Subject Review. Antipsychotic Agents: A Clinical Update

Transcription

1 Subject Review Antipsychotic Agents: A Clinical Update JOHN L. BLACK, M.D., Department of Psychiatry and Psychology; ELLIOTT RICHELSON, M.D., Department of Psychiatry and Psychology and Department of Pharmacology; JARRETT W. RICHARDSON, M.D., Department of Psychiatry and Psychology Antipsychotic agents have many indications and are frequently used. All physicians, regardless of their subspecialty, will most likely treat patients who receive these drugs. This article is designed to help nonpsychiatric physicians use antipsychotics appropriately. The indications, recommended dosages, side effects, and drug interactions of antipsychotic medications are reviewed. Receptor binding data are used to help predict the side-effect profile of these agents. Knowledge of these side effects and of the patient's medical condition helps the physician select a drug that the patient can tolerate. Management of overdose situations is discussed. Antipsychotic agents, also called neuroleptics, are drugs used to control the symptoms of schizophrenia and other types of psychosis. The term "antipsychotic" should not be taken literally, however, because the indications for these drugs have expanded beyond the field of psychiatry. Thus, physicians of many subspecialties are exposed to patients who use these drugs. In this review, we provide information about the indications for use of these drugs, recommended dosages, and potential complications. We also describe an approach for the selection of antipsychotic drugs for psychiatric patients based on knowledge of each patient's behavior and medical condition and on the side-effect profile of these agents. PHARMACOLOGIC PROPERTIES Most of the pharmacologic actions of neuroleptics can be explained in terms of their interactions with receptors on various neuronal systems. The dopaminergic neurons are of most interest because of their relationship to psychoses. Dopamine receptors have been classified as D-1, which stimulate adenylate cyclase when activated, and D-2, which may inhibit adenylate cyclase when stimulated. 1 Blockade of D-2 receptors seems to be involved in the production of extrapyramidal syndromes. Neuroleptics block both D-1 and D-2 receptors to various degrees. The ratio of D-1 to D-2 blockade is of unknown impor- Address reprint requests to Dr. J. L. Black, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN tance in psychiatry. A strong correlation has been noted between D-2 receptor blockade and potency in terms of daily dosage of antipsychotic agents 2 a finding that indicates that this property has a role in the therapeutic action of these drugs. Antipsychotic drugs do not interact exclusively with D-1 and D-2 receptors. They are known to block histamine H^ histamine H 2, oh-adrenergic, a 2 -adrenergic, muscarinic, and serotoninergic receptors as well. 2 ' 3 The magnitude of the affinity of a drug for a receptor determines its likelihood of causing certain side effects and some drug interactions (Tables 1 and 2). As noted before, the therapeutic dose of a neuroleptic correlates with its affinity for dopamine D-2 receptors of the human brain. 2 In clinical practice, the dose of a neuroleptic is titrated to achieve this D-2 receptor blockade. Because these drugs block other receptors, an action that could lead to adverse effects, it would be useful to know what other receptors are being antagonized at the same time. This information can be derived by comparing the affinity of a drug for other receptors relative to its affinity for the D-2 receptor. For example, the affinity of chlorpromazine for the histamine H^ receptor is twice that for the D-2 receptor (Table 1). This finding indicates that when D-2 receptor blockade is achieved with this drug, then histamine H, blockade will also occur. On the basis of the data shown in Table 1, one can see that α,-receptor antagonism will be a prominent feature of treatment with chlorpromazine, whereas antagonism of Mayo Clin Proc 60: ,

