19 PSYCHOTROPIC DRUGS The reality is more complex since the receptor binding profile of clozapine and the newer atypical antipsychotic agents suggests that D 2 -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 D 2 -receptor compared with classical drugs but binds more avidly to other dopamine subtypes (e.g. D 1 , D 3 and D 4 ). 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 antagonist at a 2 -adrenoceptors than the classical drugs and also blocks histamine and serotonin receptors (5HT 2 and others). The newer atypical psychotropics vary widely in their receptor binding profiles. Olanzapine and quetiapine bear resemblance to the profile of cloza- pine in that their therapeutic effects appear to derive from action on different receptors and transmitter systems. All atypicals (except amisulpride) exhibit greater antagonism of 5HT 2 -receptors than D 2 - receptors compared with the classical agents. Atypical drugs that do antagonise dopamine D 2 - receptors appear to have affinity for those in the Fig. 19.3 Sagittal brain section illustrating dopaminergic pathways. I. Mesolimbic pathway (overactive in psychotic illness according to the dopamine hypothesis of schizophrenia).VTA= ventrotegmental area. 2. Nigrostriatal pathway (involved in motor control, underactive in Parkinson's Disease and associated with extrapyramidal motor symptoms). 3. Tuberoinfundibular pathway (inhibits prolactin release from the hypothalamus). mesolimbic system (producing antipsychotic effect) rather than the nigrostriatal system (associated with unwanted motor effects). In contrast to classical antipsychotics, risperidone shares with clozapine an ability antagonise a 2 -adrenoceptors, a property which may have utility in the treatment of schizo- phrenia and is seen as an area of interest for developing new drugs. PHARMACOKINETICS Like antidepressants, antipsychotics are well absorbed and distributed after oral administration. In situations where very rapid relief of symptoms or disturbed behaviour is required, faster uptake into plasma can be achieved through the intramus- cular route. Again in common with antidepressants, antipsychotics are mainly metabolised by cyto- chrome P450 isoenzymes in the liver, e.g. CYP 2D6 (zuclopenthixol, risperidone [Table 19.2a]), CYP 3A4 (sertindole [Table 19.2b]), CYP 1A2 (olanzapine, clozapine). Metabolism of some compounds is parti- cularly complex (e.g. chlorpromazine, haloperidol), involving more than one main pathway, utilising several P450 enzymes or resulting in the production of many inactive metabolites. Antipsychotic plasma 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 left with unresolved negative symptoms such as apathy, flattening of affect and alogia. Evidence suggests that clozapine and the newer atypicals have a significant advantage over classical drugs against negative symptoms. Clozapine has a 382 19 ANTI PSYCHOTI CS further advantage over all other antipsychotics, whether classical or atypical, in that it may be effective when other antipsychotics prescribed at adequate doses have failed or are not tolerated. Schizophrenia often runs a chronic relapsing and remitting course. Less than one-quarter of patients who experience a psychotic episode and are diag- nosed as having schizophrenia succeed in avoiding further episodes. Nevertheless, taking antipsychotics as prophylaxis significantly reduces the likelihood of relapse. MODE OF USE Since the potency (therapeutic efficacy in relation to weight) of antipsychotic agents varies markedly between compounds, it is useful to think of the effective antipsychotic dose of classical agents in terms of ''chlorpromazine equivalents' (see Table 19.5). For example, haloperidol has a relatively high anti- psychotic potency, such that 2-3 mg is equivalent to chlorpromazine 100 mg, whereas sulpiride 200 mg (low potency) is required for the same antipsychotic effect. Patients who are 'neuroleptic naive' (i.e. have never previously taken any antipsychotic agent) should start at the lowest available dosage, such as haloperidol 0.5 mg/day or chlorpromazine 25 mg/ day, in case the patient is particularly susceptible to adverse effects, especially extrapyramidal motor symptoms. Conservative starting doses are also recommended in the elderly and for patients with learning disabilities who may require antipsychotics for psychosis or severe behavioural disturbance. The dose can be titrated up at intervals, until the desired effect in treating psychotic symptoms, calming disturbed behaviour or effecting sedation is achieved. The interval depends on the context, with the urgency of the situation and previous use of antipsychotics being factors which would 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 should be instigated as soon as an adequate period of assessment has allowed a provisional diagnosis to be established. For each antipsychotic agent there is a licensed maximum