Clinicians Desktop Reference

for Clinical & Cost Utility of Latest Antipsychotics

CUtLASS

Contents Procedure for Enrolment & Commencement of Treatment Overview of Treatment Arms for Atypical / Conventional comparison and Clozapine / Atypical comparison Conventional Antipsychotic Medication
Summary Table - Maximum BNF dose, side effects, pharmacology Goals & Efficacy Acute Phase Stabilization Phase Stable Phase Side Effects Common Side Effects: Sedation Anticholinergic Cardiovascular Acute Extrapyramidal Side Effects Akinesia or Bradykinesia Dystonia Akathisia Prophylactic treatment of EPSE Neuroleptic Malignant Syndrome Chronic Extrapyramidal side effects - Tardive Dyskinesia Risk Factors Severity Screening Work Up Treatment Discontinuation or Dose Reduction Treatment Agents Clozapine Other side effects i. Seizures ii. Endocrine effects iii. Weight gain iv. Effects on sexual function v. Allergic and hepatic effects vi. Ophthamic effects Pigmentary retinopathies and corneal opacities vii. Haematological effects Overdose and toxic effects Sudden Death

Pages 4

5 6-17
7 8

9-15 9

10-11

11 11 12-13

14

15 16

Implementation Route of Administration Depot Vs Oral in Stable Phase Dosage Strategy Low Vs High Potency antipsychotics Best Daily Dose Medication Interactions

17 17

Atypical Antipsychotic Medication

Summary Table Maximum BNF dose, side effects, pharmacology Summary of Prescribing Information Olanzapine, Risperidone, Quetiapine Comparative Costs of Atypicals Risperidone Olanzapine Quetiapine Amisulpiride Gaols & Efficacy, Side Effects, Implementation Gaols & Efficacy, Side Effects, Implementation Gaols & Efficacy, Side Effects, Implementation Gaols & Efficacy, Side Effects, Implementation

18-30
18 19 20 21-22 23 24 25 26-30 26 27 27 28 28 28 29 30

Clozapine Gaols & Efficacy General, Treatment Resistance, Treatment Intolerance Side Effects Treatment of Tardive Dyskinesia Titration Drug Interactions Dosing Regimen Management of Adverse Events Role of Plasma Clozapine Measurement

Other Medications Used in Schizophrenia

Lithium Benzodiazepines Anticonvulsants Other Medications Gaols & Efficacy, Side Effects, Implementation Gaols & Efficacy, Side Effects, Implementation Gaols & Efficacy, Side Effects, Implementation

31-33
31 32 33 33

References

34-39

Clinical & Cost Utility of the Latest Antipsychotics : Enrolment Procedures Are you thinking of changing your patients drug treatment?
Thinking of changing to an atypical? Thinking of changing from an atypical? Thinking of using adjunctive therapy? Inadequate response to two antipsychotic drugs? Thinking of using clozapine?

CUtLASS

Does the patient meet eligibility criteria for the study?

Inclusion criteria
Clinical diagnosis of schizophrenia, schizoaffective disorder or delusional disorder Age 18-65

Exclusion criteria
Substance misuse or medical disorder the major causative factor for psychotic symptoms. History of neuroleptic malignant syndrome

Is the patient interested in entering the study? Please give them the patient information sheet to read and consider.
Confirm the best contact method for the trial support clinician to contact the patient later that day or the following day. Fill out the eligibility form and fax it to the trial office at: Tel / Fax : 970 9119; internal ext. 41119

What happens next? The trial support clinician will visit the patient as soon as possible, obtain written consent and perform baseline assessments. You will be contacted with the randomisation result by the trial support clinician.

Starting Treatment The trial support will liase with you to commence the treatment of your choice within the randomised treatment group. Medication can be prescribed by the trial support clinician after randomisation, if you wish.

Treatment Arms For Atypical / Conventional Comparison & Clozapine / Atypical Comparison

Intervention protocol for Atypical / Typical Comparison

Intervention protocol Clozapine / Atypical Comparison

Thinking of changing to an atypical? Thinking of changing from an atypical? Thinking of using adjunctive therapy?

Inadequate response to two antipsychotic drugs? Thinking of using clozapine?

RANDOMISATION

RANDOMISATION

New atypical drug

e.g.
Risperidone

Conventional drug
If intolerant previously: Add anticholinergic drug or beta blocker Reduce dose Change to alternative conventional e.g. thioridazine or sulpiride If resistant previously: Change to alternative oral conventional Change to depot Add adjunctive drug eg lithium

Clozapine

New atypical drug

e.g. Risperidone

Olanzepine Quetiapine

Olanzepine Quetiapine

CONVENTIONAL ANTIPSYCHOTIC MEDICATIONS The conventional antipsychotic medications are equally effective in the treatment of psychotic symptoms of schizophrenia (with the exception of mepazine and promazine), although they vary in potency and their propensity to induce side effects. The conventional antipsychotics can be classified into three groups according to their antipsychotic potency: The high-potency agents include haloperidol and fluphenazine; The intermediate-potency medications include loxapine and perphenazine; The low-potency agents include chlorpromazine and thioridazine. The table below outlines the main classes of conventional antipsychotics, main drugs within each class, maximum BNF daily dosages and guide to their propensity to produce some of the most common side effects. Key to table + ++ +++ mild moderate severe

Conventional Neuroleptics Group / Class Drug Max BNF Dose / day 1g 1g 800mg 800mg 300mg Relative side effects at average dosage EPSE ++ ++? + + + AntiCardiac cholinergic +++ ++ +++ ++ ++ + ++ + + ++ Hypo- Sedation tension +++ +++ ++ ++ ++ +++ +++ ++ ++ +++ Minor O.D. +++ ? ++ ++ ++ Moderate D2 Moderate anti-Ach Class D2 receptor blockade & Anticholinergic propensity

Phenothiazines Aliphatic Chlorpromazine Methotri meprazine Promazine Piperidine Thioridazine Pericyazine Piperazine Fluphenazine (Depot) Perphenazine Trifluoperazine Thioxanthines Flupenthixol (Depot) Zuclopenthixol (Depot) Butyrophenones Haloperidol (Depot) Droperidol Diphenylbutylpiperidines Pimozide (ECG prior and at >16mg) Dibenzoxazepine Loxapine Substutited Benzamides Sulpiride

20mg 100 4/52 24mg -18mg 400 1/52 150mg 600 1/52 120mg 300 4/52 120mg (P.O.) 90mg (I.V.) 20mg

+++ +++ +++ +++ ++ ++ +++ +++ +++ +++ +++

++ ++ + -++ +++ ++ ++ + + ++

+ + + + --+ + + + +

+ + + + --+ + + + ++

++ ++ ++ + + + ++ ++ + ++ ++

+ + ++ ++ + + ? ? + ? +

Higher D2 Lower anti-Ach

++

+++

++

250mg

+++

++

++

2.4g

--

--

? specificity for D2 in A10 mesolimbic system

CONVENTIONAL ANTIPSYCHOTIC MEDICATIONS 1. GOALS AND EFFICACY. A. Acute phase. The evidence supporting the effectiveness of these agents in reducing psychotic symptoms in acute schizophrenia comes from studies carried out in the 1960s (2, 3) as well as numerous clinical trials that have taken place since then (1,4). These studies demonstrated the efficacy of antipsychotic medications for every subtype and subgroup of schizophrenic patients. Klein and Davis (6) and Davis et al. (4) found that, with the exception of mepazine and promazine, all of these agents were equally effective. Response Rates (1,3). Approximately 60% of patients treated for 6 weeks (Vs 20% on placebo) complete remission or experience only mild symptoms. 40% of medication-treated patients(Vs 80% on placebo) continue to show moderate to severe psychotic symptoms. 8% of medication-treated patients(Vs 50% on placebo) show no improvement or worsening A patient's prior history of a medication response is a fairly reliable predictor of how the patient will respond to a subsequent trial (7, 8). B. Stabilisation phase. Empirical research provides relatively little guidance for psychiatrists who are making decisions about medication and dose during this phase. The use of antipsychotic medications during this phase is based on the clinical observation that patients relapse abruptly when medications are discontinued during this phase of treatment. C. Stable phase. (Relapse Prevention) A large number of studies (9, 10) have compared relapse rates for stabilised patients who were kept on their medication regimens and those who were changed to placebo. During the first year only about 30% of those continuing to take medications relapsed, whereas about 65% of those taking placebo relapsed. Even when compliance with medication treatment was assured by the use of depot medications, as many as 24% of patients relapsed in a year (11). Kane(10) reviewed studies in which the medications of well-stabilised patients were discontinued and found that 75% of patients relapsed within 6-24 months. A number of studies have focused on the use of antipsychotic medications after recovery from a first episode of schizophrenia. Carefully designed double-blind studies indicate that 40% to 60% of patients relapse if they are untreated during the year following recovery from a first episode (13, 14).

2. SIDE EFFECTS. COMMON SIDE EFFECTS. SEDATION. Sedation is the most common single side effect of antipsychotic medications (4). Most patients experience some sedation, particularly with the low-potency agents, such as chlorpromazine. Sedation is most pronounced in the initial phases of treatment. Most patients develop some tolerance to the sedating effects with continued administration. Lowering of the daily dose, consolidation of divided doses into one evening dose, or changing to a less sedating antipsychotic medication can be helpful. ANTICHOLINERGIC EFFECTS. The anticholinergic effects of antipsychotic medications (along with the effects of anticholinergic antiparkinsonian medications when concurrently administered) can produce a variety of adverse effects, including dryness of mouth, blurring of vision, constipation, tachycardia, and urinary retention. These can occur in one form or another in 10% to 50% of treated patients (16, 17). These side effects can be particularly troublesome for older patients (e.g., older men with benign prostatic hypertrophy) (16). Although most of these effects are mild and tolerable, serious consequences can occur. For example, death can result from ileus of the bowel if not detected in time. In addition, some patients experience problems with thermoregulation and can develop hyperthermia, particularly in warm weather. Central anticholinergic toxicity can lead to impaired memory and cognition, confusion, delirium, somnolence, and hallucinations (18,19). Such symptoms are more likely to occur with medications that have more potent anticholinergic effects and in elderly or medically debilitated patients. Cessation of treatment usually results in reversal of symptoms. In cases where it is clear that anticholinergic effects are responsible, parenteral physostigmine (0.5-2.0 mg i.m. or i.v.) may be used to reverse the symptoms, although this should be done only under close medical monitoring. CARDIOVASCULAR EFFECTS Tachycardia can result from the anticholinergic effects of antipsychotic medications but may also occur as a result of postural hypotension. The antiadrenergic effects of antipsychotic medications cause hypotension. When this is severe it can lead to syncopal episodes. Patients who experience severe postural hypotension must be cautioned against getting up quickly and without assistance. The elderly are particularly prone to this adverse effect, and syncopal episodes may contribute to an increased incidence of hip fractures in elderly women. Other management strategies include the use of support stockings, increased dietary salt, and administration of the salt/fluid-retaining corticosteroid fludrocortisone, to increase intravascular volume. Tachycardia due to anticholinergic effects without hypotension can be managed with low doses of a peripherally acting blocker (e.g., atenolol) (20).