2 778 ANTIPSYCHOTIC AGENTS Mayo Clin Proc, November 1985, Vol 60 Table 1. Affinity* of Certain Antipsychotic Agents for Several Neurotransmitter Receptorst 2 Antipsychotic agent: generic name (trade name) Chlorpromazine (Thorazine) Chlorprothixene (Taractan) Fluphenazine (Permitil, Prolixin) Haloperidol (Haldol) Loxapine (Loxitane) Mesoridazine (Serentil) Molindone (Moban) Perphenazine (Trilafon) Prochlorperazine (Compazine) Thioridazine (Mellaril) c/s-thiothixene (Navane) Trifluoperazine (Stelazine) Dopamine D Histamine Receptor Adrenergic H, Muscarinic *10~ 7 x 1/K d, in which K d is the equilibrium dissociation constant in molarity. All receptors were from h luman brain except the histamine H 2 receptor, which was from guinea pig brain. ta higher numerical value indicates greater binding and greater antagonism of a given receptor. histamine H 2 and a 2 -adrenergic receptors will be essentially nonexistent. Using this approach, we have determined the recommended drug for various conditions (Table 3). This approach, however, is only an approximation, which is the best information that can be obtained until data become available from a clinical study that compares all 12 compounds listed in Table 1. DRUG SELECTION Functional Psychoses. The delusions, hallucinations, thought disorders, and bizarre behavior associated with the functional psychoses (Table 4) are usually diminished when any antipsychotic agent is administered in an adequate dose for an appropriate duration. 4,5 These socalled positive psychotic symptoms are much more responsive than the negative symptoms of affective blunting, alogia, avolition, anhedonia, and attentional impairment. Patients with primarily negative symptoms respond poorly to neuroleptic treatment. 6,7 No one antipsychotic agent is superior to another for elimination of the delusions, hallucinations, or thought disorders associated with psychoses. 4,5 A specific antipsychotic agent is often selected to treat a given patient because the side effects of that drug are useful for controlling other aspects of the patient's illness, such as agitation or withdrawal, or the side-effect profile of a particular drug is best for a patient with a concurrent medical condition. Table 3 lists drugs that can be used in psychiatric patients who have various psychopathologic conditions and medical disorders. Readers should refer to this table for the following discussion. Psychiatric Conditions. The most important factor in the selection of an antipsychotic agent is the patient's history. If a patient has been successfully treated previously with a given agent and has had tolerable side effects, that agent should be the drug of choice. Agitated psychotic patients who require sedation may be treated with neuroleptics that are potent histamine H, antagonists, and withdrawn patients may respond to less sedating agents, although the efficacy of these drugs in these situations is controversial. 8,9 Pimozide is reported to be effective in delusional parasitosis but has not been proved to be superior to other antipsychotic agents. 10 Thioridazine and mesoridazine should be avoided in patients with a tendency to attempt suicide because an overdose of these drugs causes cardiac conduction aber- Table 2. Adverse Effects Caused by Blockade of Muscarinic, Histamine H,, Histamine H 2,. a,-adrenergic, and a 2 -Adrenergic Receptors 2 Type of receptor blockade Adverse effects Muscarinic Histamine H, Histamine H 2 a,-adrenergic a 2 -Adrenergic Urinary retention Memory dysfunction Dry mouth Blurred vision Constipation Speech blockade Sedation Hypotension (?) Weight gain (?) Depression (?) Postural hypotension Light-headedness Reflex tachycardia

3 Mayo Clin Proc, November 1985, Vol 60 ANTIPSYCHOTIC AGENTS 779 Table 3. Antipsychotic Agents of Choice for Various Conditions Condition Recommended drug*. Psychiatric Agitation and psychosis Withdrawal and psychosis Suicidal tendency Tendency for severe parkinsonism or acute dystonia Tendency for akathisia Elderly, medical history unknown, dehydration Ophthalmologic Accommodation difficulties, Sjögren's syndrome Allergies Pulmonary Chronic obstructive pulmonary disease Cardiovascular Coronary artery disease Hypertension treated with prazosin Arrhythmia Gastrointestinal Nausea and vomiting Diarrhea Urologie Urinary retention Endocrinologic Galactorrhea, menstrual irregularity caused by use of neuroleptic, breast cancer Neurologic Parkinson's disease Delirium Dementia with behavioral disorganization Chlorpromazine, loxapine, mesoridazine, thioridazine Fluphenazine, haloperidol, molindone, trifluoperazine Avoid mesoridazine and thioridazine Chlorpromazine, mesoridazine, thioridazine Chlorpromazine, loxapine, mesoridazine, thioridazine Fluphenazine, haloperidol, molindone, perphenazine, thiothixene, trifluoperazine Fluphenazine, haloperidol, loxapine, molindone, perphenazine, prochlorperazine, thiothixene, trifluoperazine Chlorpromazine, loxapine, mesoridazine, thioridazine Fluphenazine, haloperidol, loxapine, molindone, perphenazine, prochlorperazine, thiothixene, trifluoperazine