dose; for example up to 1000 mg of chlorpromazine/day may be given under the United Kingdom licence. Prescribing beyond the licensed maximum dose requires specialist consent. When two antipsychotics are co-prescribed, the maximum antipsychotic dose should not exceed 1000 mg of chlorpromazine equivalents/day except under specialist supervision. For some antipsycho- tics the licenced maximum dose is considerably less than 1000 mg of chlorpromazine equivalents/day. For instance, the licenced maximum dose of thioridazine was reduced to 600 mg/day following 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, which patients may find threatening.The voices may also give commands.Visual hallucinations are rare. Delusions, most commonly persecutory.'Passivity phenomena' include delusions of thought broadcasting, thought insertion or thought withdrawal, made actions, impulses or feelings. Bizarre behaviours including agitation, sexual disinhibition, repetitive behaviour, wearing of striking but inappropriate clothing. Thought disorder manifest by failure in the organisation of speech such that it drifts away from the point (tangentiality), never reaches the point (circumstantiality), moves from one topic to the next illogically (loosened associations, knight's move thinking), 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). Affective flattening manifest by unchanging facial expression with lack of communication through expression, poor eye contact, lack of responsiveness, psychomotor slowing Alogia (literally'absence of words' manifesting clinically as a lack of spontaneous speech (poverty of speech). Anhedonia (inability to derive pleasure from any activity) and Associality (narrowing of repertoire of interests and impaired relationships) Apathy IAvolution involving lack of energy, lack of motivation to work, participate in activities or initiate any goal-directed behaviour, and poor personal hygiene. Attention problems involving an inability to focus on any one issue or engage fully with communication. 383 19 PSYCHOTROPIC DRUGS that plasma electrolytes and an ECG should be checked on introducing or increasing the dose of thioridazine and that an ECG should be seen before prescribing pimozide and sertindole. Prescription of atypical antipsychotics follows similar rules to those for classical drugs, starting at low doses in neuroleptic naive patients. Whereas there is a wide range of effective doses for many classical agents (e.g. chlorpromazine 25-1000 mg/ day), much narrower ranges have been defined for atypical agents (Table 19.5). While classical anti- psychotics are licenced for the management of acutely disturbed behaviour as well as for schizo- phrenia, atypical agents are generally licenced only for the latter indication, although that for risperi- done is broader. For most atypical agents used in schizophrenia, a brief period of dose titration by protocol up to a stated lowest therapeutic dose is usual, e.g. risperidone 4 mg/day, quetiapine 300 mg/day. Dose increases are indicated where there is no response after 2 weeks and these may be repeated until the maximum licenced dose is achieved. Clozapine may be initiated only under specialist supervision and only after two other antipsychotic agents have failed through lack of efficacy or adverse effects. Additionally, leucocyte count moni- toring is mandatory (danger of agranulocytosis) and blood pressure checking is required (for hypo- tensive effect). Patients are most vulnerable to agranulocytosis on initiation of therapy with 75% of cases occurring in the first 18 weeks. The dose titration schedule must be followed strictly, starting with clozapine 12.5 mg nocte and working up over a period of four weeks to a target therapeutic dose of 450 mg/day. Alternative administration strategies in acute use of antipsychotics Some of the antipsychotics are available as intra- muscular injections for patients who are unable or unwilling to swallow tablets (as is common in psychosis or severe behavioural disturbance). Halo- peridol is most often used for these indications on psychiatric inpatient wards (chlorpromazine i.m. being restricted due to hypotension and skin nodule formation). Olanzapine may be given i.m. for acute behavioural disturbance in schizophrenia. This drug is also presented as a Velotab' which dissolves rapidly on contact with the tongue allow- ing drug to be absorbed despite lack of cooperation from a disturbed patient. Long-acting (depot) injections Haloperidol, zudopenthixol, fluphenazine, flupentixol and pipothiazine are available as depot intramuscular injections for maintenance treatment of patients with schizophrenia and other chronic psychotic disorders. Provided the patient is willing to agree to have depot injections, usually by a community psychiatric nurse at intervals of 2-4 weeks, the need to take tablets two or three times a day is removed. Poor compliance