic AMP 'second messenger' system and mono- 'flight of ideas' (acceleration of the pattern of aminergic and cholinergic neurotransmitters. thought with rapid speech). Hypomania is a less dramatic and dangerous presentation but retains Pharmacokinetics. Knowledge of pharmacokinetics the features of elation or irritability and the biolo- of lithium is important for successful use since gical symptoms, abnormalities in speech being the therapeutic plasma concentration is close to the limited to increased talkativeness and in social toxic concentration (low therapeutic index). Lithium conduct to overfamiliarity and mild recklessness. is a small ion that, given orally, is rapidly absorbed Depressive episodes may include any of the depres- throughout the gut. High peak plasma concentra- sive symptoms described before and may include tions are avoided by using sustained-release formu- psychotic features. lations which deliver the peak plasma lithium Lithium salts were known anecdotally to have concentrations in about 5 h. At first lithium is beneficial psychotropic effects as long ago as the distributed throughout the extracellular water but middle of the 19th century but scientific evidence with continued administration it enters the cells of their efficacy followed a serendipitous discovery. and is eventually distributed throughout the total In 1949, during a search for biologically active body water with a somewhat higher concentration substances in mania, urine from manic patients was in brain, bones and thyroid gland. The apparent injected into guinea pigs. The animals appeared to volume of distribution is about 50 1 in a 70 kg be affected by the accompanying large amounts of person (whose total body water is about 40 1) which urea and it was postulated that administration is compatible with the above. Lithium is easily of urate would exacerbate manic effects. Lithium dialysable from the blood but the concentration urate, which is highly soluble, was selected to gradient from cell to blood is not great and the conduct investigations into urate toxicity. It was intracellular concentration (which determines toxi- found to be sedative and to protect against manic city) falls slowly. Lithium enters cells about as urine toxicity. Lithium carbonate was tried in manic readily as does sodium but does not leave as readily patients, was found to be effective in the acute state (mechanism uncertain). Being a metallic ion it is not and, later, to prevent recurrent attacks.3 metabolised, nor is it bound to plasma proteins. Lithium salts are ineffective for prophylaxis of Only the kidneys eliminate lithium. Like sodium, bipolar affective disorder in around 35% of patients it is filtered by the glomerulus and 80% is reabsorbed and cause several unwanted effects. The search by the proximal tubule but it is not reabsorbed by for alternatives has produced drugs that are more the distal tubule. Intake of sodium and water are familiar as anticonvulsants, notably carbamazepine the principal determinants of its elimination. In and sodium valproate, and possibly lamotrigine. sodium deficiency lithium is retained in the body, thus concomitant use of a diuretic can reduce lithium clearance by as much as 50% and precipitate toxi- LITHIUM city. Sodium chloride and water are used to treat The mode of action is not fully understood. The lithium toxicity. main effect of lithium is probably to inhibit hydro- With chronic use the plasma tl/2 of lithium is lysis of inositol phosphate, so reducing the recycling 15-30 h. Lithium is usually given 12-hourly to of free inositol for synthesis of phosphatidylino- avoid unnecessary fluctuation (peak and trough concentrations) and maintain a plasma concentra- tion just below the toxic level. A steady-state 3 Cade J F. 1970 The story of lithium. In: Ayd F J, Blackwell B plasma concentration will be attained after about (eds) Biological psychiatry. Lippincott, Philadelphia. 5-6 days (i.e. 5 x tl/2) in patients with normal renal 389
19 PSYCHOTROPIC DRUGS function. Old people and patients with impaired guided by monitoring of the plasma concentration renal function will have a longer tl/2 so that steady once a steady state is reached. Increments are state will be reached later and dose increments made at weekly intervals until the concentration must be adjusted accordingly. lies within the required range of 0.4-1 mmol/1 (maintenance at the lower level is preferred for Indications and use. Lithium carbonate is effective elderly patients). The timing of blood sampling is treatment in > 75% of episodes of acute mania or important. By convention a blood sample is taken hypomania. Because its therapeutic action takes 2-3 prior to the morning dose, as close as possible to weeks to develop, lithium is generally used in com- 12 h after the evening dose. When the therapeutic bination with a benzodiazepine such as lorazepam range is reached, the plasma concentration should or diazepam (or with an antipsychotic agent where be checked every three months. Likewise, for there are