Fluphenazine, haloperidol, molindone, perphenazine, thiothixene, trifluoperazine Fluphenazine, molindone, perphenazine, thiothixene, trifluoperazine Avoid mesoridazine and thioridazine Any neuroleptic except thioridazine Chlorpromazine, mesoridazine, thioridazine Fluphenazine, haloperidol, loxapine, molindone, perphenazine, pro- ' chlorperazine, thiothixene, trifluoperazine Switch to chlorpromazine, loxapine, mesoridazine, molindone, thioridazine Chlorpromazine, mesoridazine, thioridazine Fluphenazine, haloperidol, molindone, perphenazine, thiothixene, trifluoperazine Fluphenazine, haloperidol, molindone, perphenazine, thiothixene, trifluoperazine *Drugs are listed alphabetically. See text for explanation of how these drugs were chosen. rations. 11 Patients who are likely to have severe druginduced parkinsonism and acute dystonia respond best to a drug with high antimuscarinic potential because this therapy tends to moderate the D-2 antagonism and thus diminish the effects of these conditions. If a patient tends to have akathisia (motor restlessness), high-potency D-2 antagonists should be avoided. Table 4. Functional Psychoses Treated With Antipsychotic Drugs Schizophrenia Schizoaffective disorders Mania Major depressive disorders with psychotic features Paranoid disorders Atypical psychoses for example, delusional parasitosis Selection of drugs for elderly psychotic patients, those with unknown medical histories, and dehydrated patients necessitates special care. The drug with the lowest side-effect profile should be used. Molindone seems to be a good drug for these patients because of weak action at all receptor sites, but it is not available in parenteral form. Except for the side effects of more potent D-2 blockade, fluphenazine, haloperidol, perphenazine, thiothixene, and trifluoperazine also have low side-effect profiles. Only trifluoperazine is unavailable in parenteral form. Ophthalmologic Conditions. Patients who have difficulty with accommodation, who wear contact lenses, or who have Sjögren's syndrome should be treated with agents with low antimuscarinic potential. Antimuscarinic drugs interfere with the function of the ciliary muscle and hence affect accommodation. Antimuscarinic agents also prevent normal lacrimation. Allergies. Allergic conditions should not be treated primarily with antipsychotic agents because antihistaminic agents cause fewer side effects. If a patient who requires an antipsychotic drug needs treatment for a concomitant allergic condition, neuroleptics with a high affinity for histamine Ητ receptors could be considered. Pulmonary Disorders. Patients with chronic obstructive pulmonary disease (emphysema, chronic bronchitis, or asthma) have difficulties clearing secretions. Highly antimuscarinic agents cause drying of these secretions and can exacerbate this problem. Therefore, low-potency antimuscarinics should be chosen for these patients. Cardiovascular Conditions. Agents that are highly antagonistic to a,-adrenergic, muscarinic, and histamine H, receptors should not be used in patients in whom tachycardia and postural hypotension could be dangerous. Patients with coronary artery disease may be at increased risk for myocardial infarction when subjected

4 780 ANTIPSYCHOTIC ACENTS Mayo Clin Proc, November 1985, Vol 60 to sustained tachycardia. Hypertensive patients who are being treated with prazosin may experience potentiation of side effects and hypotensive effects if a neuroleptic with high o^-adrenergic affinity is administered. In those patients with arrhythmias, use of thioridazine should be avoided because of its ability to prolong Q-T intervals, an outcome that can be arrhythmogenic. 12 Gastrointestinal Disorders. Psychotic patients with the irritable bowel syndrome will obtain some relief with highly antimuscarinic agents because they cause constipation. (Of course, these drugs should be used with caution in constipated patients.) Psychotic patients with concomitant peptic ulcer disease may benefit by use of the agents with high affinity for histamine H 2 receptors, but the neuroleptics tested thus far have much lower activity than cimetidine and probably produce little change in gastric acidity. Urologie Conditions. Patients with a tendency to have urinary retention, such as those with prostatic hypertrophy or neurogenic bladder, should be given drugs with low antimuscarinic activity. Drugs with high antimuscarinic potential prevent parasympathetic nerves from producing normal contraction of the detrusor muscle and relaxation of the internal urethral sphincter. Endocrinologic Conditions. Dopamine is the major inhibitory factor that prevents secretion of prolactin by the pituitary gland. Dopamine antagonists cause an increase in prolactin levels, which can result in galactorrhea in female patients. Neuroleptics may be contraindicated if a patient has carcinoma of the breast, because of the trophic activity of prolactin on breast tissue. Neuroleptics, however, do not increase the incidence of breast cancer in patients who receive long-term treatment with these drugs. 