with oral medication is the most common cause of admission to hospital with a relapse of schizophrenia. A reduced initial dose of the depot medication should be given, with a review for unwanted effects after 5-10 days. Rapid tranquillisation Rapid tranquillisation protocols have been devised for patients who are severely disturbed and violent or potentially violent and have not responded to nonpharmacological approaches. The risks from administering psychotropic drugs (e.g. cardiac arrhythmia with high-dose antipsychotics) may greatly outweigh the risk of leaving the patient untreated, including physical trauma and the consequences of over-stressing the cardiovascular system. A benzodiazepine, e.g. lomzepam 1-2 mg i.v. (into a large vein) failing which i.m. (dilute with an equal volume of water or physiological saline) is the first option if the patient is not already receiving an antipsychotic drug. Patients requiring rapid tranquillisation are commonly taking antipsycho- tics for established illness and an additional anti- psychotic may then be used if the patient has not received an adequate dose; otherwise a benzo- diazepine should given. Haloperidol 2-10 mg i.m. is currently preferred for rapid tranquillisation, but new protocols may evolve with the development of atypical antipsychotics that can be given i.m. When i.m. antipsychotic or benzodiazepine tranquilliser is given as an emergency, pulse, blood pressure, 384 19 ANTI PS YC HOTI CS temperature and respiration should be monitored, and pulse oximetry (oxygen saturation) if con- sciousness is lost. When at least two doses of haloperidol i.m. fail to produce the desired result, zuclopenthixol acetate i.m. is an alternative. This heavily sedating drug usually produces a calming effect within 2 h, persisting for 2-3 days if used at appropriate dose. Zuclopenthixol acetate should never be prescribed to the neuroleptic naive. Patients must be observed with the utmost care following admin- istration. Some will require a second dose within 1-2 days. Amylobarbitone and paraldehyde have a role in emergencies when antipsychotic and benzodiazepine options have been exhausted. ADVERSE EFFECTS (see Table 19.5) Active psychotic illnesses often cause patients to have poor insight into their condition; unwanted drug effects can compromise already fragile com- pliance and lead to avoidable relapse. Classical antipsychotics It is rare for any patient taking classical anti- psychotic agents completely to escape their adverse effects. Thus it is essential to discuss with patients the possibility of unwanted effects and regularly to review this aspect of their care. Extrapyramidal symptoms. All classical anti- psychotics are capable of producing these effects because they act by blocking dopamine receptors in the nigrostriatal pathway. The result is that some 75% of patients experience extrapyramidal symptoms which may appear shortly after starting the drug or increasing its dose (acute effects), or some time after a particular dose level has been established (tardive effects, see p. 387). Acute extrapyramidal symptoms. Dystonias are manifest as abnormal movements of the tongue and facial muscles with fixed postures and spasm, including torticollis and bizarre eye movements ('oculogyric crisis'). Parkinsonian symptoms result in the classical triad of bradykinesia, rigidity and tremor. Both dystonias and parkinsonian symptoms are believed to result from a shift in favour of cholinergic rather than dopaminergic neurotrans- mission in the nigrostriatal pathway (see p. 422). Anticholinergic agents, e.g. procyclidine, orphe- nadrine or benztropine, restore the balance in fav- our of dopaminergic transmission but are liable to provoke antimuscarinic effects (dry mouth, urine retention, constipation, exacerbation of glaucoma and confusion) and they offer no relief for tardive dyskinesia, which may even worsen. They should be used only in response to clear dystonic or parkinsonian symptoms rather than for prophyl- axis. Benzodiazepines, with their general inhibitory effects, are an alternative. Thioridazine and related Type 2 phenothiazines are less likely to provoke extrapyramidal effects as they also block cholinergic transmission (but patients may suffer antimusca- rinic effects). Note that confusion from anticholiner- gic effects may mimic or complicate schizophrenic thought disorder. Akathisia is a state of motor and psychological restlessness, in which patients exhibit persistent foot tapping, moving of legs repetitively and being unable to settle or relax. A strong association has been noted between its presence in treated schizo- phrenics and subsequent suicide. A (3-adrenoceptor blocker is the best treatment, although anticholiner- gic agents may be effective where akathisia coexists with dystonias and parkinsonian symptoms. Differ- entiating symptoms of psychotic illness from adverse drug effects is often