EXTRAPYRAMIDAL SIDE EFFECTS. Of the spectrum of adverse effects of antipsychotic medications, the neurologic side effects are the most troublesome (21, 22). Although the various types of antipsychotic agents differ in their propensity for causing these side effects, they are all capable of producing them. Approximately 60% of patients who receive acute treatment with antipsychotic medication develop clinically significant extrapyramidal side effects in one form or another (21, 22, 30). ACUTE EXTRAPYRAMIDAL SIDE EFFECTS are signs and symptoms that occur in the first days and weeks of antipsychotic medication administration, are dose dependent, and are reversible upon medication dose reduction or discontinuation. There are four types of acute extrapyramidal side effects: parkinsonism, dystonia, and akathisia, which are quite common, and neuroleptic malignant syndrome, which occurs infrequently but is potentially life threatening (26-29). MEDICATION-INDUCED PARKINSONISM, characterised by the symptoms of idiopathic Parkinson's disease (rigidity, tremor, akinesia, and bradykinesia), has been found in 20% of patients treated with antipsychotics (26, 31). These symptoms arise in the first days and weeks of antipsychotic medication administration and are dose dependent. Curiously, some patients who develop parkinsonian symptoms may, upon substantial dose increases, experience a lessening, rather than worsening, of symptoms. This unexpected result has been hypothesised to be due to an increase in the intrinsic anticholinergic activity provided by antipsychotic medications at higher doses (32). Medication-induced parkinsonism resolves after discontinuation of antipsychotic medication, although some cases of persisting symptoms have been reported. Akinesia or bradykinesia, is a feature of medication-induced parkinsonism; a patient with this condition appears to be slow moving, indifferent to stimuli, and emotionally constricted. It has been noted alone or with other extrapyramidal side effects in almost one-half of patients treated with antipsychotics. In very severe cases, it may mimic catatonia. Depressive symptoms can also be present in over 50% of patients with akinesia, in which case the syndrome is termed "akinetic depression" (33, 34). DDx & Rx Symptoms of medication-induced parkinsonism need to be carefully distinguished from negative symptoms of schizophrenia. Parkinsonian side effects usually respond to a reduction in antipsychotic medication dose or treatment with antiparkinsonian medication. Weak dopamimetic medications, such as amantadine, can be used as second-line or additional treatments. The efficacy of these medications is good, but some patients who improve with antiparkinsonian medication continue to have residual parkinsonian symptoms. Dystonia. Acute dystonia is characterised by the spastic contraction of discrete muscle groups. Dystonic reactions occur in 10% of patients initiating therapy. Risk factors include young age, male gender, use of high-potency medications, high doses, and intramuscular administration. Dystonic reactions frequently arise after the first few doses of medication (90% occur within the first 3 days) (36). They can occur in various body regions but most commonly affect the neck, eyes, and torso (29), hence, the terms "torticollis," "laryngospasm," "oculogyric crisis," and "opisthotonos". These reactions are sudden in onset, are dramatic in appearance, and can cause patients great distress. For some patients these conditions, e.g., laryngospasm, can be dangerous and even life threatening. Rx Acute dystonic reactions respond dramatically to the administration of anticholinergic or antihistaminic medication, usually given parenterally (intramuscularly or intravenously). Afterwards, these patients are usually maintained with an oral regimen of anticholinergic antiparkinsonian medication to prevent the recurrence of acute dystonic reactions. Akathisia, is characterised by somatic restlessness that is manifest subjectively and objectively in 20%-25% of patients treated with antipsychotics (27, 34). Patients characteristically complain of an inner sensation of restlessness and an irresistible urge to move various parts of their bodies. Objectively, this appears as increased motor activity. The most common form involves pacing and an inability to sit still. This side effect is often extremely distressing to patients, is a frequent cause of non-compliance with antipsychotic treatment, and, if allowed to persist, can produce dysphoria and possibly aggressive or suicidal behaviour (38). Rx Akathisia is less responsive to treatment than are parkinsonism and dystonia. A first step that may improve akathisia symptoms is a small, slow reduction in antipsychotic dose. Anticholinergic antiparkinsonian medications have limited efficacy. Centrally acting blockers, such as propranolol, have been suggested by 10

some to be the most effective form of treatment for akathisia (39), although the need remains for further double blind, controlled comparisons of treatments. Propranolol is usually administered at doses between 30 to 90 mg/day, which is titrated to produce clinical response while blood pressure and pulse rate are monitored. Benzodiazepines can also be used to treat akathisia. Lorazepam and clonazepam are the most commonly used, but most benzodiazepines may be beneficial. DDx A common problem that arises in assessing patients with akathisia is distinguishing this side effect from psychomotor agitation associated with the psychosis. This may be a difficult clinical distinction to make. In such cases the non-specific effects of benzodiazepines on akathisia and agitation can be useful, although the dose necessary for therapeutic effects on psychotic agitation usually is higher than that required for akathisia (40). Prophylactic treatment EPSE Given the high rate of acute extrapyramidal side effects among patients receiving antipsychotic medications, the prophylactic use of antiparkinsonian medications may be considered. The benefit of this approach has been demonstrated in several studies. For example, Hanlon et al. (41) found that only 10% of patients taking perphenazine with an antiparkinsonian medication developed an extrapyramidal side effect, in contrast to 27% of patients without an antiparkinsonian medication. The risk is that some patients may be treated unnecessarily with these medications (40). In addition, the presence of acute extrapyramidal side effects can provide useful clinical information (e.g., as a risk factor for subsequent development of tardive dyskinesia). Prophylactic antiparkinsonian medication may be considered for patients with a prior history of susceptibility to acute extrapyramidal side effects and for patients whose anticipated negative attitudes and non-compliance with treatment may be reinforced by the occurrence of adverse reactions. Choice of Anticholinergic The major differences among the anticholinergic medications are in their potencies and duration of action. Patients who are very sensitive to anticholinergic side effects (e.g., dry mouth, blurred vision, and constipation) may require lower doses or less potent preparations (e.g., trihexyphenidyl, procyclidine hydrochloride). The need for anticholinergic medications should be reevaluated after the acute phase of treatment is over and whenever the dose of antipsychotic medication is changed. Neuroleptic malignant syndrome, is characterised by the triad of rigidity, hyperthermia, and autonomic instability, including hypertension and tachycardia (28), and it is often associated with elevated serum creatine kinase activity. This condition can be sudden and unpredictable in its onset, is frequently misdiagnosed, and can be fatal in 5%-20% of cases if untreated (43). The prevalence is uncertain, but neuroleptic malignant syndrome may occur in as many as 1%-2% of patients treated with antipsychotic medications (43). Neuroleptic malignant syndrome usually occurs early in the course of treatment, often within the first week after treatment is begun or the dose is increased. Risk factors include young age, male gender, pre-existing neurological disability, physical illness, dehydration, rapid escalation of dose, use of high-potency medications, and use of intramuscular preparations. Rx The first step in treatment is to discontinue the antipsychotic medication; then supportive treatment for the fever or cardiovascular symptoms should be provided. Treatments that have been used to accelerate the reversal of the condition include dopamine agonists, such as bromocriptine, pergolide, and lisuride, and antispasticity agents, such as dantrolene sodium (44). Recently, another antispasticity compound, azumolene, was suggested as a potential treatment for neuroleptic malignant syndrome (45). After several weeks of recovery, patients may be retreated with antipsychotic medication cautiously (46). Generally, treatment is resumed with a lower-potency antipsychotic medication than the precipitating agent, with gradually increased doses.

11

CHRONIC EXTRAPYRAMIDAL SIDE EFFECTS Chronic extrapyramidal side effects are signs and symptoms that occur after months and years of antipsychotic medication administration, are not clearly dose dependent, and may persist after medication discontinuation. TARDIVE DYSKINESIA. Tardive dyskinesia is a hyperkinetic abnormal involuntary movement disorder caused by sustained exposure to antipsychotic medication that can affect neuromuscular function in any body region but is most commonly seen in the oral-facial region (17, 47). Tardive dyskinesia may arise after exposure to any antipsychotic medication except clozapine. (While there is substantial evidence that patients treated with clozapine do not develop tardive dyskinesia, for risperidone there have been insufficient numbers of patients treated on a long-term basis to draw firm conclusions about its tardive dyskinesia risk; a case report of such an association has been published [48].) Tardive dyskinesia occurs at a rate of approximately 4% per year of antipsychotic medication treatment in adult psychiatric populations (17, 47). Risk Factors Various factors are associated with greater vulnerability to tardive dyskinesia. Schizophrenia itself may be associated with a risk of spontaneous dyskinesia indistinguishable from medicationinduced tardive dyskinesia (49). Other risk factors include older age, female gender combined with postmenopausal status, diagnosis of affective disorder (particularly major depressive disorder), concurrent general medical disease such as diabetes, use of high doses of antipsychotic medications (50, 52). Severity Although the majority of patients who develop tardive dyskinesia have mild symptoms, a proportion (approximately 10%) develop symptoms of moderate or severe degrees. Screening Patients receiving antipsychotic medication treatment on a sustained basis (for more than 4 weeks) should be evaluated regularly (approximately every 3 months or more often, depending on the frequency of visits) for side effects, including extrapyramidal side effects and signs of tardive dyskinesia. Work up Once symptoms are identified, a work up to rule out potential idiopathic causes of tardive dyskinesia should be performed (17). This includes a standard neurological examination, a family history check for neurological disease (e.g., Huntington's disease), and laboratory tests (Renal, Liver & Bone profiles, FBC, and T4 measurement). Treatment Discontinuation or Dose Reduction If idiopathic causes are ruled out, the patient may be considered to have tardive dyskinesia and treatment options should be considered. Discontinuation of medication should be considered only if the patient is in full remission or very stable with few residual positive symptoms or if the patient insists on stopping medication. The options include dose reduction and switching to a newer antipsychotic medication. The dose can gradually (over 12 weeks) be reduced by 50%. Frequently, this will lead to a decrease or remission of tardive dyskinesia. An initial increase in symptoms after withdrawal or dose reduction (withdrawal dyskinesia) may also occur in some patients. With sustained medication exposure without dose reduction after the development of tardive dyskinesia, the likelihood of reversibility diminishes. In some cases symptoms can persist despite long periods of time without medication. Despite the fact that continued treatment with antipsychotic medication increases the chances for persistence of tardive dyskinesia symptoms, the severity of tardive dyskinesia does not seem to increase over time at steady, moderate doses. If medication discontinuation or dose reduction does not produce substantial improvement in tardive dyskinesia symptoms within 6 to 12 months, then the severity and degree of distress the symptoms cause the patient should be evaluated. If they are mild or non-distressing, no further interventions might be made. 12

The documentation in the clinical record should reflect that a risk-benefit analysis favoured continued maintenance of antipsychotic treatment despite mild tardive dyskinesia, to prevent the likelihood of relapse. However, if the symptoms are severe or distressing to the patient, treatment for the tardive dyskinesia should be considered. Treatment Agents A large number of agents have been extensively studied for their therapeutic effects on tardive dyskinesia, and the results have been mixed (17). The general pattern in these studies has been for treatments to appear to be effective in open trials but to show no significantly greater efficacy than placebo in double-blind trials. Moreover, the amount of improvement in patients' symptoms has been neither substantial nor consistent. Clozapine Several uncontrolled studies have evaluated clozapine as a treatment for tardive dyskinesia. Lieberman et al. (53) reviewed eight studies that monitored the outcome of tardive dyskinesia. Approximately 43% of the cases improved, suggesting that clozapine may be effective in reducing abnormal movements. Despite the fact that none of the trials was adequately controlled, conversion to clozapine is the preferred treatment option. It is not known whether risperidone may be similarly beneficial for patients with tardive dyskinesia. This seems less likely, as a case of tardive dyskinesia in a patient receiving risperidone has been reported (48). More recent treatments - remain experimental Among the more recent treatments that have been used and are currently being evaluated are vitamin E, amantadine, L-dopa, and selegiline, but these remain experimental (54-56). Largely on the basis of preclinical evidence, various agents have been suggested as having potentially preventive effects on development of tardive dyskinesia. These include lithium, vitamin E, L-dopa, amantadine, and selective MAO-B inhibitors, such as selegiline (54, 55, 57-59). Their preventive efficacy for tardive dyskinesia remains unproven.