13 Elevated prolactin levels can also contribute to menstrual irregularities and sexual dysfunction. Changing the regimen to a lower potency dopamine D-2 antagonist may produce a lower level of hyperprolactinemia, which may cause these side effects to subside. Neurologic Disorders. Preexisting Parkinson's disease can confound the use of neuroleptics because all effective agents are D-2 antagonists, which can exacerbate Parkinson's disease. Although the administration of antipsychotic agents is best avoided in patients who have Parkinson's disease, if they are indicated and unavoidable, the drug chosen should have high antimuscarinic activity (to decrease the potential for exacerbation of the parkinsonian symptoms). 14 In addition, all neuroleptics reputedly lower the seizure threshold of patients and may cause an increased frequency of seizures in those with epilepsy. 15,16 In the treatment of psychotic patients with Parkinson's disease or epilepsy, a neurologist should be consulted. GENERAL DOSAGE GUIDELINES The therapeutic dosage range for antipsychotic drugs is broad (Table 5). 18 The routine use of huge doses of a neuroleptic to induce a rapid change in psychotic behavior does not shorten the hospital stay and promotes the development of adverse reactions. 19 Most acute psychotic episodes can be controlled with an amount of antipsychotic drug that is equal to 100 to 300 mg of chlorpromazine per day. 20 Chronically psychotic patients with an acute exacerbation may require larger doses. Psychotic mentation will not clear immediately. The neuroleptic must often be administered at therapeutic levels for a minimum of 10 days before mentation is improved appreciably. Increasing the dose does not produce a more rapid change in psychotic mentation unless the patient has been receiving a subtherapeutic dose. Giving higher doses, however, often produces sedation, which controls the behaviorally disorganized patient. Other factors help to determine the appropriate drug dosage. Elderly patients usually require less medication, especially if they are demented or have liver impairment. In patients on long-term therapy for psychosis, drug tolerance may develop and necessitate the use of higher dosages. Patients who smoke or have hepatic enzymes induced by other factors metabolize antipsychotic drugs more rapidly and may need higher doses. In children, the dose should be based on body weight and the guidelines from the Food and Drug Administration. Most patients with schizophrenia have optimal results with long-term maintenance therapy. 21 Some patients Table 5. Potency and Range of Oral Dose of Neuroleptics Approximate amount of drug needed Range of Antipsychotic agent: to equal 100 mg of daily oral generic name (trade name) chlorpromazine' 617 dose (mg) Aliphatic Chlorpromazine (Thorazine) Piperazine Fluphenazine (Permitil, Prolixin) Perphenazine (Trilafon) Prochlorperazine (Compazine) Trifluoperazine (Stelazine) Piperidine Mesoridazine (Serentil) Thioridazine (Mellaril) Butyrophenone Haloperidol (Haldol) Thioxanthene Chlorprothixene (Taractan) Thiothixene (Navane) Dihydroindolone Molindone (Moban) Dibenzoxazepine Loxapine (Loxitane) ,

5 Mayo Clin Proc, November 1985, Vol 60 ANTIPSYCHOTIC AGENTS 781 will recover from psychosis and never require neuroleptics again. Therefore, a very slow tapering of the dose of antipsychotic medication should be attempted 3 to 6 months after all psychotic symptoms have been controlled in these patients. The recommended approach is to decrease the dose minimally every 3 to 4 weeks because dosage changes will not be reflected in the patient's behavior and mentation for up to a month or more subsequently. In patients who require long-term maintenance therapy, a similar approach may be used to determine the minimal dose of antipsychotic agent necessary to maintain optimal control of the symptoms. When the patient shows signs of increasing psychotic symptoms, the tapering of the dose is discontinued, and the dose is increased to the lowest amount that will control the symptoms. During long-term maintenance therapy, antipsychotic