difficult: drug-induced akathisia may be mistaken for agitation induced by psychosis. Tardive dyskinesia affects about 25% of patients taking classical antipsychotic drugs, the risk increasing with length of exposure. It was formerly thought to be a consequence of up-regulation or supersensitivity of dopamine receptors. A preferred explanation is that tardive dyskinesia is a conse- quence of oxidative damage after neuroleptic- induced increases in glutamate transmission. Patients display a spectrum of abnormal movements from minor tongue protusion, lip-smacking, rotational tongue movements and facial grimacing, choreo- athetoid movements of the head and neck and even to twisting and gyrating of the whole body. It is less 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 Classical Chlorpromazine Thioridazine Trifluoperazine Haloperidol Sulpiride Zuclopenthixol Atypical Clozapine** Olanzapine Quetiapine Risperidone Amisulpride CPZ Equiv Dose 100mg 50 mg 5mg 3 mg 200 mg 25 mg Min eff. dose (/day) 300 mg 5-1 0 mg 300 mg 4mg 800 mg Max dose (/day) 1 000 mg 300 mg* 50 mg 30 mg 2400 mg 150mg Max dose (/day) 900 mg 20 mg 750 mg I6mg 1 200 mg Structure Type 1 Phenothiazine Type 2 Phenothiazine Type 3 Phenothiazine Butyrophenone Substituted benzamide Thioxanthene Dibenzodiazepine Theinobenzodiazepine Dibenzothiazepine Benzisoxazole 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. Any anticholinergic agent should be withdrawn immediately. Reduction of the dose of classical anti- psychotic is often advised but psychotic symptoms may then worsen or be 'unmasked'. Alternatively, an atypical antipsychotic can provide rapid improvement whilst retaining control of psychotic symptoms. Atypical drugs, particularly at high doses, can yet cause extrapyramidal effects and this strategy is not always helpful. If the classical antipsychotic is simply continued, tardive dyskinesia remits spontaneously in around 30% of patients within a year but since the condition is difficult to tolerate, patients may be keen to try other medications, even where evidence suggests that the success rates for remission are limited. These include vitamin E, benzodiazepines, (3-blockers, bromocriptine and tetrabenazine. Clozapine, which does not appear to cause tardive dyskinesia, may be used in severe cases where continuing antipsychotic treatment is required and symptoms have not responded to other medication strategies. Cardiovascular effects. Postural hypotension may result from blockade of oc-adrenoceptors; it is dose-related. Prolongation of the QT interval in the cardiac cycle may rarely lead to ventricular arrhyth- mias and sudden death (but particular warnings and constraints apply to the use of thioridazine and pimozide). Prolactin elevation. Classical antipsychotics raise plasma prolactin concentrations by their blocking action on dopamine receptors in the tuberoinfundi- bular pathway (Fig. 19.3 and p. 711) and can cause 386 19 ANTIPSYCH OTI CS gynaecomastia and galactorrhoea in both sexes, and menstrual disturbances. A change to an atypical agent such as quetiapine or olanzapine (but not risperidone or amisulpride) should minimise these effects. If continuation of the existing classical antipsychotic is obligatory, a dopamine agonist such as bromocriptine or amantadine may be beneficial. Sedation. In the acute treatment of psychotic illness this may be a highly desirable property but it may be unwelcome as the patient seeks to resume work, study or relationships. Classical antipsychotics may also be associated with: • weight gain (a problem with almost all classical antipsychotics with the exception of loxapine, most pronounced with fluphenazine and flupentixol) • seizures (chlorpromazine and thioridazine are especially likely to lower the convulsion threshold) • interference with temperature regulation (hypothermia or hyperthermia, especially in the elderly) • skin problems (phenothiazines, particularly chlorpromazine, may provoke photosensitivity necessitating advice about limiting exposure to sunlight. Rashes and urticaria may also occur) • sexual dysfunction (ejaculatory problems through a-adrenoceptor blockade) • retinal pigmentation (chlorpromazine, thioridazine, vision is affected if dose is prolonged and high) • corneal and lens opacities • blood dyscmsias (agranulocytosis and leucopenia) • osteoporosis (associated with prolactin elevation) • jaundice (including cholestatic). Atypical antipsychotics Atypical drugs can provoke a range of adverse effects that is similar to that of the classical anti- psychotics but is generally lesser in degree (with exceptions). The following are the main differences. Atypical antpipsychotics provoke fewer extra- pyramidal effects (less blockade of dopamine D 2 - receptors in the nigrostriatal pathway). Neverthe- less, extrapyramidal effects are seen, notably with high dose of risperidone (8-12 mg per day) and olanzapine (> 