also psychotic features). toxicity monitoring, thyroid function (especially in For prophylaxis, lithium is indicated when there women) and renal function (plasma creatinine and have been two episodes of mood disturbance in electrolytes) should be measured before initiation two years, although in some cases it is advisable and every 3 months during therapy. to continue with prophylactic use after one severe episode. When an adequate dose of lithium is Patient education about the role of lithium in taken consistently, around 65% of patients achieve the prophylaxis of bipolar affective disorder and improved control of their illness. discussion of the pros and cons of taking the drug Patients who start lithium only to discontinue are particularly important to encourage compliance it within two years have a significantly poorer with therapy; treatment cards, information leaflets outcome than matched patients who are not given and where appropriate, video material are used. any pharmacological prophylaxis. The existence of this 'rebound effect' dictates that persistence with Adverse effects. Lithium is associated with three long-term treatment is of great importance. categories of adverse effects. Lithium is also used to augment the action of antidepressants in treatment-resistant depression • Those experienced at plasma concentrations (see p. 375). within the therapeutic range (see above) include fine tremor (especially involving the fingers; if Pharmaceutics. It is important for any patient to this is difficult to tolerate a (3-blocker may adhere to the same pharmaceutical brand, as the dose benefit), constipation, polyuria and polydipsia of lithium ion (Li+) delivered by each tablet depends (due to loss of concentrating ability by the distal on the pharmaceutical preparation. For example, renal tubules), metallic taste in the mouth, each Camcolit 250 mg tablet contains 6.8 mmol, each weight gain, oedema, goitre, hypothyroidism, Liskonium 450 mg tablet contains 12.2 mmol and acne, rash, diabetes insipidus and cardiac each Priadel 200 mg tablet contains 5.4 mmol of Li+. arrhythmias. There can also be mild cognitive Thus the proprietary name must be stated on the and memory impairment. prescription. Some patients cannot tolerate slow- • Signs of intoxication, associated with plasma release preparations because release of lithium ions concentrations greater than 1.5 mmol/1 are distally in the intestine causes diarrhoea; they may mainly gastrointestinal (diarrhoea, anorexia, be better served by the liquid preparation, lithium vomiting) and neurological (blurred vision, citrate, which is absorbed proximally. Patients who muscle weakness, drowsiness, sluggishness and are naive to lithium should be started at the lowest coarse tremor, leading on to giddiness, ataxia dose of the preparation selected. Any change in and dysarthria). preparation demands the same precautions as does • Frank toxicity, due to severe overdosage or rapid initiation of therapy. reduction in renal clearance, usually associated with plasma concentration greater than Monitoring. The difference between therapeutic 2 mmol/1, constitutes an acute medical and toxic doses is narrow and therapy must be emergency. Hyperreflexia, hyperextension of 390
MOOD S T A B I L I S E R S 19 limbs, convulsions, toxic psychoses, syncope, Valproic acid oliguria, coma and even death may result if Valproic acid is the drug of first choice for treatment is not instigated urgently. prophylaxis of bipolar affective disorder in the United States, despite the lack of robust clinical trial Overdose is treated by use of i.v. fluid to maintain evidence in support of this indication. But treat- a good urine output guided by frequent measure- ment with valproic acid is easy to initiate (especially ment of plasma electrolytes and osmolality. Hyper- compared to lithium), it is well tolerated and its natraemia indicates probable diabetes insipidus use appears likely to extend if the evidence-base and isotonic dextrose should then be used until expands. As the semisodium salt, valproic acid is plasma sodium concentration and osmolality become licenced for use in the treatment of acute mania normal. Isotonic saline forms part of the fluid unresponsive to lithium. (Note: sodium valproate, see regimen (but overuse may result in hypernatrae- p. 420, is unlicenced for this indication.) mia) and potassium supplement will be required. Treatment with carbamazepine or valproic acid Haemodialysis is effective but may have to be appears not to be associated with the 'rebound repeated frequently as plasma concentration rises effect' of relapse into manic symptoms that may after acute reduction (due to equilibration as lithium accompany early withdrawal of lithium therapy. leaves cells and also by continued absorption from sustained-release formulations). Other drugs Interactions. Several types of drug interfere with Evidence is emerging regarding the efficacy of lithium excretion by the renal tubules, causing lamotrigine in prophylaxis of bipolar affective the