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OTHER SIDE EFFECTS. Seizures. Antipsychotic medications can lower the seizure threshold and result in the development of generalised grand mal seizures (60). low-potency conventional The antipsychotic medications and clozapine confer the greatest risk. The frequency of seizures is dose related, with higher doses associated with greater risk. The seizure rates are below 1% for all conventional antipsychotic medications at usual dose ranges (61). Patients with a history of an idiopathic or medication-induced seizure have a higher risk. Rx If a patient experiences a seizure, antipsychotic medication (with the exception of clozapine) should be withdrawn or the dose reduced by 50% until a neurologic evaluation is completed. Endocrine effects Galactorrhoea and oligomenorrhoea. All standard antipsychotic medications increase prolactin secretion by blocking the inhibitory actions of dopamine on lactotrophic cells in the pituitary. Risperidone can produce hyperprolactinemia comparable to that caused by typical compounds, whereas clozapine does not elevate prolactin beyond normal levels (62). The resultant hyperprolactinemia can lead to galactorrhoea (secretion of liquid from the nipples) in 1% to 5% of patients and menstrual cycle changes (e.g., oligomenorrhoea) in up to 20% of women. Rx Reduction in medication dose may decrease the severity or alleviate these effects. When the antipsychotic dose must be maintained and galactorrhea is severe or for women with menstrual disturbances, low doses of bromocriptine (2-10 mg/day) or amantadine may be used (63). Weight gain. Weight gain occurs with most antipsychotic medications in up to 40% of treated patients (60). The most notable exception is molindone, which may not cause significant weight gain. The dose of antipsychotic medication may be reduced and efforts at dietary control initiated. There are few pharmacological treatments with proven efficacy; one report suggests that amantadine may reverse antipsychotic-induced weight gain (63). An endocrine mechanism has not been established (60). Effects on sexual function. Disturbances in sexual function can occur (64). Erectile dysfunction occurs in 23%-54% of men (36). Other effects can include ejaculatory disturbances in men and loss of libido or anorgasmia in women and men. In addition, with specific antipsychotic medications, including thioridazine and risperidone (28), retrograde ejaculation has been reported. Rx These effects are mainly due to antiadrenergic and antiserotonergic effects. Dose reduction or discontinuation usually results in improvement or elimination of symptoms. Imipramine, 25-50 mg h.s., may be helpful for treating retrograde ejaculation induced by thioridazine (65). If dose reduction or a switch to an alternative medication is not feasible, yohimbine (an 2 antagonist) or cyproheptadine (a 5-HT2 antagonist) can be used (60). Allergic and hepatic effects Cutaneous reactions occur infrequently with antipsychotic medications. Medication discontinuation or administration of an antihistamine is usually effective in reversing these symptoms. Photosensitivity also occurs infrequently and is most common with the low-potency phenothiazine medications; patients should be instructed to avoid excessive sunlight and/or use sunscreen (1). Elevation of liver enzyme levels and cholestatic jaundice. Jaundice has been noted to occur in 0.1%-0. 5% of patients taking chlorpromazine (1). This usually occurs within the first month after the initiation of treatment and generally requires discontinuation of treatment. Given the relative infrequency of antipsychotic-induced jaundice, other aetiologies for jaundice should be evaluated before the cause is judged to be antipsychotic medication. Ophthalmic effects Pigmentary retinopathies and corneal opacities can occur with chronic administration of the low-potency medications thioridazine and chlorpromazine, particularly at high doses (e.g., more than 800 mg/day of thioridazine). For this reason, patients maintained with these medications should have periodic ophthalmic examinations (approximately every 2 years for patients with a cumulative treatment of more than 10 years). A maximum dose of 800 mg/day of thioridazine is recommended (60). With the increased use of high-potency medications in the past two decades, there has been virtually no reporting of this side effect (4). Haematological effects. Haematological effects, including inhibition of leukopoiesis, can occur with use of antipsychotic medications. Such effects include a benign leukopenia and the more serious agranulocytosis. The best data exist for chlorpromazine, with which benign leukopenia occurs in up to 10% of patients and agranulocytosis occurs in 0.32% 0of patients (60). 14

OVERDOSE & TOXIC EFFECTS Overdose Antipsychotic medications have a very high therapeutic index (8). Consequently, overdoses rarely are fatal unless they are complicated by pre-existing medical problems or concurrent ingestion of alcohol or other medications. Symptoms of overdose are generally characterised by exaggerations of the adverse effects, with respiratory depression and hypotension presenting the greatest danger. Treatment is symptomatic and supportive 1) inducing emesis and gastric lavage; 2) ensuring airway patency and maintenance of respiration; 3) maintaining blood pressure with intravenous fluids, plasma, concentrated albumin, and vasopressor agents; and 4) anticholinergic agents to counteract extrapyramidal signs (42). Sudden Death "Sudden death" -described as "a natural death, occurring instantaneously, or within one hour of the onset of symptoms, in a patient who may or may not have known pre-existing disease but in whom the time and mode come unexpectedly"- has been reported to occur in patients receiving antipsychotic medications (66). However, the rate of sudden death has not been found to be higher in patients receiving psychotropic medication (including antipsychotic medications) than in the general U.S. population (66). Although psychotropic medication treatment could have a purely coincidental association with sudden death, as suggested by the lack of an abnormally high incidence, there are a number of possible causes of death for individuals who are receiving antipsychotic medications. These include heart arrhythmia caused by cardiac toxicity, hypotension, seizure, aspiration, asphyxiation, megacolon and paralytic ileus, heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, and physical exhaustion. It has been suggested that the pharmacological actions of psychotropic medications could interact with stress in psychotic and agitated patients to make them more vulnerable to cardiovascular and autonomic system complications (66). Consequently, efforts to reduce possible risk factors for such complications should be considered, particularly for agitated, physically debilitated, and elderly patients. These considerations include a) minimisation of medication dose; b) judicious use of physical restraints; c) adequate hydration and attention to thermoregulation, particularly in hot weather; d) attention to signs of emerging neuroleptic malignant syndrome (rigidity, hyperthermia, blood pressure variability). In light of these considerations, psychiatrists should use the minimum antipsychotic medication dose necessary, monitor patients' vital signs and neurologic status, and ensure adequate hydration and a well-ventilated, temperature-controlled treatment setting (66).

15

3. IMPLEMENTATION. A) Route of administration. Short-acting intramuscular medications reach a peak concentration 30-60 minutes after the medication is administered, whereas oral medications reach a peak in 2-3 hours (67). As a result, the calming effect of the antipsychotic may begin more quickly when the medication is administered parenterally. However, this calming effect on agitation is different from the true antipsychotic effect of these medications, which may require several days or weeks (6). A single or twice-daily dose of an oral preparation will result in steady-state blood levels in 2-5 days (67). Long-acting depot antipsychotic medications (Fluphenazine decanoate or enanthate and haloperidol decanoate) require at least 3 to 6 months to reach a steady state (68). As a result, they are seldom used during acute treatment, when the psychiatrist is adjusting the dose in accordance with therapeutic and side effects. Depot Vs Oral Administration in Stable Phase The advantage of depot medications has been best demonstrated in studies such as those conducted by Johnson (69) under conditions that resemble most closely those in community clinics. In these studies, patients with histories of poor compliance were included in the population and the amount of contact between patients and staff was limited. Depot medications are thought to be especially helpful in the maintenance phase. Janicak et al. (1) examined six studies that compared the risk of psychotic relapse in patients who were randomly assigned to receive either oral or depot medication. The longest of those studies (70) lasted 2 years and showed a relapse rate of 65% for patients taking oral medication and a rate of 40% for patients taking depot medication. Although the remaining five studies, all of which lasted 1 year or less, had inconsistent results, a meta-analysis of all six studies showed a significantly lower relapse rate in patients who received depot treatment (p< 0.0002) (1). B) Dosage strategy. Low Vs High Potency Antipsychotics High-potency antipsychotic medications, such as haloperidol and fluphenazine, have a greater tendency to cause extrapyramidal side effects than the low-potency medications, such as chlorpromazine and thioridazine. However their side effects are easier to manage than the sedation and orthostatic hypotension associated with low-potency agents. High-potency medications can more safely be administered intramuscularly, since they seldom cause hypotension. In addition, because of sedation, orthostatic hypotension, and lethargy, the dose of a low-potency medication should be increased gradually, whereas an adequate dose of a high-potency medication can usually be achieved within a day or two.