20 mg/day). Clozapine and olanzapine are the most likely of the atypical agents to cause anticholinergic (anti- muscarinic) effects. They are more likely than other atypicals to cause weight gain (glucose tolerance may be impaired and should be monitored in susceptible individuals) and are second only to quetiapine in their sedative effects. Sexual dysfunction and skin problems are rare with atypical anti- psychotics. Risperidone and amisulpride are as likely as classical antipsychotics to raise prolactin concentrations and cause galactorrhoea. Clozapine warrants further mention, given its value for patients with treatment-resistant schizo- phrenia or severe treatment-related extrapyramidal symptoms. It may cause postural hypotension and tachycardia, and provoke seizures in 3-5% of patients at doses above 600 mg/day. Most important is the risk of agranulocytosis in up to 2% of patients (compared with 0.2% in classical antipsychotics). When clozapine was first licenced without require- ments for regular white count monitoring, the haematological problems caused appreciable morta- lity. Thanks to strict monitoring, there have been no recorded deaths from agranulocytosis since clozapine was reintroduced in the United Kingdom, and internationally the death rate among the small minority who develop agranulocytosis is now less than 1 in 1000. Neuroleptic malignant syndrome The syndrome may develop in up to 1% of patients using antipsychotics and is more prevalent at high doses. The elderly, and those with organic brain disease, hyperthyroidism or dehydration are thought to be most susceptible. Clinical features include: • fever • confusion or fluctuating consciousness • rigidity of muscles which may become severe • autonomic instability manifest by labile blood pressure • tachycardia • urinary incontinence or retention. Raised plasma creatine kinase concentration and white cell count are suggestive (but not conclusive) of neuroleptic malignant syndrome. There is some clinical overlap with the 'serotonin syndrome' (see 387 19 PSYCHOTROPIC DRUGS p. 376) and concomitant use of SSRI antidepressants (or possibly TCAs) with antipsychotics may increase risk. It is essential to discontinue the antipsychotic when the syndrome is suspected and to be ready to transfer the patient to a medical ward for rehydra- tion. Benzodiazepines are indicated for sedation and their transquillising effect may be useful where active psychosis has to be left untreated. Dopamine agonists (bromocriptine, dantrolene) are beneficial in some cases. There is also evidence to support a role for electroconvulsive therapy in treatment of neuroleptic malignant syndrome. Even when recognised and treated, the condition carries a mortality of 12-15%, through cardiac arrhythmia, rhabdomyolysis or respiratory failure. The condition usually lasts for 5-7 days after the antipsychotic is stopped but may continue longer when a depot preparation has been used. Fortunately those who survive tend to have no long lasting physical effects from their ordeal. CLASSICAL VERSUS ATYPICAL ANTIPSYCHOTICS As atypical antipsychotics have become established as alternatives to classical agents, clinicians are presented with the dilemma as to which should be their first choice in patients with schizophrenia and psychotic illnesses, and indeed whether there is sufficient justification to transfer a patient stabilised on a classical agent over to an atypical. Atypical antipsychotics may have advantages in three areas. First, they appear to be better tolerated, 2 in particular being less likely than classical agents to induce extrapyramidal effects and hyperprolac- 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 agents) produced rather different results. Although the atypicals retained their advantage in causing extrapyramidal side effects less frequently, overall tolerability and efficacy appeared to be similar. Geddes J et al 2000 Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. British Medical Journal 321: 1371-1376. tinaemia (with gynaecomastia and galactorrhoea), although these latter remain common with risperi- done and amisulpride. Improved tolerance is reflected in better compliance with taking atypical agents, so lessening the chance of psychosis being untreated with the likelihood of relapse once remission has been achieved. Secondly, atypical antipsychotics are more efficacious against the negative symptoms of schizophrenia which are particularly debilitating in chronic illness. Thirdly, clozapine (but not the newer atypicals) is more effective than classical agents for resistant schizophrenia. Atypical antipsychotics are significantly more expensive than classical drugs. In some countries this will be the overriding argument for retaining classical agents as first choice drugs in schizoph- renia. Additionally, if a patient is successfully main- tained on a classical antipsychotic, transfer to