medication can be given in a single daily dose, usually at bedtime. Split doses are not necessary to maintain therapeutic blood levels because the half-life of all these drugs is 24 hours or more. Many side effects can be minimized by administering the drug at bedtime, because the patient is asleep when these effects are at a peak. Fluphenazinedecanoate, administered intramuscularly, is commonly used in noncompliant patients. For the administration of this medication, experience is necessary, and a psychiatrist may be best qualified. Before patients are treated with fluphenazine decanoate, they should be given an oral fluphenazine preparation for a few days to see whether this high-potency neuroleptic can be tolerated. Decanoate derivatives of several other neuroleptics have been synthesized but are not marketed in the United States. Haloperidol decanoate is used in Europe and may become available in the United States shortly. Some studies have shown a correlation between blood levels of antipsychotic agents and the response to treatment. 22,23 The utility of blood level monitoring during neuroleptic treatment has not been determined. DRUG COMBINATIONS The combination of tricyclic antidepressants and neuroleptics in depressed or apathetic patients with schizophrenia may produce some improvement in mood but at the possible expense of worsening the thought disorder. 24 Similarly, the use of benzodiazepines in combination with neuroleptics in the treatment of psychosis increases sedation and forces clinicians to prescribe lower doses of the neuroleptic, which may prevent improvement of the patient's condition. A recent study, however, indicated that, when used in high doses with neuroleptics, benzodiazepines may benefit recalcitrant patients with paranoid schizophrenia. 25 This mode of treatment is controversial and should be studied further. Patients with a schizoaffective disorder may require a combination of an antipsychotic, lithium, and possibly an antidepressant, and full therapeutic dosages of each may be necessary for optimal control of symptoms. 26 Treatment of such complicated patients is best done by a psychiatrist. Patients with major depressive episodes with psychotic features may require both a neuroleptic and an antidepressant in full therapeutic doses of each. Frequently, such patients respond best to electroconvulsive therapy alone. Neuroleptics are used with lithium in patients who have mania because this drug combination controls the behavioral aberrations more quickly than does lithium alone. After the mania has been controlled, the regimen of the neuroleptic should be tapered and ultimately it should be discontinued. ORGANIC PSYCHIATRIC CONDITIONS If a demented patient exhibits paranoia, irritability, nocturnal confusion, combativeness, or impulsivity, the use of a neuroleptic may be beneficial (Table 6). Neuroleptic agents, however, will not improve cognitive capacity. In fact, memory impairment may be exacerbated if the drug used has high antimuscarinic activity, 27 such as chlorpromazine, mesoridazine, and thioridazine (Table 1). Patients who have dementia are also usually elderly and often have medical illnesses that would be compounded by antimuscarinic and antihistaminic agents. Thus, the best drugs in this situation are fluphenazine, haloperidol, molindone, perphenazine, thiothixene, and trifluoperazine. Haloperidol, 0.5 to 1 mg orally twice daily, is administered most frequently. 28 Although these drugs may be given indefinitely, the need for continued therapy should be reassessed frequently. In patients with delirium, the use of neuroleptics may also control agitated behavior. Frequently, haloperidol in a dosage of 0.5 to 5 mg orally or intramuscularly twice daily is effective. Once the underlying cause of the delirium has been identified and corrected, use of the drug should be discontinued. Neuroleptics that are strongly antimuscarinic, such as chlorpromazine, meso- Table 6. Organic Psychiatric Disorders Treated With Antipsychotic Drugs Dementia with behavioral disorganization Delirium with behavioral disorganization Substance-induced delirium, delusions, and hallucinations Organic mental disorders with delusions, hallucinations, or personality changes