16

Best Daily Dose Acute Phase Finding the best dose of a conventional antipsychotic is complicated by a number of factors. i) Patients with schizophrenia demonstrate large differences in the dose of antipsychotic they can tolerate and the dose required for an antipsychotic effect. ii) A patient's age may determine the appropriate dose; the elderly are frequently more sensitive to both the therapeutic and toxic effects of antipsychotics. iii) In addition, it is difficult to determine dose by assessing antipsychotic effectiveness, since it may take many days at a therapeutic dose before there is an appreciable decrease in psychosis (5, 8). Results of 19 controlled trials suggested that daily doses below 250 mg of chlorpromazine (or 5 mg of haloperidol or fluphenazine) are less adequate for many acutely psychotic patients than are moderate doses, between 300 and 600 mg. In the studies reviewed by Baldessarini et al. (74), response was typically measured by improvement in the score on the excitement, agitation, or psychosis subscale of the Brief Psychiatric Rating Scale (BPRS) (75), and the proportions of patients responding to low doses after 1 and 2-10 days were 38% and 50%, respectively; these rates compared unfavorably with the improvement rates of 61% and 56% among patients taking moderate doses for similar periods. Many psychiatrists have treated acutely psychotic patients with high doses of high-potency antipsychotic medications during the first days of treatment. This treatment is based on the belief that higher doses result in a more rapid improvement than that resulting from moderate doses (76). However, Baldessarini et al. (74) found that high daily doses (more than 800 mg of chlorpromazine equivalents daily) were no more effective, or faster acting than were moderate doses (500-700 mg/day).. These studies indicate that higher doses are no more effective than normal doses, but they are associated with a greater incidence of side effects. Maintenance Phase Baldessarini et al. (74) reviewed 33 randomised trials in which high doses (mean, 5200 mg/day of chlorpromazine equivalents) were compared to moderate doses (mean, 400 mg/day) during maintenance treatment. The moderate doses were more effective in improving clinical state in over two-thirds of the trials. In addition, in 95% of the studies the higher doses resulted in greater neurologic side effects. Studies of doses less than 200 mg/day of chlorpromazine equivalents tended to show that such doses were less effective than higher doses. An international consensus conference (77) made the reasonable recommendation of a reduction in antipsychotic dose of approximately 20% every 6 months until a minimal maintenance dose is reached. A minimal dose was considered to be as low as 2.5 mg of oral fluphenazine or haloperidol daily, 50 mg of haloperidol decanoate every 4 weeks, or 5 mg of fluphenazine decanoate every 2 weeks. Low Dose Depot Maintenance Studies by three separate groups have compared low doses to high doses of fluphenazine decanoate. Initially, Kane et al. (81) found that patients receiving very low doses (mean, 2.5 mg every 2 weeks) were significantly more likely to relapse over the course of 1 year than were patients receiving standard doses (12.5-50.0 mg every 2 weeks) (56% versus 7%). In a subsequent report, Kane et al. (82) demonstrated that patients given a slightly higher dose (2.5-10.0 mg every 2 weeks) showed a non-significant difference in relapse after 1 year from patients given standard doses (24% versus 14%). Marder et al. (83) found no significant difference in relapse between low doses (mean, 5 mg every 2 weeks) and standard doses (25-50 mg every 2 weeks) after 1 year but did detect a significant difference in relapse between low doses and standard doses (70% versus 35%) after 2 years. Hogarty et al. (84) reported no difference in relapse rates between low doses (mean, 3.8 mg every 2 weeks) and standard doses (25 mg every 2 weeks) after 2 years. Collectively, these studies indicate that doses of fluphenazine decanoate in the range of 5-10 mg every 2 weeks may be as clinically effective as conventional doses of 25-50 mg every 2 weeks. In consideration of a low-dose depot antipsychotic strategy, the beneficial side effect profile associated with the use of lower doses should also be considered. Kane et al. (81) found that low-dose users had fewer early signs of tardive dyskinesia after 1 year than did standard-dose users. In the Marder et al. study (83), lower doses were associated with significantly less discomfort (as measured with the SCL-90-R [85]), psychomotor retardation and akathisia after 2 years. Hogarty et al. (84) reported that patients receiving minimal doses had less muscle rigidity, akathisia, and other side effects at 1 year and had greater improvements in instrumental and interpersonal role performances at 2 years. C) Medication interactions. A number of medication interactions can have clinically important effects for patients who are treated with antipsychotic medication (36). Certain heterocyclic antidepressants, most selective serotonin reuptake inhibitors (SSRIs), some blockers, and cimetidine may increase plasma levels and increase side effects. On the other hand, barbiturates and carbamazepine decrease plasma levels. 17

ATYPICAL ANTIPSYCHOTICS

Group / Class

Drug

Max BNF Dose / day

Relative side effects at average dosage EPSE AntiCardiac cholin-+ + -+ -+ -Hypo- Sedation tension + -+ -+? ++ + -Minor O.D. ? -? --

Class D2 receptor blockade 5HT2 receptor blockade Other receptor blockade

Risperidone Olanzapine Quetiapine Amisilpiride

(16mg) (20mg ?) 750mg 800mg

+? --+

High 5ht2a / Low D2 5HT2a & 5ht2c 5-HT3 , 5-HT6, / low D2 D1-5 , M1-5, alpha, and H1 5HT2+6, / D2 - alpha1 , H1, sigma

? selectivity for mesolimbic D2

Clozapine

900mg

--

+++

+++

+++

5HT2a & 5HT2c, 5-HT6 5-HT1A, / low D2 alpha1+2, H1D1-4, muscarinic.

18

ATYPICAL ANTIPSYCHOTICS Atypical Antipsychotics Prescribing Information Summary Sheet Formulations Olanzapine (Zyprexa, Eli Lilly & Co) 2.5mg, 5mg, 7.5mg, 10mg film-coated tablets Indications Treatment of schizophrenia Initial dose (by Psychiatrist) Adults: 10mg nocte Elderly, hepatic/renal impairment: 5mg nocte Maintenance dose (by GP) Adults: 15mg nocte (range 10-20mg nocte) Adverse effects Common: Somnolence, weight gain Other: Dizziness, increased appetite, peripheral oedema, orthostatic hypotension, constipation, dry mouth, transient asymptomatic elevations of ALT/AST, transient increase in prolactin (rarely symptomatic) Rare: NMS, blood dyscrasias, tardive dyskinesia, seizures Common: Insomnia, agitation, anxiety, headache Other: Somnolence, fatigue, dizziness, hypotension, tachycardia, weight gain. EPSE and hyperprolactinaemia are doserelated and increase at doses above 8mg/day. Rare: NMS, blood dyscrasias, tardive dyskinesia, seizures. One year cost (MIMS 7/99) 10-20mg/day 1375-2750

Risperidone (Risperdal, Janssen-Cilag Ltd)

1mg, 2mg, 3mg, 4mg, 6mg scored tablets and 1mg/1ml liquid

Treatment of acute and chronic schizophrenic psychoses, and other psychotic conditions, in which +ve and/or ve symptoms are prominent

Adults: Day 1-3: 1mg bd or 2mg od Day 4-6: 2mg bd or 4mg od Day 7 on: 3mg bd or 6mg od. Elderly, hepatic/renal impairment: 0.5mg od increased every 57 days in 0.5mg increments Adults: Day 1: 25mg bd Day 2: 50mg bd Day 3: 100mg bd Day 4 on: 150mg bd Elderly, hepatic/renal impairment: 25mg nocte increased every 2-3 days in 25mg increments

Adults: 3mg bd or 6mg od (range: 4-8mg/day) NB. Doses > 8mg/day are no more effective but do increase risk of EPSE & hyperprolactinaemia Adults: 300-450mg per day in two divided doses (max 750mg/day)

4-8mg/day 940-1880

Quetiapine (Seroquel, Zeneca Ltd)

25mg, 100mg, 150mg, 200mg filmcoated tablets

Treatment of schizophrenia

Common: Somnolence, dizziness, constipation, postural hypotension, tachycardia, dry mouth, asymptomatic elevations of ALT/AST Other: Weight gain, asthenia, rhinitis, dyspepsia Rare: NMS, seizures, blood dyscrasias

300750mg/day 1375-2750 NB. 100mg, 150mg and 200mg tablets are the same price

a.atypical.gui

19

COSTS 1 year treatment (MIMS April 1998) Low 300mg 1,950 4mg 936 12mg 1,326 10mg 1,365 50mg 100 300mg 1,365 Medium 600mg 3,900 6mg 1,417 20mg 1,326 15mg 2,054 800mg 1,456 450mg 1,716 High 900mg 5,850 8mg 1,872 24mg 1,768 20mg 2,730 1200mg 2,184 750mg 3,081

CLOZAPINE RISPERIDONE SERTINDOLE OLANZAPINE AMISULPIRIDE QUETIAPINE

20

RISPERIDONE DRUG Risperidone CLASS Benzisoxazole derivative PHARMACOLOGY Antagonist 5-HT2 , D2 DOSE Start - 2mg/day Maintenance - 2-8mg Range - 0.5-8mg INDICATIONS Treatment of schizophrenia, relapse prevention EFFICACY 1. Significant effect on positive and negative symptoms. 2. Some evidence of superiority in positive and possibly negative symptoms, compared with Haloperidol. 3. Hypeolactinaemia and EPSE equivalent to halaperidol at higher doses. 4. 2 comparative studies with Olanzapine a) Lilly sponsored - Olanzapine superior. b) Janssen sponsored - Risperidone superior. SIDE-EFFECTS Agitation, weight gain, headache, EPSE at higher doses, symptoms of hyperprolactinaemia. Risperidone is an antipsychotic medication from a chemical class that is different from that of either conventional antipsychotic medications or clozapine. Its distinct properties have been attributed to central antagonism of both serotonin and dopamine receptors. 1) Goals and efficacy. Several studies provide evidence of risperidone's antipsychotic efficacy, and some suggest it may be more useful than conventional antipsychotic medications in treating negative symptoms. However, there are limitations in these data, including the fact that the largest trials compared multiple risperidone doses to a single dose of haloperidol (25, 107, 108). Johnson and Johnson (109) have criticized the Risperidone Study Group trial (107), which did not control for prior medication history and had a relatively short washout period. A large double-blind trial by Mller-Spahn et al. (108) was an 8-week international multisite study that compared 10 mg/day of haloperidol and 1, 4, 8, 12, or 16 mg/day of risperidone. Although 1 mg/day of risperidone was the least effective dose, 4, 8, and 12 mg/day of risperidone all proved to be more effective in reducing symptoms than 10 mg/day of haloperidol (which had efficacy comparable to that of 16 mg/day of risperidone). Some evidence for the efficacy of risperidone at treating specifically positive or negative symptoms comes from a large double-blind study carried out in the United States (71) and Canada (25). In this 8-week trial, four doses of risperidone (2, 6, 10, and 16 mg/day) were compared to 20 mg/day of haloperidol or placebo. In the U.S. study, improvement in total PANSS score was seen among significantly greater proportions of patients treated with 6 and 16 mg/day of risperidone than among haloperidol-treated patients. PANSS scores for positive symptoms were significantly lower among patients treated with 6, 10, and 16 mg/day of risperidone or with haloperidol than among patients given placebo. PANSS scores for negative symptoms were significantly lower than for placebo-treated patients among the patients treated with 6 and 16 mg/day of risperidone but not for patients given other risperidone doses or haloperidol. The findings from the Canadian component of the trial were similar. On the total PANSS and the positive symptom subscale, all risperidone groups (except 2 mg/day), but not the haloperidol group, had significantly better scores than did the placebo group. On the PANSS negative symptom subscale, only 6 mg/day of risperidone was significantly superior to placebo. The authors of these studies concluded that there was strong evidence for the efficacy of risperidone in treating positive symptoms and a suggestion that risperidone may be more effective for negative symptoms than conventional antipsychotics. Although the U.S.-Canadian trials showed that the most effective risperidone dose, 6 mg/day, was significantly more effective than the 20-mg/day dose of haloperidol, this trial may have given risperidone an unfair advantage since multiple risperidone doses were compared to only a single haloperidol dose. The findings from the U.S.-Canadian trials will need to be verified, particularly in studies that use haloperidol at other doses or use other antipsychotic medications. Davis and Janicak (115) conducted a meta-analysis of five double-blind controlled trials. They found that risperidone given at daily doses of 6-12 mg was significantly more effective than typical doses of standard antipsychotics (e.g., haloperidol, 10-20 mg daily). There have been no controlled trials providing information about the effectiveness of risperidone in preventing relapse during the stable phase of treatment. 21