an atypical agent is difficult to justify. Where a classical antipsychotic is not achieving optimal results or causes unwanted effects, a more persuasive case for change to an atypical can be made. But economic analysis must take into account factors beyond the crude cost of drugs. If atypical antipsychotics truly cause fewer distressing extra- pyramidal symptoms and improve compliance, they may prevent relapse of psychotic illness and protect patients against lasting damage from periods of untreated psychosis. Greater effective- ness in treating negative symptoms would afford patients with schizophrenia more opportunity of re-integrating into the community and to make positive contributions to society rather than the alternative of long-term institutionalisation. Such 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. Mood stabilisers In bipolar affective disorder patients suffer episodes of mania, hypomania and depression, classically with periods of normal mood in between. Manic episodes involve greatly elevated mood, often interspersed with periods of irritability or undue 388 MOOD STABILISERS 11 excitement, accompanied by biological symptoms (increased energy, restlessness, decreased need for sleep, increased sex drive), loss of social inhibitions, irresponsible behaviour and grandiosity. Psychotic features may be present, particularly disordered thinking manifested by grandiose delusions and 'flight of ideas' (acceleration of the pattern of thought with rapid speech). Hypomania is a less dramatic and dangerous presentation but retains the features of elation or irritability and the biolo- gical symptoms, abnormalities in speech being limited to increased talkativeness and in social conduct to overfamiliarity and mild recklessness. Depressive episodes may include any of the depres- sive symptoms described before and may include psychotic features. Lithium salts were known anecdotally to have beneficial psychotropic effects as long ago as the middle of the 19th century but scientific evidence of their efficacy followed a serendipitous discovery. In 1949, during a search for biologically active substances in mania, urine from manic patients was injected into guinea pigs. The animals appeared to be affected by the accompanying large amounts of urea and it was postulated that administration of urate would exacerbate manic effects. Lithium urate, which is highly soluble, was selected to conduct investigations into urate toxicity. It was found to be sedative and to protect against manic urine toxicity. Lithium carbonate was tried in manic patients, was found to be effective in the acute state and, later, to prevent recurrent attacks. 3 Lithium salts are ineffective for prophylaxis of bipolar affective disorder in around 35% of patients and cause several unwanted effects. The search for alternatives has produced drugs that are more familiar as anticonvulsants, notably carbamazepine and sodium valproate, and possibly lamotrigine. LITHIUM The mode of action is not fully understood. The main effect of lithium is probably to inhibit hydro- lysis of inositol phosphate, so reducing the recycling of free inositol for synthesis of phosphatidylino- 3 Cade J F. 1970 The story of lithium. In: Ayd F J, Blackwell B (eds) Biological psychiatry. Lippincott, Philadelphia. sitides. These intracellular molecules are part of the transmembrane signalling system that is important in regulating intracellullar calcium ion concentra- tion, which subsequently affects neurotransmitter release. Other putative mechanisms involve the cyclic AMP 'second messenger' system and mono- aminergic and cholinergic neurotransmitters. Pharmacokinetics. Knowledge of pharmacokinetics of lithium is important for successful use since the therapeutic plasma concentration is close to the toxic concentration (low therapeutic index). Lithium is a small ion that, given orally, is rapidly absorbed throughout the gut. High peak plasma concentra- tions are avoided by using sustained-release formu- lations which deliver the peak plasma lithium concentrations in about 5 h. At first lithium is distributed throughout the extracellular water but with continued administration it enters the cells and is eventually distributed throughout the total body water with a somewhat higher concentration in brain, bones and thyroid gland. The apparent volume of distribution is about 50 1 in a 70 kg person (whose total body water is about 40 1) which is compatible with the above. Lithium is easily dialysable from the blood but the concentration gradient from cell to blood is not great and the intracellular concentration (which determines toxi- city) falls slowly. Lithium enters cells about as readily as does sodium but does not leave as readily (mechanism uncertain). Being a metallic ion it is not metabolised, nor is it bound to plasma proteins. Only the kidneys eliminate lithium. Like sodium, it is filtered