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the first 2 months of treatment They subside on discontinuance of the drug There is cross-sensitivity among all of the phenothiazines, and a drug from a different group should be used when allergic reactions occur Clozapine is associated with a 16% risk of agranulocytosis (higher in persons of Ashkenazi Jewish ancestry), and its use must be strictly monitored with weekly blood counts during the first 6 months of treatment, with monitoring every other week thereafter Discontinuation of the medication requires weekly monitoring of the white blood cell count for 1 month Recently, clozapine has been associated with fatal myocarditis and is contraindicated in patients with severe heart disease In addition, clozapine lowers the seizure threshold and has many side effects, including sedation, hypotension, increased liver enzyme levels, hypersalivation, respiratory arrest, weight gain, and changes in both the ECG and the EEG Photosensitivity, retinopathy, and hyperpigmentation are associated with use of fairly high dosages of chlorpromazine and thioridazine The appearance of particulate melanin deposits in the lens of the eye is related to the total dose given, and patients on long-term medication should have periodic eye examinations Teratogenicity has not been causally related to these drugs, but prudence is indicated particularly in the first trimester of pregnancy The seizure threshold is lowered, but it is safe to use these medications in epileptics who take anticonvulsants The neuroleptic malignant syndrome (NMS) is a catatonia-like state manifested by extrapyramidal signs, blood pressure changes, altered consciousness, and hyperpyrexia; it is an uncommon but serious complication of neuroleptic treatment Muscle rigidity, involuntary movements, confusion, dysarthria, and dysphagia are accompanied by pallor, cardiovascular instability, fever, pulmonary congestion, and diaphoresis and may result in stupor, coma, and death The cause may be related to a number of factors, including poor dosage control of neuroleptic medication, affective illness, decreased serum iron, dehydration, and increased sensitivity of dopamine receptor sites Lithium in combination with a neuroleptic drug may increase vulnerability, which is already increased in patients with an affective disorder In most cases, the symptoms develop within the first 2 weeks of antipsychotic drug treatment The syndrome may occur with small doses of the drugs Intramuscular administration is a risk factor Elevated creatine kinase and leukocytosis with a shift to the left.

FIGURE 7-26 Details of condition record (note Matl f settl eld)

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QTc prolongation is a side effect of many medications and suggests a possible risk for arrhythmia Among atypical neuroleptics, only ziprasidone carries a special warning regarding the risk of QTc prolongation Adapted, with permission, from American Diabetes Association: Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes Diabetes Care 2004 Feb;27(2):596 601

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nerable to extrapyramidal side effects High-potency neuroleptics often require antiparkinsonism drugs (see Table 24 6) The neuroleptic dosage should be reduced, and immediate relief can be achieved with antiparkinsonism drugs in the same dosages as above After 4 6 weeks, these antiparkinsonism drugs can often be discontinued with no recurrent symptoms In any of the extrapyramidal symptoms, amantadine, 100 400 mg daily, may be used instead of the antiparkinsonism drugs Neuroleptic-induced catatonia is similar to catatonic stupor with rigidity, drooling, urinary incontinence, and cogwheeling It usually responds slowly to withdrawal of the offending medication and use of antiparkinsonism agents Tardive dyskinesia is a syndrome of abnormal involuntary stereotyped movements of the face, mouth, tongue, trunk, and limbs that may occur after months or (usually) years of treatment with neuroleptic agents The syndrome affects 20 35% of patients who have undergone long-term neuroleptic therapy Predisposing factors include older age, many years of treatment, cigarette smoking, and diabetes mellitus Pineal calcification is higher in this condition by a margin of 3:1 There are no known differences among any of the antipsychotic drugs in the development of this syndrome Although the atypical antipsychotics appear to offer lower risk, the CATIE study did not address the long-term effects of these drugs Early manifestations include fine worm-like movements of the tongue at rest, difficulty in sticking out the tongue, facial tics, increased blink frequency, or jaw movements of recent onset Later manifestations may include bucco-linguo-masticatory movements, lip smacking, chewing motions, mouth opening and closing, disturbed gag reflex, puffing of the cheeks, disrupted speech, respiratory distress, or choreoathetoid movements of the extremities (the last being more prevalent in younger patients) The symptoms do not necessarily worsen and in rare cases may lessen even though neuroleptic drugs are continued The dyskinesias do not occur during sleep and can be voluntarily suppressed for short periods Stress and movements in other parts of the body will often aggravate the condition Early signs of dyskinesia must be differentiated from those reversible signs produced by ill-fitting dentures or nonneuroleptic drugs such as levodopa, TCAs, antiparkinsonism agents, anticonvulsants, and antihistamines Other neurologic conditions such as Huntington s chorea can be differentiated by history and examination The emphasis should be on prevention Use the least amount of neuroleptic drug necessary to mute the psychotic symptoms; atypical drugs appear to offer less risk as first line agents Detect early manifestations of dyskinesias When these occur, stop anticholinergic drugs and gradually discontinue neuroleptic drugs Weight loss and cachexia sometimes appear on withdrawal of neuroleptics In an indeterminate number of cases, the dyskinesias will remit Keep the patient off the drugs until reemergent psychotic symptoms dictate their resumption, at which point they are restarted in low doses and gradually increased until there is clinical improvement If neuroleptic drugs are restarted, clozapine and olanzapine appear to offer less risk of recurrence The use of adjunctive agents such as benzodiazepines or lithium may help directly or indirectly by.

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