In an open clinical trial, Addington et al. (116) found that patients treated with risperidone for 1 year had a significant (20%) reduction in the number of days they were hospitalized, compared to the year before risperidone treatment. 2) Side effects. Extrapyramidal side effects. Studies using multiple doses of risperidone (25, 107) have shown that this medication causes a dose-related increase in extrapyramidal side effects. Several of these studies indicate that the severity of extrapyramidal side effects with risperidone is lower than with conventional antipsychotic medications. As mentioned previously, this evidence is limited by the fact that in the largest studies risperidone was compared to only a single dose of haloperidol: 10 mg/day in the study by Peuskens et al. (107) and 20 mg/day in the study by Chouinard et al. (25). Risperidone produces some drowsiness and orthostatic hypotension. Other common side effects Other common side effects among patients treated with 8 mg/day of risperidone or 10 mg/day of haloperidol that were noted by the Risperidone Study Group included the following: weight gain, decreased sexual interest and erectile dysfunction. . Kopala and Honer (118) and Remington and Adams (119) each reported a case in which risperidone appeared to induce obsessive-compulsive symptoms. Risperidone elevates prolactin levels, and as a result it may cause galactorrhea and menstrual disturbances. Several cases of neuroleptic malignant syndrome associated with risperidone have also been described and were reviewed by Marder (120). It is unknown whether risperidone is associated with the same risk of tardive dyskinesia as conventional antipsychotic medications. 3) Implementation. The recommended procedures for starting risperidone treatment are the same as those for treating patients with conventional antipsychotics. Studies comparing different doses of risperidone indicate that it is most effective at 4 to 6 mg daily (25, 107). Higher doses may lead to extrapyramidal side effects without greater effectiveness. Although risperidone itself has an elimination half-life of only 3 hours, its metabolite has an elimination half-life of about 24 hours. As a result, most patients can be managed with single daily doses of risperidone. However, since risperidone can cause orthostatic hypotension, twice-daily dosing may be useful during the titration phase and for patients who may be vulnerable to orthostatic changes, such as the elderly.

22

OLANZAPINE. DRUG Olanzapine (Zyprexa) CLASS Thienobenzodiazepine PHARMACOLOGY Antagonist 5HT2A/C , 5-HT3 , 5-HT6, / D1-5 , M1-5, alpha, and H1 High 5HT2A /D2 ratio DOSE Start - 10mg Maintenance - 10mg Range - 5-20mg INDICATIONS Treatment of Schizophrenia, and relapse prevention. EFFICACY 1. Significant effect on positive and possibly negative symptoms. 2. More effective than Haloperidol on positive and negative symptoms. 3. Few side-effects than Haloperidol. 4. Company sponsored trial showed superior efficacy and tolerability compared with Risperidone over 28 weeks. 5. Some evidence for efficacy in affective and neurocognitive domains. 6. No effect in treatment resistant patients. SIDE-EFFECTS Somnolence, dizziness, increased appetite, weight gain, mild antimuscaranic, peripheral oedema. Higher doses possibility of hyerprolactinaemia, EPSE.

A) Goals and efficacy. The efficacy of olanzapine was evaluated in a 6-week, double-blind comparison of three dose ranges of olanzapine; 2.5-7.5 (low dose), 7.5-12.5 (medium dose), and 12.5-17.5 (high dose) mg/day?haloperidol (10-20 mg/day), and placebo involving 335 patients with acute episodes of schizophrenia (122). The middle and highest doses of olanzapine and haloperidol were significantly more effective than placebo, as measured by reduction in total BPRS score. Although the capacity of olanzapine to reduce negative symptoms was assessed, the results were inconclusive (the low and high doses, but not the middle dose, led to small decreases in symptoms). The same authors (123) also reported results from a 6-week international, multicenter trial in which a single dose range of olanzapine (5-20 mg/day) was compared to a single dose range of haloperidol (5-20 mg/day) in 1,996 patients, most of whom had schizophrenia but some of whom had schizoaffective or schizophreniform disorder. Patients treated with olanzapine showed a significantly greater reduction in total BPRS symptoms (11% versus 8% reduction) and BPRS negative symptoms. B) Side effects. The most common side effects of olanzapine are sedation and a decrease in standing systolic blood pressure; olanzapine has also been associated with weight gain. EPSE In the study reported by Beasley et al. (122), the low, medium, and high olanzapine doses were associated with decreases in parkinsonism and akathisia, whereas haloperidol was associated with increases when the patients were studied as a group. The high-dose olanzapine group was significantly more likely to receive antiparkinsonian medications on one or more occasions than the placebo patients (p< 0.02) but were less likely to receive such medications than the haloperidol-treated patients (p< 0.001). Data cited in the patient package insert for olanzapine indicate that on the basis of adverse events reports, patients taking medium- and high-dose olanzapine had statistically significantly more akathisia than patients taking placebo; the package insert also noted, however, that patients taking olanzapine (all doses) did not differ significantly from patients taking placebo in rates of akathisia and parkinsonism when these outcomes were determined by rating scales. In addition, olanzapine has not been found to increase prolactin secretion levels above normal. C) Implementation. Olanzapine is an effective antipsychotic when administered in doses of 10-20 mg/day in the acute phase of schizophrenia. At this time there are no data on its use for treatment-resistant patients, for elderly patients, or in long-term treatment. The manufacturer has recommended starting patients at 10 mg/day. Clinicians concerned about the potential for orthostatic hypotension, especially in the elderly, should start patients at 5 mg/day and gradually increase the dose by 5 mg/day until patients are receiving 10-20 mg/day. Since Olanzapine is associated with weight gain, weight should be monitored and patients should be counselled about weightcontrol strategies.

23

QUETIAPINE. DRUG Quetiapine (Seroquel) CLASS Dibenzothiazepine PHARMACOLOGY Antagonist - alpha1 , H1, sigma 5HT2+6, D2 To a lesser extent - 5-HT1A , D1 DOSE Start - 25mg bd Maintenance - 300-450mg/day Range - 150-750mg/day INDICATIONS Treatment of schizophrenia and relapse prevention. EFFICACY 1. Significant effect on positive and negative symptoms. 2. As effective as reference drugs. 3. Low incidence (placebo levels) of EPSE and no evidence of an increase in prolactin levels. 4. No comparison data with other atypicals. 5. Awaiting results of treatment resistance trials. SIDE-EFFECTS Somnolence, dizziness, anti-muscarnic, asymptomatic liver enzyme abnormalities, asthenia, rhinitis, dyspepsia, weight gain.

A)Goals and efficacy. The short-term efficacy of quetiapine for acute schizophrenia has been evaluated in two 6-week multicenter, randomized, double-blind placebo-controlled trials. An early study compared a low dose (up to 250 mg/day) and higher dose (up to 750 mg/day) of quetiapine to placebo in 109 patients with schizophrenia (129). Compared to placebo, any use of quetiapine was associated with a significantly greater reduction in total BPRS score, BPRS activation and thought disturbance subscale scores, and summary scores on the Scale for the Assessment of Negative Symptoms (SANS) (130). A second trial, comparing the same low and higher dose ranges of quetiapine to placebo in 190 patients with schizophrenia, had similar results (129). Use of any dose of quetiapine was again associated with significantly greater reductions in total BPRS score compared to placebo; the higher dose of quetiapine was significantly more effective than placebo in reducing scores on the BPRS subscales for thought disturbance, hostile/suspiciousness, activation, anxiety/depression, and anergia. Quetiapine has also been investigated in two 6-week multicenter, randomized, double-blind trials in which patients treated with a conventional antipsychotic served as controls. Borison et al. (209) compared five fixed doses of quetiapine (75, 150, 300, 600, or 750 mg/day), haloperidol (12 mg/day), and placebo in 361 patients with schizophrenia. Quetiapine at all doses, as well as haloperidol, was more effective than placebo in reducing the total BPRS score and the score on the BPRS positive symptom cluster; the most effective dose of quetiapine was 300 mg/day. Quetiapine at 300 mg/day, but not haloperidol, was also significantly more effective than placebo in reducing the SANS summary score. In a trial comparing quetiapine (up to 750 mg/day) to chlorpromazine (up to 750 mg/day) in 201 subjects with schizophrenia, there were no significant differences between the two groups in reduction in total BPRS score, BPRS factor scores, or SANS summary score (129). B) Side effects. EPS In all three placebo-controlled trials, quetiapine had no greater propensity to cause extrapyramidal side effects than did placebo. In the comparison of quetiapine and chlorpromazine, neither active medication was found to cause extrapyramidal side effects, making the results difficult to interpret (129). The most common side effects of quetiapine are drowsiness, constipation, dry mouth, weight gain, and orthostatic hypotension. It does not elevate prolactin levels above the normal range. C) Implementation. Quetiapine has been used and found to be effective at doses between 150 and 800 mg/ day. Since it has a half-life of 6.9 hours, it should be administered 2 to 3 times daily. Although the comparison of five fixed doses suggests that 300 mg/day may be the most effective dose (131), there is insufficient published information with which to make other prescribing recommendations.

24

AMISULPIRIDE

DRUG CLASS

Amisulpiride (Solian) Substituted Benzamide Antagonist Start Maintenance Range D2 , D3, limbic specificity claimed 200mg bd 60-1200mg day 50-300mg chronic syndrome 400-1200mg acute syndrome

PHARMACOLOGY

INDICATIONS Treatment of schizophrenia EFFICACY 1. 2. 3. 4. 5. Significant effect on positive and negative symptoms. As good as Haloperidol in treatment of positive symptoms. Some evidence of increased superiority over Haloperidol in negative syndromes. Hyperprolatinaemia and ESPE at higher doses. No comparison data with other Atypicals, in particular no comparison with far cheaper - Supiride.

SIDE-EFFECTS Insomnia, agitation, anxiety, somnolence, gi upset, symptoms of hyperprolactinaemia and EPSE, weight gain.

25

CLOZAPINE DRUG Clozapine (Clozaril) CLASS Dibenzazepine PHARMACOLOGY Antagonist - alpha1+2, H1 , 5-HT2, 5-HT6 5-HT1A, D1-4, muscarinic. DOSE Start 12.5mg bd Maintenance - 200/450mg divided doses/day Range 50-900mg INDICATIONS Schizophrenia in patients unresponsive to or intolerant of at least conventional drugs. EFFICACY 1. Superior to conventional drugs in treatment resistance. Schizophrenia 30-60% response. 2. Delayed use may reduce effectiveness. 3. Less clear view on efficacy in negative symptoms, may reduce secondary negative symptoms but not primary. 4. Minimal EPSe, and some effectiveness in treating TD. 5. Some evidence for a significant decrease in suicide rates. SIDE-EFFECTS Neutropenia, agranulocytosis (2 deaths in >11,000 prescriptions), drowsiness, agitation, fatigue, anti-muscarinic, hypersalivation, asymptomatic liver enzyme abnormalities,hyper/hypotension, myoclonic jerks, epileptogenic.