by the glomerulus and 80% is reabsorbed by the proximal tubule but it is not reabsorbed by the distal tubule. Intake of sodium and water are the principal determinants of its elimination. In 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- city. Sodium chloride and water are used to treat lithium toxicity. With chronic use the plasma t l / 2 of lithium is 15-30 h. Lithium is usually given 12-hourly to avoid unnecessary fluctuation (peak and trough concentrations) and maintain a plasma concentra- tion just below the toxic level. A steady-state plasma concentration will be attained after about 5-6 days (i.e. 5 x t l / 2 ) in patients with normal renal 389 19 PSYCHOTROPIC DRUGS function. Old people and patients with impaired renal function will have a longer t l / 2 so that steady state will be reached later and dose increments must be adjusted accordingly. Indications and use. Lithium carbonate is effective treatment in > 75% of episodes of acute mania or hypomania. Because its therapeutic action takes 2-3 weeks to develop, lithium is generally used in com- bination with a benzodiazepine such as lorazepam or diazepam (or with an antipsychotic agent where there are also psychotic features). For prophylaxis, lithium is indicated when there have been two episodes of mood disturbance in two years, although in some cases it is advisable to continue with prophylactic use after one severe episode. When an adequate dose of lithium is taken consistently, around 65% of patients achieve improved control of their illness. Patients who start lithium only to discontinue it within two years have a significantly poorer outcome than matched patients who are not given any pharmacological prophylaxis. The existence of this 'rebound effect' dictates that persistence with long-term treatment is of great importance. Lithium is also used to augment the action of antidepressants in treatment-resistant depression (see p. 375). Pharmaceutics. It is important for any patient to adhere to the same pharmaceutical brand, as the dose of lithium ion (Li + ) delivered by each tablet depends on the pharmaceutical preparation. For example, each Camcolit 250 mg tablet contains 6.8 mmol, each Liskonium 450 mg tablet contains 12.2 mmol and each Priadel 200 mg tablet contains 5.4 mmol of Li + . Thus the proprietary name must be stated on the prescription. Some patients cannot tolerate slow- release preparations because release of lithium ions distally in the intestine causes diarrhoea; they may be better served by the liquid preparation, lithium citrate, which is absorbed proximally. Patients who are naive to lithium should be started at the lowest dose of the preparation selected. Any change in preparation demands the same precautions as does initiation of therapy. Monitoring. The difference between therapeutic and toxic doses is narrow and therapy must be guided by monitoring of the plasma concentration once a steady state is reached. Increments are made at weekly intervals until the concentration lies within the required range of 0.4-1 mmol/1 (maintenance at the lower level is preferred for elderly patients). The timing of blood sampling is important. By convention a blood sample is taken prior to the morning dose, as close as possible to 12 h after the evening dose. When the therapeutic range is reached, the plasma concentration should be checked every three months. Likewise, for toxicity monitoring, thyroid function (especially in women) and renal function (plasma creatinine and electrolytes) should be measured before initiation and every 3 months during therapy. Patient education about the role of lithium in the prophylaxis of bipolar affective disorder and discussion of the pros and cons of taking the drug are particularly important to encourage compliance with therapy; treatment cards, information leaflets and where appropriate, video material are used. Adverse effects. Lithium is associated with three categories of adverse effects. • Those experienced at plasma concentrations within the therapeutic range (see above) include fine tremor (especially involving the fingers; if this is difficult to tolerate a (3-blocker may benefit), constipation, polyuria and polydipsia (due to loss of concentrating ability by the distal renal tubules), metallic taste in the mouth, weight gain, oedema, goitre, hypothyroidism, acne, rash, diabetes insipidus and cardiac arrhythmias. There can also be mild cognitive and memory impairment. • Signs of intoxication, associated with plasma concentrations greater than 1.5 mmol/1 are mainly gastrointestinal (diarrhoea, anorexia, vomiting) and neurological (blurred vision, muscle weakness, drowsiness, sluggishness and coarse tremor, leading on to giddiness, ataxia and dysarthria). • Frank toxicity, due to severe overdosage or rapid reduction in renal clearance, usually associated with plasma concentration greater than 2 mmol/1, constitutes an acute