plasma concentration to rise. These include disorder and treatment of bipolar depression. Other diuretics (thiazides more than loop type), ACE drugs which have been used in augmentation of inhibitors and angiotensin-11 antagonists, and non- existing agents include the anticonvulsant gaba- steroidal anti-inflammatory analgesics. Theophylline pentin, the benzodiazepine clonazepam, and the and sodium-containing antacids reduce plasma calcium channel blocking agents verapamil and lithium concentration. The effects can be important nimodipine. because lithium has such a low therapeutic ratio. Diltiazem, verapamil, carbamazepine and pheny- toin may cause neurotoxicity without affecting the plasma lithium. Concomitant use of thioridazine should be avoided as ventricular arrhythmias may Drugs used in anxiety and result. sleep disorders The disability and health costs caused by anxiety Carbamazepine disorders are comparable to those of other common Carbamazepine is licenced as an alternative to medical conditions such as diabetes, arthritis or lithium for prophylaxis of bipolar affective dis- hypertension. People with anxiety disorders expe- order, although clinical trial evidence is actually rience impaired physical and role functioning, more stronger to support its use in the treatment of acute work days lost due to illness, increased impairment mania. Carbamazepine appears to be more effective at work and high use of health services. Our under- than lithium for rapidly cycling bipolar disorders, standing of the nature of anxiety has increased i.e. with recurrent swift transitions from mania to greatly from advances in research in psychology depression. It is also effective in combination with and neuroscience. It is now possible to distinguish lithium. Its mode of action is thought to involve different types of anxiety with distinct biological agonism of inhibitory GABA transmission at the and cognitive symptoms. Clear criteria have been GABA-benzodiazepine receptor complex (see also accepted for the diagnosis of various anxiety Epilepsy, p. 417). disorders. The last decade has seen developments 391
11 PSYCHOTROPIC DRUGS in both drug and psychological therapies such that a range of treatment options can be tailored to individual patients and their condition. The GABAA- benzodiazepine receptor complex This subject is central to any discussion of anxiety and its treatment. Gamma aminobutyric acid (GABA) Fig. 19.4 Schematic representation of the GABAA- is probably the most important inhibitory trans- benzodiazepine (B2D) receptor complex. Note that drugs that mitter in the central nervous system. GABAergic bind to the benzodiazepine (B2D) receptor site do not open the chloride channel directly but rather augment the capacity of neurones are distributed widely in the CNS but are GABA to do so. Conversely agents such as the barbiturates at virtually absent outside the brain and the spinal lower doses enhance GABA action but at higher doses act directly cord. GABA controls the state of excitability in to open the chloride channel. all brain areas and the balance between excitatory inputs (mostly glutamatergic) and the inhibitory GABAergic activity determines the prevailing level of neuronal activity. If the balance swings in favour Classification of anxiety of GABA, then sedation, amnesia, muscle relaxation disorders and ataxia appear and nervousness and anxiety are reduced. The mildest reduction of GABAergic The diagnostic criteria of DSM-IV (Diagnostic and activity elicits arousal, anxiety, restlessness, insomnia Statistical Manual) or ICD 10 (International Classi- and exaggerated reactivity. fication of Disease) are generally used. Both divide When GABA binds with the GABAA-benzodia- anxiety into a series of sub-syndromes with clear zepine receptor complex, the permeability of the operational criteria to assist in distinguishing them. central pore of the receptor to chloride ions increases, At any one time many patients may have symp- allowing more ions into the neurone and decreasing toms of more than one syndrome but making the excitability. Classical benzodiazepines (BDZs) in primary diagnosis is important as this markedly clinical use enhance the effectiveness of GABA by influences the choice of treatment. lowering the concentration of GABA required for The key features of each anxiety disorder are opening the channel, so enabling the GABAergic given below, with a practical description of the circuits to produce a larger inhibitory effect (Fig. preferred choice of medication, its dose and 19.4). These drugs are agonists at the receptor and duration. there is an antagonist (flumazenil) which prevents agonists from binding at the receptor site and PANIC DISORDER enhancing GABA function. Drugs that act as agonists at this receptor are The main feature is recurrent, unexpected panic used mostly but not exclusively in sleep and attacks. These are discrete periods of intense fear anxiety disorders. Benzodiazepines (see later) have accompanied by characteristic physical symptoms hypnotic, sedative, anxiolytic, anticonvulsant and such as skipping or pounding heart, sweating, (central) muscle relaxant actions. They form a sig- hot flushes or chills, trembling/shaking, breathing nificant but not the only part of available pharma- difficulties, chest pain, nausea, diarrhoea and other cological treatments, as the following account will gastrointestinal symptoms, dizziness or light- illustrate. headedness. The first panic attack often occurs 392