1) Goals and efficacy. General Clozapine is an atypical antipsychotic medication that is distinguished from other antipsychotic medications by its lack of extrapyramidal side effects. However, it causes potentially fatal agranulocytosis in about 1% of patients. Baldessarini and Frankenberg (23) reviewed 14 double-blind studies that compared clozapine with a conventional antipsychotic. They found that 9% more of the subjects taking clozapine had improved symptoms and that those patients' mean clinical ratings improved 13% more than did the ratings of the patients taking conventional antipsychotics, although neither difference was statistically significant. The researchers concluded that clozapine is at least as effective as conventional medications. Other reviewers (87-89) have noted that the advantages of clozapine are most apparent when the dose is over 300 mg/day. Treatment Refractory Illness Clinical trials with clozapine indicate that certain populations of patients with schizophrenia are likely to improve if their treatment is changed from a conventional antipsychotic to clozapine. The strongest evidence is for patients whose illness is refractory to conventional antipsychotic medications. A multicenter study by Kane et al. (90) defined treatment-resistant patients as those who had not responded to three different conventional antipsychotics before the study and then subsequently did not respond to a 6-week trial of haloperidol at the start of the study. Improvements in symptoms and global clinical ratings occurred in 30% of the patients treated with clozapine for 6 weeks, in contrast to only 4% of the patients treated with chlorpromazine. Breier et al. (169) followed outpatients who had persistent positive or negative symptoms after treatment with conventional antipsychotics and who had residual symptoms after a 6-week trial of fluphenazine. The patients were treated for 1 year with clozapine, and outcome measures were compared with those in the year before clozapine treatment. After clozapine treatment, the patients had significantly fewer symptom relapses (20% versus 86%) and significantly fewer hospitalisations (8% versus 38%). Clozapine's effectiveness in a typical inpatient setting was evaluated in a randomized trial involving 202 patients with treatment-resistant schizophrenia (93). At the end of the 6-week clinical trial the proportion of patients who were judged to be improved was 30%. At the end of 12 weeks (29%) and at 1 year (33%) the proportions were similar. This descriptive epidemiologic study shows clinical practitioners the contrast between the greater external validity (generalizability) of the field trial and the greater internal validity of the short-term randomized clinical trial, although in this instance the data are quite consistent. Together the studies offer a spectrum of short- and long-term effectiveness of clozapine. Treatment Intolerance Clozapine has also been evaluated specifically in the treatment of patients who are unable to tolerate conventional antipsychotic medications because of side effects, particularly extrapyramidal symptoms and tardive dyskinesia. The only controlled trial involving this population was reported by Claghorn et al. (94), who studied patients with active psychotic symptoms and adverse neurologic reactions after treatment with at least two conventional antipsychotics. At the end of the 8-week randomized trial, the clozapine-treated patients had a 23% reduction in positive and negative symptoms, whereas the chlorpromazine-treated patients had a 15% reduction. Also, 58% of the chlorpromazine-treated patients but only 11% of the clozapine-treated patients had to drop out of the study because of extrapyramidal symptoms. 26

Support for clozapine's effectiveness in the stable or maintenance phase of treatment is based on a number of open-label studies. Meltzer et al. (89) studied patients who had previously not responded in at least three trials of different conventional antipsychotics. The rehospitalization rate after 1 year of treatment was 83% lower than that in the year before clozapine treatment. Miller et al. (95) found that the number and duration of hospitalizations among patients treated with clozapine for 2.5 years were significantly lower than those during an equal period before clozapine treatment. Breier et al. (91) also showed that, compared to the year preceding treatment, patients treated with clozapine had significantly fewer symptom relapses (mean, 0.3 versus 2.0) and hospitalizations (mean, 0.4 versus 1.3). All of these studies included patients who were treated with clozapine because they had not responded to previous treatments. Taken together, these studies provide some evidence that clozapine prevents relapse in stabilized patients. Moreover, each study found that a number of patients demonstrated improvements in social and occupational functioning. Although these studies are encouraging, they are limited since they included only clozapine responders who continued to take the medication and no other medication was compared to clozapine. 2) Side effects. A) Common, dose-related side effects. Clozapine is associated with sedation, weight gain, hypersalivation, tachycardia, orthostatic hypotension, and fever (88). The first three are extremely common, occurring in the majority of patients, particularly in the initial phase of treatment. Seizures Clozapine is also associated with a dose-related risk of seizures. The overall seizure rate is 2.8%; with low-dose treatment (<300 mg/day) the risk is 1%, with medium doses (300-599 mg/day) the risk is 2.7%, and with high doses (>599 mg/day) the risk is 4.4%. The seizure risk for clozapine is also related to rapid increases in dose. Therefore, the rate of titration should not exceed guidelines. B) Less common, idiosyncratic side effects. Agranulocytosis Clozapine causes agranulocytosis in approximately 1% of patients who receive it (96). Agranulocytosis is defined as a granulocyte count less than 500/mm3 (79). Although the danger of this life-threatening condition can be minimized by weekly blood monitoring, it remains higher than for any other antipsychotic medication. Agranulocytosis is usually reversible if treatment is discontinued immediately (97). Patients with agranulocytosis should not receive clozapine again. Through 1995, clozapine had been associated with 382 cases of agranulocytosis and 12 fatalities in the United States in about 100,000 "starts" of clozapine treatment( Sandoz Pharmaceuticals Corp.). Rx When agranulocytosis develops, patients are given intensive treatment for the secondary complications, e.g., sepsis (98). Granulocyte colony stimulating factor has been used to accelerate granulopoietic function and shorten recovery time (98, 99). Treatment of Tardive Dyskinesia There is also evidence that clozapine is less likely to cause tardive dyskinesia than other antipsychotic medications and may be an effective treatment for tardive dyskinesia and tardive dystonia (although clozapine is not a cure for tardive dyskinesia, it may allow time for recovery from tardive dyskinesia in some patients) (53, 100). 3) Implementation. Clozapine treatment should not be initiated if the initial WBC count is less than 3500/mm3 or if the patient has a history of a myeloproliferative disorder or a history of clozapine-induced agranulocytosis or granulocytopenia. Controlled trials provide only limited guidance regarding the optimal dose of clozapine for schizophrenia. Since there have been no trials in which patients were randomly assigned to different doses of clozapine, the only available data are based on studies in which psychiatrists used what they considered the most effective dose. Fleischhacker et al. (102) reviewed 16 controlled trials from Europe and the United States. The mean dose from the European trials was 283.7 mg/day, and the U.S. mean was 444 mg/day. Plasma Levels Some investigators have suggested measuring plasma levels of clozapine and achieving levels between 200 and 400 ng/ml (typically associated with a dose of 300-400 mg/day) (36). The clinical utility of plasma levels and the correlation of plasma levels with efficacy or side effects remain uncertain, however (103). Titration Patients who are treated with clozapine should be started with an initial dose of 12.5-25.0 mg/day. At this dose they should be monitored for signs of orthostatic hypotension, tachycardia, sedation, and respiratory depression. The dose of clozapine should be gradually increased in 12.5-25.0-mg daily increments until a target dose is reached at the end of 2 weeks. 27

Subsequent dose increases should be made in increments no greater than 100 mg and no more frequently than once or twice weekly (101). Time to Improvement Although most clozapine responders demonstrate clinical improvement during the first 6 weeks of treatment, others respond more slowly. Experts differ as to the appropriate length of a clozapine trial; some suggest trials of at least 6 months (87), and others suggest that trials should not exceed 2-4 months (104). Twelve-week empirical trials of clozapine appear to be adequate to determine whether a patient is likely to respond to this medication. Drug Interactions The elimination half-life of clozapine is approximately 12 hours, indicating that patients are likely to reach a steady-state plasma concentration after 1 week (105). SSRIs (e.g., fluoxetine, paroxetine), valproic acid, and nefazodone (106) may increase clozapine plasma levels. The concomitant use of medications such as carbamazepine can lower the WBC count and increase the potential danger of agranulocytosis; it should therefore be avoided. Some cases of respiratory or cardiac arrest have occurred among patients receiving benzodiazepines or other psychoactive medications concomitantly with clozapine. Whileno specific interaction between clozapine and benzodiazepines has been established, judicious use is advised when benzodiazepines or other psychotropic medications are administered with clozapine (101).

CLOZAPINE DOSING REGIMEN Many of clozapines adverse effects are dose-dependent and are possibly associated with a rapid increase in dose. Adverse effects such as oversedation and postural hypotension tend to be more common at the beginning of therapy. To minimise these problems it is important to start therapy at a low dose and to increase slowly. Clozapine should be started at a dose of 12.5mg nocte. On day two, the dose can be increased to 12.5mg twice daily. If the patient is tolerating the clozapine, the dose can then be increased by 25mg to 50mg a day, until a dose of 300mg a day is reached. This can usually be achieved in two to three weeks. Further dosage increases should be made slowly in increments of 50mg to 100mg each week. A dose of 450mg/day or a plasma level of 350mcg/L should be aimed for. The total clozapine dose should be divided and, if sedation is a problem, the larger portion of the dose can be given at night. The following table is a suggested starting regime for clozapine. This is a cautious regimen more rapid increases have been used in exceptional circumstances.

Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 18 21 28

Morning Dose 12.5 25 25 25 25 50 50 75 75 100 100 125 125 150 150 200 200

Evening Dose 12.5 12.5 25 25 50 50 50 75 75 100 100 125 125 150 150 200 200 250

If the patient is not tolerating a particular dose, decrease to one which was being tolerated. If the adverse effect resolves, increase the dose again but at a slower rate. If for any reason a patient misses less than two days clozapine, restart at the dose prescribed before the event. Do not administer extra tablets to catch up. If more than two days are missed: restart at 12.5mg once daily and increase slowly (but at a faster rate than in drug-nave patients). 28

Clozapine : Management of Adverse Effects Adverse Effect Sedation Timecourse First 4 weeks. May persist but usually wears off. First 4 weeks. May persist, but usually wears off. Often very troublesome at night. Usually persists First 4 weeks First 4 weeks, but often persists. Action Give smaller dose in the mornings. Some patients can only cope with single night-time dosing. Reduce dose if necessary. Give hyoscine 300mcg (Kwells) sucked and swallowed at night. Patients do not always mind excess salivation: treatment not always required. Recommend high fibre diet. Bulk forming laxatives +/- stimulants may be used. Advise patient to take time when standing up. Reduce dose or slow down rate of increase. Often occurs if dose escalation is too rapid. Inform patient that it is not dangerous. Give small dose of betablocker if necessary. Dietary counselling is essential. Advice may be more effective if given before weight gain occurs. Weight gain is common and often profound (>2 stone) Give antipyretic but check FBC. NB. This fever is not usually related to blood dyscrasias. Dose/dose increase related. Consider prophylactic valproate* if on high dose. After a seizure withhold Clozapine for one day. Restart at reduced dose. Give sodium valproate. May give anti-emetic. Avoid prochlorperazine and metoclopramide (EPSE). Try manipulating dose schedule. Avoid fluids before bedtime. In severe cases, desmopressin is usually effective. Stop clozapine; admit to hospital.