medical emergency. Hyperreflexia, hyperextension of 390 19 limbs, convulsions, toxic psychoses, syncope, oliguria, coma and even death may result if treatment is not instigated urgently. Overdose is treated by use of i.v. fluid to maintain a good urine output guided by frequent measure- ment of plasma electrolytes and osmolality. Hyper- natraemia indicates probable diabetes insipidus and isotonic dextrose should then be used until plasma sodium concentration and osmolality become normal. Isotonic saline forms part of the fluid regimen (but overuse may result in hypernatrae- mia) and potassium supplement will be required. Haemodialysis is effective but may have to be repeated frequently as plasma concentration rises after acute reduction (due to equilibration as lithium leaves cells and also by continued absorption from sustained-release formulations). Interactions. Several types of drug interfere with lithium excretion by the renal tubules, causing the plasma concentration to rise. These include diuretics (thiazides more than loop type), ACE inhibitors and angiotensin-11 antagonists, and non- steroidal anti-inflammatory analgesics. Theophylline and sodium-containing antacids reduce plasma lithium concentration. The effects can be important 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 result. Carbamazepine Carbamazepine is licenced as an alternative to lithium for prophylaxis of bipolar affective dis- order, although clinical trial evidence is actually stronger to support its use in the treatment of acute mania. Carbamazepine appears to be more effective than lithium for rapidly cycling bipolar disorders, i.e. with recurrent swift transitions from mania to depression. It is also effective in combination with lithium. Its mode of action is thought to involve agonism of inhibitory GABA transmission at the GABA-benzodiazepine receptor complex (see also Epilepsy, p. 417). MOOD STABILISERS Valproic acid Valproic acid is the drug of first choice for prophylaxis of bipolar affective disorder in the United States, despite the lack of robust clinical trial evidence in support of this indication. But treat- ment with valproic acid is easy to initiate (especially compared to lithium), it is well tolerated and its use appears likely to extend if the evidence-base expands. As the semisodium salt, valproic acid is licenced for use in the treatment of acute mania unresponsive to lithium. (Note: sodium valproate, see p. 420, is unlicenced for this indication.) Treatment with carbamazepine or valproic acid appears not to be associated with the 'rebound effect' of relapse into manic symptoms that may accompany early withdrawal of lithium therapy. Other drugs Evidence is emerging regarding the efficacy of lamotrigine in prophylaxis of bipolar affective disorder and treatment of bipolar depression. Other drugs which have been used in augmentation of existing agents include the anticonvulsant gaba- pentin, the benzodiazepine clonazepam, and the calcium channel blocking agents verapamil and nimodipine. Drugs used in anxiety and sleep disorders The disability and health costs caused by anxiety disorders are comparable to those of other common medical conditions such as diabetes, arthritis or hypertension. People with anxiety disorders expe- rience impaired physical and role functioning, more work days lost due to illness, increased impairment at work and high use of health services. Our under- standing of the nature of anxiety has increased greatly from advances in research in psychology and neuroscience. It is now possible to distinguish different types of anxiety with distinct biological and cognitive symptoms. Clear criteria have been accepted for the diagnosis of various anxiety disorders. The last decade has seen developments 391 [...]... GABAA-benzodiazepine receptor complex, the permeability of the central pore of the receptor to chloride ions increases, allowing more ions into the neurone and decreasing excitability Classical benzodiazepines (BDZs) in clinical use enhance the effectiveness of GABA by lowering the concentration of GABA required for opening the channel, so enabling the GABAergic circuits to produce a larger inhibitory effect (Fig 19.4)... This may suffice but some patients experience severe, unremitting anxiety and the best resort is to chronic maintenance treatment with a benzodiazepine (analogous to long-term drug use in epilepsy) Such clinically supervised benzodiazepine use is justified because, without treatment, patients often derive comfort from the most widely accessible, easily available anxiolytic, alcohol Specific phobia A specific . psychomotor slowing Alogia (literally'absence of words' manifesting clinically as a lack of spontaneous speech (poverty of speech). Anhedonia . disease, hyperthyroidism or dehydration are thought to be most susceptible. Clinical features include: • fever • confusion or fluctuating consciousness •