CLASSIFICATION OF ANXIETY DISORDERS 19 without warning but may subsequently become Antidepressants (both SSRIs and TCAs) have a associated with specific situations e.g. in a crowded slower onset of action and, indeed, may induce an shop, driving. Anticipatory anxiety and avoidance initial increase in both anxiety and panic frequency, behaviour develop in response to this chain of such that a patient may discontinue medication, events. The condition must be distinguished from even after a single dose. This provoking reaction alcohol withdrawal, caffeinism, hyperthyroidism usually lasts for only 2-3 weeks after which panic and (rarely) phaeochromocytoma. frequency and severity improve but patients need Patients experiencing panic attacks often do not help to stay on treatment over this period. The know what is happening to them, and because the doctor needs to give a clear explanation of the likely symptoms are similar to those of cardiovascular, course of events and the antidepressant should be respiratory or neurological conditions, often present started at half the usual initial dose to reduce the to nonpsychiatric services e.g. casualty depart- likelihood of exacerbation. Where the exacerbation ments, family doctors, medical specialists, where is particularly of anxiety, a short course of a long- they may either be extensively investigated or acting benzodiazepine can provide benefit. The given reassurance that there is nothing wrong. A dose of antidepressant required to treat panic dis- carefully taken history reduces the likelihood of this order is generally as high or higher than that for occurrence. depression and maximal benefit may not emerge for 8-12 weeks. Patients should therefore receive as Treatment. The choice lies between a fast-acting high a dose as can be tolerated for this length of benzodiazepine such as alprazolam (1-3 mg/day p.o.) time. and a drug with delayed efficacy but fewer problems If there is no response to adequate trial of an of withdrawal such as a TCA, e.g. clomipramine SSRI, followed by a TCA, the MAOI, phenelzine (100-250 mg/day p.o.) or an SSRI, e.g. paroxetine should be used at doses of up to 90 mg/d. MAOIs (20-50 mg/day p.o.). The different time course of tend to produce less exacerbation at the beginning these two classes of agent in panic disorder is of treatment than the other antidepressants but depicted in Fig. 19.5 (see also Tables 19.5 and 19.6). can increase anxiety and panics in more sensitive Benzodiazepines rapidly reduce panic frequency individuals. and severity and continue to be effective for months; significant tolerance to the therapeutic action is SOCIAL ANXIETY DISORDER uncommon. On withdrawal of the benzodiazepine, even when it is gradual, increased symptoms of The essential feature of social phobia is a marked anxiety and panic attacks may occur, reaching a and persistent fear of performance situations when maximum when the final dose is stopped. Indeed, patients feel they will be the centre of attention and about 20% of patients find they are unable to with- will do something humiliating or embarrassing. draw and remain long-term on a benzodiazepine. The situations that provoke this fear can be quite specific, for example public speaking, or be of a much more generalised nature involving fear of most social interactions, for example initiating or maintaining conversations, participating in small groups, dating, speaking to anyone in authority. Exposure to the feared situation almost invariably provokes anxiety with similar symptoms to those experienced by patients with panic attacks but some seem to be particularly prominent and difficult i.e. blushing, tremor, sweating and a feeling of 'drying up' when speaking. Fig. 19.5 Schematic representation of the time course of panic Treatment. The drugs with established efficacy treatments. are the SSRI, paroxetine, the MAOI, phenelzine and 393