Hypersalivation

Constipation Hypotension Tachycardia

Weight gain

Usually during the first year of treatment

Fever Seizures

First 3 weeks May occur at any time

Nausea Noctural enuresis`

First 6 weeks May occur at any time

Neutropenia/agranulocytosis

First 18 weeks (but may occur at any time)

Usual dose of sodium valproate is 1000-2000mg/day. Plasma levels may be useful as a rough guide to dosing aim for 50-100mg/l. Use of modified release preparation (Epilim Chrono) may aid compliance: can be given once daily and may be better tolerated. a.clozapine.dosing and side-effects

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Role of plasma clozapine measurement The CLOZARIL Patient Monitoring Service can arrange, on request, measurement of plasma clozapine and of one of its major metabolites norclozapine. This service is not routinely required in patient management, but in certain situations it may be helpful. Blood is best taken immediately before the normal morning dose (trough level). If it is not possible, it is important to note the time of sampling with respect to dosage since this may influence the result. There appears to be a definite relationship between the dose of Clozaril and clozapine plasma concentration (table 1), although the relationship is not always consistent. Table Mean clozapine and norclozapine plasma concentrations (mg/L) in patients1 Clozapine Norclozapine Mean 0.26 0.31 0.38 0.47 0.65 SD 0.14 0.14 0.27 0.30 0.37 Range 0.07-0.42 0.08-0.51 0.16-0.95 0.19-1.04 0.29-1.26 Mean 0.16 0.20 0.20 0.28 0.39 SD 0.06 0.07 0.13 0.15 0.12 Range 0.09-0.27 0.11-0.33 0.07-0.47 0.13-0.48 0.23-0.55 n 5 10 8 9 6

Dose (mg/day) 125-350 400-500 500-600 600-700 700-900

Because of the wide inter-patient variability in the pharmacokinetics of clozapine, it is not possible to define a desired therapeutic range for trough concentrations at present2. However, several studies suggest that efficacy may be associated with trough clozapine concentrations above 0.35 mg/L3,4,5. The major metabolite of clozapine is norclozapine, the plasma concentration of which is well correlated with that of the parent drug and measures about 70% of the clozapine concentration.1 There is no clearly established upper limit although it has been suggested that trough clozapine concentrations above 1mg/L should not be exceeded persistently. Attempts to define a therapeutic range for plasma clozapine are difficult because of the increased response observed with duration of therapy in some patients. Hence the mainstay of dose adjustment is clinical response and the occurrence of side effects not plasma concentrations. Plasma clozapine measurement may be helpful when assessing: Lack of efficacy it may be helpful to assess poor responders at the three month stage provided that the dose has been unchanged for seven days (in order to achieve a steady state). If the plasma clozapine concentration is less than 0.35 mg/L then dosage increase is probably indicated. Compliance it is important to note that measurement of plasma clozapine and norclozapine will only confirm compliance in the preceding few days. It will not give any indication of compliance in the interval between tests. Dose optimisation particularly in patients whose drug clearance may be reduced by hepatic or renal dysfunction, and where there is the potential for drug interactions (eg. cytochrome P450 inhibitors/inducers such as cimetidine, some SSRIs, phenytoin). Diagnoses of adverse effects where they limit further dose escalation, or where they may be dose-related. Requesting Plasma Levels. The Clozaril Patient Monitoring Service has introduced a special form to assist in the collation of plasma concentration data. Certain items are essential to the useful interpretation of these data. These include: reason for requesting level, Clozaril dose, time of last dose, and time the sample was taken. References 1. McCarthy P.T., Hughes S., Paton C. Measurement of Clozapine and Norclozapine in Plasma/Serum by High Chromatography with Ultraviolet Detection. Biomedical Chromatography with Ultraviolet Detection. Biomedical Chromatography 1995; 9:36-41. 2. Haring C., Fleischhacker W.W., Schett P., et al. Influence of Patient-Related Variables on Clozapine Plasma Levels. Am J Psych 1990; 147:1471-75. 3. Miller D.D., Fleming F., Holman T.L. and Perry P.J. Plasma Clozapine Concentrations as a Predictor of Clinical Response: A Follow-Up Study. J Clinical Psychiatry 1994; 55: (Suppl B) 117-121 4. Kronig M.H., Munne R.A., Szymanski S., et al. Plasma Clozapine Levels and Clinical Response for TreatmentRefractory Schizophrenic Patients. Am J Psych 1995; 152(2): 179-82 5. Perry P.J., Miller D.D., Arndt S.V. and Cadoret R.J. Clozapine and Norclozapine Plasma Concentrations and Clinical Response of Treatment-Refractory Schizophrenic Patients. Am J Psych 1991;148(2): 231-5.

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OTHER MEDICATIONS Various ancillary medications have been used to enhance the therapeutic efficacy of antipsychotic medications and to treat residual symptoms, including positive (210), negative (165, 211), and affective symptoms (212). LITHIUM 1.Goals and efficacy. Studies evaluating the antipsychotic properties of lithium alone indicate that it has limited effectiveness as monotherapy in schizophrenia and may be harmful for some patients. Augmentation When added to antipsychotic medications, lithium has been shown to augment the antipsychotic response, in general, as well as improve negative symptoms specifically. Growe et al. (137) compared the addition of lithium (serum levels maintained at 0.5-1.0 meq/liter) or placebo for 4 weeks to an antipsychotic regimen in a double-blind crossover trial. When treated with lithium, patients showed a significantly lower level of psychotic excitement than when treated with placebo. There were trends toward less seclusiveness and retardation as well. Small et al. (138) also studied the addition of lithium (levels maintained at 0.6-1.0 meq/liter) or placebo for 4 weeks to antipsychotics in a double-blind crossover trial. The addition of lithium was associated with significantly greater improvements, relative to placebo, in overt psychotic symptoms, excitement, mannerisms/posturing, irritability, cooperativeness, personal neatness, and social competence. Affective Symptoms Lithium has also has been shown to have specific therapeutic benefits for schizophrenic patients with affective symptoms. Lerner et al. (139) investigated the addition of lithium (300 mg/day) or placebo for 6 weeks to a regimen of haloperidol for schizophrenic patients judged to have either elevated or nonelevated BPRS depression scores. Lithium produced significantly greater reductions in BPRS depression-anxiety scores in the depressed patients with schizophrenia than did placebo; the mean reduction for the lithium-treated patients was 26%. In the nondepressed patients with schizophrenia, there was no difference in impact on BPRS depression-anxiety ratings between the lithium and placebo conditions. Comparing the depressed patients with schizophrenia to the nondepressed patients with schizophrenia, lithium had a significantly greater ability to decrease thought disorder than did placebo. The requirement for haloperidol decreased the most among the lithium-treated depressed group (by a mean of 26.1 mg/day); no decrease in haloperidol requirement was noted among the placebo-treated depressed patients. Indirect evidence for the efficacy of lithium for schizophrenic patients with affective symptoms comes from several studies demonstrating that lithium plus antipsychotic medication is effective for patients with schizoaffective disorder (140-143). 2.Side effects. The side effects of lithium include polyuria, polydipsia, weight gain, cognitive problems, tremor, sedation or lethargy, impaired coordination, gastrointestinal distress, hair loss, benign leukocytosis, acne, and edema. These have been reviewed in detail in the Practice Guideline for the Treatment of Patients With Bipolar Disorder (144). The combination of an antipsychotic medication and lithium may increase the possibility of the development of neuroleptic malignant syndrome. However, the evidence for this association comes mainly from some debated reports of cases or series of cases, rather than quantitative data. Most reported cases of neuroleptic malignant syndrome in patients treated with lithium plus antipsychotic medication have occurred in cases of high lithium levels associated with dehydration. Estimates of the incidence of toxic reactions, in general, vary. Small et al. (138) found that 5% of patients developed a toxic reaction consisting of confusion and moderate memory loss while taking antipsychotic medication plus lithium (serum level, 0.6-1.0 meq/liter). However, in one study (136) the proportion of patients was considerably higher; over 50% of patients treated with lithium alone developed symptoms of a toxic-confusional state (mean level, 0.75 meq/liter; only one subject had a level above 1.0 meq/liter). No specific combination of medications is contraindicated, but psychiatrists should maintain an increased level of vigilance for signs of toxicity, particularly in the initial stage of treatment. 3.Implementation. Generally, lithium is added to the antipsychotic medication that the patient is already receiving, after the patient has had an adequate trial of the antipsychotic medication but has reached a plateau in the level of response and residual symptoms persist. The dose of lithium is that required to obtain a blood level in the range of 0.8 to 1.2 meq/liter. Response to treatment usually appears promptly; a trial of 3 to 4 weeks is adequate for determining whether there is a therapeutic response, although some investigators have noted that improvements may emerge only after 12 weeks or more (145). Patients should be monitored for adverse effects that are commonly associated with lithium (e.g., polyuria, tremor) and with its interaction with an antipsychotic medication (e.g., extrapyramidal side effects, confusion, disorientation, other signs of neuroleptic malignant syndrome) (146), particularly during the initial period of combined treatment.

31

BENZODIAZEPINES Adjunctive Therapy Double-blind studies evaluating benzodiazepines as adjuncts to antipsychotic medications were also reviewed by Wolkowitz and Pickar (147). Seven of 16 studies showed some positive effect on anxiety, agitation, psychosis, or global impairment; five of 13 showed efficacy in treating psychotic symptoms specifically. The reviewers concluded that benzodiazepines may improve the response to antipsychotic medications. Some studies indicate that the effectiveness of benzodiazepines as adjuncts to antipsychotic medications is limited to the acute phase and may not be sustained. Altamura et al. (149) found that clonazepam plus haloperidol, but not haloperidol alone or placebo, produced significant lowering of total BPRS scores after 1 week. This reduction, which was primarily due to decreases in anxiety and tension, disappeared by the end of the 4-week study. Wolkowitz and Pickar (147) suggested that benzodiazepines as adjuncts to antipsychotic medications may be most useful in the acute management of psychotic agitation. The efficacy for patients with prominent agitation was one of their most consistent findings, although none of the double-blind studies reviewed had evaluated this issue specifically. Some retrospective and open-label studies support the practice of adding a benzodiazepine to antipsychotic medication for this indication, and it has become a relatively common practice in many inpatient settings. Salzman et al. (151) reported that when lorazepam was added to antipsychotic medication for management of severe disruptive episodes, the mean dose and average number of doses of antipsychotic medication required were only half those needed when just antipsychotic medication was given. 2.Side effects. Benzodiazepines have some limitations in schizophrenia. Their common side effects include sedation, ataxia, cognitive impairment, and a tendency to cause behavioral disinhibition in some patients. This last side effect can be a serious problem in patients who are being treated for agitation. Reactions to withdrawal from benzodiazepines can include psychosis and seizures. In addition, patients with schizophrenia are vulnerable to both abuse of and addiction to these agents. 3.Implementation. A number of benzodiazepines have been evaluated, but few studies have compared the effectiveness of more than one. In the absence of clear differences in the efficacy of different medications, other issues guide the choice of a benzodiazepine, including the available routes of administration, risk of respiratory arrest, and abuse potential. With these considerations in mind, many psychiatrists choose lorazepam, which can be administered intramuscularly, intravenously, or orally, has a limited propensity to cause respiratory arrest, and has less abuse potential than other shorter-acting medications. The reviewed studies also provide little information regarding the most effective dose. The authors reported that studies with positive results used significantly higher doses of adjunctive benzodiazepines than studies with negative results (54.1 versus 22.0 mg/day of diazepam equivalents).