19 PSYCHOTROPIC DRUGS TABLE 19.5 Relative effectiveness of pharmacological treatments for anxiety disorders Benzodiazepine SSRI TCA Other Panic disorder ++ +++ +++ MAOI ++ Social phobia + ++ + MAOI++ (social anxiety disorder) Generalised anxiety disorder ++ ++ ++ Venlafaxine++ MAOI+ Buspirone++ Obsessive-compulsive disorder -/+ ++ ++ (Clomipramine) Addition of antipsychotics Post-traumatic stress disorder + ++ + Acute stress reaction ++ TABLE 19.6 Properties of anti-anxiety drugs Benzodiazepines Buspirone Antidepressants SSRIs TCAs Onset fast slow slow slow Initial worsening of symptoms no rarely sometimes (especially Withdrawal symptoms panic) Acute yes (~30%) no sometimes sometimes Chronic ?yes(~10%) no no no Abuse potential low zero zero zero Interactions with alcohol marked slight Adverse effects Sedation yes no no some TCAs Amnesia yes no no mild Cardiovascular no no no yes Gastrointestinal no slight yes no Sexual no no yes no Depression sometimes no no no Relative safety in overdose yes yes yes no the RIMA, moclobemide in the same doses as for persistent re-experiencing of the traumatic event, depression. These achieve equivalent degrees of persistent avoidance of stimuli associated with the improvement; phenelzine has a slightly faster onset trauma and numbing of general responsiveness, of action but produces more adverse effects. Some and persistent symptoms of increased arousal. In benzodiazepines and other SSRIs are reported to taking a history the association with the event is provide benefit but evidence for their therapeutic usually obvious. PTSD is differentiated from acute efficacy is less conclusive. $-adrenoceptor blockers stress disorder (below) by its persistence—the continue to be widely used despite their having symptoms of the latter resolve within about 4 no proven efficacy in social phobia. But they have weeks. Depression quite commonly coexists with a place in the treatment of specific performance PTSD and should be enquired for in the history. anxiety in, e.g. musicians, when management of the tremor is crucial. Treatment is poorly researched; there have been The duration of treatment is as for depression or few properly controlled trials and almost all open longer, for this can be a lifelong condition. trials have been conducted on small numbers of patients long after the causative incident. The wide range of drugs that has been reported to provide POST-TRAUMATIC STRESS DISORDER some benefit includes benzodiazepines, TCAs and (PTSD) MAOIs; paroxetine (SSRI) (20-50 mg/day p.o.) is Symptoms characteristically follow exposure to an now licenced for this indication in the UK. The extreme traumatic stressor event. These include preferred treatment immediately following the 394
CLASSIFICATION OF ANXIETY DISORDERS 19 incident should probably be a short course of a Treatment. Historically benzodiazepines have been benzodiazepine to promote sleep and help seen as the most effective treatment for GAD for minimise mental rehearsal of the trauma that may they rapidly reduce anxiety and improve sleep and lead to its perpetuation. Long-term therapy appears somatic symptoms. Consequently patients like taking to be indicated at doses in the same range as for them but the chronic nature of GAD raises issues of other anxiety disorders. duration of treatment, tolerance, dependence and withdrawal reactions. ACUTE STRESS DISORDER/ Buspirone is structurally unrelated to other anxio- ADJUSTMENT DISORDER lytics and was the first nonbenzodiazepine to Acute stress disorder is anxiety in response to a demonstrate efficacy in GAD. Its mode of action recent extreme stress. Although in some respects it is unclear, although we know it suppresses 5HT is a normal and understandable reaction to an neurotransmission through a selective activation of event, the problems associated with it are not only the inhibitory presynaptic 5HTlA-reactor. Buspirone the severe distress the anxiety causes but also the has a t1/2 of 7 h, and is metabolised in the liver; it has risk that it may evolve into a more persistent state. an active metabolite that may accumulate over weeks. Twice daily dosing is suitable, with the usual Treatment. A benzodiazepine used for a short time range being 15-30 mg/d p.o., maximum 45 mg/d. is the preferred approach for treating overwhelm- Buspirone is generally less effective and slower ing anxiety that needs to be brought rapidly under in action than benzodiazepines and does not control. It particularly relieves the accompanying improve sleep; it does not benefit benzodiazepine anxiety and sleep disturbance. A drug with a slow withdrawal symptoms. The advantages are that onset of action such as oxazepam (60-120 mg/day it does not seem to cause dependence or withdrawal p.o.) causes less dependence and withdrawal, and reactions and does not interact with alcohol. It is preferred to those that enter the brain rapidly, e.g. appears to be less effective in patients who have diazepam, lorazepam. Some patients find it hard to previously received benzodiazepines and is there- discontinue the benzodiazepine, so its use should fore probably best used in benzodiazepine naive be reserved for those in whom extreme distress patients. A disadvantage is that useful anxiolytic disrupts normal coping strategies. effect is delayed for 2 or more weeks. Adverse effects can include dizziness, headache, nervousness, excitement, nausea, tachycardia and GENERALISED ANXIETY DISORDER drowsiness. (GAD) The essential feature of this condition is chronic Paroxetine (SSRI) and venlafaxine (SNRI) are anxiety and worry. To the nonsufferer the focus of effective (and are licenced for GAD in the UK), and the worry often seems to be trivial, e.g. getting the TCAs have also been shown to give benefit. These housework done or being late for appointments, drugs have a slower onset of action than benzodia- but to the patient it is insurmountable. The anxiety zepines, are less well tolerated but cause fewer is often associated with other symptoms, which problems of dependence and on withdrawal. include restlessness, difficulty in concentrating, A delayed response in GAD is not as critical as irritability, muscle tension and sleep disturbance. with acute situational anxiety. A sensible approach The course of the disorder is typically chronic with (especially in benzodiazepine naive patients) is to exacerbations at times of stress and is often asso- start with buspirone for 6-8 weeks, at least 30 mg ciated with depression. Its chronic nature with day increasing over 2-3 weeks to minimise worsening at times of stress helps to distinguish unwanted actions; patients should be warned not to GAD from anxiety in the form of episodic panic expect an immediate benefit. Those who do not attacks with associated anticipatory anxiety (panic respond should receive an antidepressant (SSRI or disorder). Hyperthyroidism and caffeinism should venlafaxine) for 6-8 weeks at full therapeutic dose. also be excluded. There remain some patients, including those with a 395
I9 PSYCHOTROPIC DRUGS long history of benzodiazepine use, who yet fail • anxiety provoked by the occurrence of such acts to respond. A benzodiazepine may be the only or thoughts. medication that provides relief for such resistant OCD on its own often starts in late adolescence and cases, and can be used as the sole treatment. has a chronic and pervasive course unless treated. OCD starting later on in life is often associated The duration of therapy depends on the nature of with affective or anxiety disorders. Symptoms often the underlying illness. If symptoms are inter- abate briefly if the individual is taken to a new mittent, i.e. triggered by anxiety-provoking situa- environment. tions, then intermittent use of a benzodiazepine (for a few weeks) may be sufficient. More typically Treatments are cognitive behavioural therapy and GAD requires treatment over 6-8 months with an SSRI or clomipramine (i.e. an antidepressant gradual withdrawal of medication thereafter. This that enhances serotonergic function), used at higher may suffice but some patients experience severe, doses and for much longer periods than for depres- unremitting anxiety and the best resort is to chronic sive disorders. Neuroleptics, atypical antipsychotics maintenance treatment with a benzodiazepine in low dose and benzodiazepines can be used (analogous to long-term drug use in epilepsy). Such successfully to augment the SSRIs if they are not clinically supervised benzodiazepine use is justified wholly effective, especially in patients with tics because, without treatment, patients often derive (habitual, repeated contraction of certain muscles). comfort from the most widely accessible, easily Psychosurgery is still occasionally used for severe available anxiolytic, alcohol. and treatment resistant cases. Interestingly, the brain pathways targeted by the surgeon are those that show abnormalities in neuroimaging (PET) studies of OCD, i.e. the basal ganglia/orbitofrontal Specific phobia pathways. A specific phobia is a fear of a circumscribed object or situation, for instance fear of spiders, fear of GENERAL COMMENTS ON DRUG flying. The diagnosis is not usually in doubt. A TREATMENT FORANXIETY course of treatment by a trained therapist, involv- DISORDERS ing graded exposure to the feared stimulus is the treatment of choice and can be very effective. By its The effective dose of antidepressant for anxiety is nature such therapy generates severe anxiety and a generally higher than that for antidepressant effect benzodiazepine may permit patients fully to engage and takes longer for improvements to be seen (at least in therapy. 4-8 weeks compared to 2-3 weeks for depression). The patient should be maintained on as high a dose as can be tolerated for at least 8 weeks before changing a medication. Educating the patient is Obsessive-compulsive crucial to obtaining cooperation. The duration of treatment is often a controversial disorder (OCD) issue. Anxiety disorders (apart from the self- limiting acute stress reaction) are chronic conditions Obsessive-compulsive disorder has two main com- and may require treatment for as long as that used ponents: in depression. In a first episode, patients may need • the repetition of acts or thoughts which are medication for at least 6 months, withdrawing over involuntary, recognised by the sufferer to be a further 4-8 weeks if they are well. Those with generated by their own brain but are not in recurrent illness may need treatment for 1-2 years keeping with their usual thought processes, to enable them to learn and put into place psycho- morals or values, and are therefore very logical approaches to their problems. In many cases distressing and the illnesses are lifelong and chronic maintenance 396