32

ANTICONVULSANTS 1.Goals and efficacy. There are no current indications for the use of the anticonvulsant medications carbamazepine and valproate in the treatment of schizophrenia alone. McElroy et al. (152) reviewed five available studies of valproate in schizophrenia and concluded that the evidence for efficacy is not compelling. One open trial of valproate as monotherapy showed reductions in psychotic symptoms in 70% of the patients. Adjunctive Therapy One open trial and one double-blind crossover study showed that the addition of valproate to antipsychotic medication significantly decreased psychotic and other psychiatric symptoms. However, none of these studies used operational criteria for the diagnosis of schizophrenia, and they may have included patients with affective or other neuropsychiatric conditions. In the two studies using operational criteria for the diagnosis of schizophrenia, valproate was either ineffective or deleterious. Some studies have shown that the anticonvulsant medications may be useful adjuncts to antipsychotic medications for special patient populations, particularly those with EEG abnormalities suggestive of seizure activity and those with agitated/violent behavior. Neppe (153) conducted a double-blind crossover study of nonepileptic patients with temporal lobe EEG abnormalities who did not respond to antipsychotic medications alone; when carbamazepine was added to the antipsychotic medication, the level of aggression was only one-half of that when placebo was added. In a retrospective study, Luchins (154) investigated adjunctive carbamazepine for violent patients with and without EEG abnormalities. In one part of the study, carbamazepine was added to the antipsychotic medication regimens of seven patients (six with schizophrenia and one with a mixed personality disorder) who had no EEG abnormalities. During carbamazepine treatment, there were 60% fewer aggressive episodes than in the period before or after the addition of carbamazepine. In the second part of this study, carbamazepine was added to the antipsychotic medication regimens of eight patients (six with schizophrenia, one with mild mental retardation, and one with an organic personality disorder) with EEG abnormalities. During the period of carbamazepine treatment, there were 37% fewer aggressive episodes than during the period before carbamazepine addition. Okuma et al. (155) studied adjunctive carbamazepine use for schizophrenic patients with agitated/violent behavior who had responded poorly to antipsychotic medication alone. Adjunctive carbamazepine treatment produced moderate to marked improvement in more patients than did placebo (43% versus 28%), although this difference was not significant. Anticonvulsants are effective in the treatment of patients with schizophrenia who have a concurrent seizure disorder (60). For these patients and for patients who have experienced a seizure while taking a medication that may have lowered the seizure threshold, e.g., clozapine, and who have a strong indication to continue, an anticonvulsant can be administered concurrently to prevent the recurrence of seizures. 2.Side effects. There are generally no additional side effects from the combination of anticonvulsant and antipsychotic medications beyond those of the individual medications themselves. Carbamazepine is not recommended for use with clozapine, because of the potential of both medications to cause agranulocytosis. 3.Implementation. These medications are generally used at the same therapeutic dose ranges and blood levels as for the treatment of seizure disorders. A complicating factor is the fact that both carbamazepine (156-158) and valproate (159) decrease the blood levels of antipsychotic medications by induction of hepatic enzymes.

OTHER MEDICATIONS Reserpine, propranolol, clonidine, and calcium channel blockers have been added to existing antipsychotic medication regimens (160-162). Their potential utility is limited and requires further investigation. Given the availability of clozapine and risperidone and the potential use of lithium, benzodiazepines, and carbamazepine as adjunctive treatments, these should be preferentially used (87).

33

References
The following coding system is used to indicate the nature of the supporting evidence in the summary recommendations and references: A.Randomized clinical trial. A study of an intervention in which subjects are prospectively followed over time; there are treatment and control groups; subjects are randomly assigned to the two groups; both the subjects and the investigators are blind to the assignments. B.Clinical trial. A prospective study in which an intervention is made and the results of that intervention are tracked longitudinally; study does not meet standards for a randomized clinical trial. C.Cohort or longitudinal study. A study in which subjects are prospectively followed over time without any specific intervention. D.Case-control study. A study in which a group of patients is identified in the present and information about them is pursued retrospectively or backward in time. E.Review with secondary data analysis. A structured analytic review of existing data, e.g., a meta-analysis or a decision analysis. F.Review. A qualitative review and discussion of previously published literature without a quantitative synthesis of the data. G.Other. Textbooks, expert opinion, case reports, and other reports not included above. 1. Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr: Principles and Practice of Psychopharmacotherapy. Baltimore, Williams & Wilkins, 1993, pp 93-184 [G] 2. Laskey JJ, Klett CJ, Caffey EM Jr, Bennett JL, Rosenblum MP, Hollister LE: Drug treatment of schizophrenic patients: a comparative evaluation of chlorpromazine, chlorprothixene, fluphenazine, reserpine, thioridazine, and triflupromazine. Dis Nerv Syst 1962; 23:698-706 [A] 3. National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group: Phenothiazine treatment in acute schizophrenia. Arch Gen Psychiatry 1964; 10:246-261 [A] 4. Davis JM, Barter JT, Kane JM: Antipsychotic drugs, in Comprehensive Textbook of Psychiatry, 5th ed, vol 2. Edited by Kaplan HI, Sadock BJ. Baltimore, Williams & Wilkins, 1989, pp 1591-1626 [G] 5. Casey JF, Lasky JJ, Klett CJ, Hollister LE: Treatment of schizophrenic reactions with phenothiazine derivatives: a comparative study of chlorpromazine, triflupromazine, mepazine, prochlorperazine, perphenazine, and phenobarbital. Am J Psychiatry 1960; 117:97-105 [A] 6. Klein DF, Davis JM: Diagnosis and Drug Treatment of Psychiatric Disorders. Huntington, NY, Krieger, 1969 [G] 7. Kolakowska T, Williams AO, Ardern M, Reveley MA, Jambor K, Gelder MG, Mandelbrote BM: Schizophrenia with good and poor outcome, I: early clinical features, response to neuroleptics and signs of organic dysfunction. Br J Psychiatry 1985; 146:229-239 [D] 8. Baldessarini RJ: Drugs and the treatment of psychiatric disorders: psychosis and anxiety, in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed. Edited by Hardman JG, Gilman AG, Limbird LE. New York, McGraw-Hill, 1996, pp 399-430 [G] 9. Davis JM: Overview: maintenance therapy in psychiatry, I: schizophrenia. Am J Psychiatry 1975; 132:1237-1245 [E] 10. Kane JM: Treatment programme and long-term outcome in chronic schizophrenia. Acta Psychiatr Scand (Suppl) 1990; 358:151-157 [F] 11. Schooler NR, Levine J, Severe JB, Brauzer B, DiMascio A, Klerman GL, Tuason VB: Prevention of relapse in schizophrenia: an evaluation of fluphenazine decanoate. Arch Gen Psychiatry 1980; 37:16-24 [A] 12. Hogarty GE, Ulrich RF, Mussare F, Aristigueta N: Drug discontinuation among long term, successfully maintained schizophrenic outpatients. Dis Nerv Syst 1976; 37:494-500 [C] 13. Kane JM, Rifkin A, Quitkin F, Nayak D, Ramos-Lorenzi J: Fluphenazine vs placebo in patients with remitted, acute first-episode schizophrenia. Arch Gen Psychiatry 1982; 39:70-73 [A] 14.Crow TJ, MacMillan JF, Johnson AL, Johnstone EC: The Northwick Park study of first episodes of schizophrenia, II: a randomised controlled trial of prophylactic neuroleptic treatment. Br J Psychiatry 1986; 148:120-127 [A] 15.Van Putten T, Marder SR: Behavioral toxicity of antipsychotic drugs. J Clin Psychiatry 1987; 48(Sept suppl):13-19 [F] 16.Cole JO, Davis JM: Antipsychotic drugs, in The Schizophrenic Syndrome. Edited by Bellak L, Loeb L. New York, Grune & Stratton, 1969, pp 478-568 [G] 17.American Psychiatric Association: Tardive Dyskinesia: A Task Force Report of the American Psychiatric Association. Washington, DC, APA, 1992 [F] 18.Arana GW, Santos AB: Anticholinergics and amantadine, in Comprehensive Textbook of Psychiatry, 6th ed, vol 2. Edited by Kaplan HI, Sadock BJ. Baltimore, Williams & Wilkins, 1995, pp 1919-1923 [G] 19.Gelenberg AJ: The catatonic syndrome. Lancet 1976; 1:1339-1341 [F] 20.Lieberman JA, Kane JM, Johns CA: Clozapine: guidelines for clinical management. J Clin Psychiatry 1989; 50:329-338 [F] 21.Ayd FJ Jr: A survey of drug-induced extrapyramidal reactions. JAMA 1961; 75:1054-1060 [D] 22.Casey DE: Neuroleptic drug-induced extrapyramidal syndromes and tardive dyskinesia. Schizophr Res 1991; 4:109-120 [G] 23.Baldessarini RJ, Frankenburg FR: Clozapine: a novel antipsychotic agent. N Engl J Med 1991; 324:746-754 [G] 24.Claus A, Bollen J, DeCuyper H, Eneman M, Malfroid M, Peuskens J, Heylen S: Risperidone versus haloperidol in the treatment of chronic schizophrenic

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inpatients: a multicentre double-blind comparative study. Acta Psychiatr Scand 1992; 85:295-305 [A] 25.Chouinard G, Jones B, Remington G, Bloom D, Addington D, MacEwan W, Labelle A, Beauclair L, Arnott W: A Canadian multicenter placebocontrolled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993; 13:25-49 [A] 26.Goetz CG, Klawans HL: Drug-induced extrapyramidal disorders: a neuropsychiatric interface. J Clin Psychopharmacol 1981; 1:297-303 [G] 27.Braude WM, Barnes TRE, Gore SM: Clinical characteristics of akathisia: a systematic investigation of acute psychiatric inpatient admissions. Br J Psychiatry 1983; 143:139-150 [C] 28.Caroff S: The neuroleptic malignant syndrome. J Clin Psychiatry 1980; 41:79-83 [F] 29.Rupniak NM, Jenner P, Marsden CD: Acute dystonia induced by neuroleptic drugs. 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