6 782 ANTIPSYCHOTIC ACENTS Mayo Clin Proc, November 1985, Vol 60 ridazine, and thioridazine (Table 1), should be avoided because high doses of neuroleptics are often needed to control the behavior of these patients. Antimuscarinic agents can produce confusion and may worsen the patient's condition. In such cases, improvement will be noted when use of the neuroleptic is discontinued. 29 Delirium, hallucinations, and delusional states caused by intoxicating amounts of abused substances can often be treated by placing the patient in a secure environment and reassuring him. Occasionally, however, supportive measures, detoxification, and antipsychotic agents are needed for severe agitation caused by an overdose. A sedating neuroleptic, such as chlorpromazine, loxapine, mesoridazine, or thioridazine, should be used in a dose that balances the control of agitation with the side effects. Dosages equivalent to 100 to 300 mg of chlorpromazine per day should be tried initially, but frequently higher dosages are necessary. The abuse of amphetamines, hallucinogens, cocaine, and depressants can cause a psychotic picture, which in the case of amphetamines and phencyclidine can be difficult to distinguish from schizophrenia and may persist for a prolonged period after the drug is no longer taken. Drug-induced psychoses should be treated with neuroleptics in doses similar to those used in the treatment of acute functional psychosis. Withdrawal of depressants and stimulants can produce delirium, but only depressant withdrawal causes hallucinations. Delirium and hallucinations related to withdrawal of a depressant are treated by placing a patient on a tapering schedule of the depressant or a substitute. Delirium tremens has been treated with phenothiazines and haloperidol, but investigators have provided firm evidence that these agents do not prevent delirium tremens and that the mortality rate is higher for patients treated with these drugs than for those given chlordiazepoxide. 30 This practice should be discontinued. Other organic mental disorders such as those that give rise to delusions, hallucinations, or changes in personality can be treated with antipsychotic agents, which may produce a measure of control. The dosages required by patients with these disorders are extremely variable. The amount of drug used should be based on the patient's response and the development of side effects. Elimination of the symptoms is frequently impossible unless the underlying organic disorder is reversible. Frequent causes of these disorders include infection, trauma, metabolic derangements, vascular events, and degenerative processes. ' NEUROLOGIC CONDITIONS Antipsychotic agents are used for several neurologic conditions (Table 7). These drugs are not curative in any of these diseases and are useful only to control certain manifestations of the diseases. Table 7. Neurologic Conditions Treated With Antipsychotic Drugs Gilles de la Tourette's syndrome Huntington's chorea Hemiballismus Chorea associated with rheumatic fever or systemic lupus erythematosus Spasmodic torticollis Meige's syndrome Gilles de la Tourette's syndrome affects persons between 2 and 5 years of age. The predominant symptoms are multiple vocal tics and involuntary tic-like muscular movements. Haloperidol is the drug of choice for treating this disorder. 33 The starting daily dose is usually 2 mg orally, and the dose is rapidly increased to produce resolution of symptoms. Often, the maximal dose is limited because of side effects. During the initial phase of treatment, relief from symptoms is often dramatic. Within 2 to 6 days, however, the symptoms often recur as the patient becomes tolerant to the sedative and akinetic effects of the drug. The dosage, which may vary from 6 to 180 mg daily, must be progressively increased to control the symptoms. Often, after the symptoms have been controlled for a variable duration, the dose of haloperidol may be decreased. The regimen should be slowly tapered until symptoms reappear. Occasionally, complete remissions occur, but no studies have proved that such an outcome was attributable to haloperidol treatment. By using this approach, a 90% reduction in symptoms is possible in most patients after 1 year. Before the availability of haloperidol, patients with Gilles de la Tourette's syndrome frequently were institutionalized. Recently, pimozide, a diphenylbutylpiperidine with some structural analogy to the butyrophenone haloperidol, has been approved for use in this disease. Huntington's chorea is manifested by progressively worsening dementia and choreiform movements. The involuntary movements may be caused by a relative excess of dopamine in the brain. Although the progress of this disease cannot be halted, the movement disorder can be diminished by using chlorpromazine (75 to 150 mg/ day orally), haloperidol (6 to 12 mg/day orally), or fluphenazine (2 to 15 mg/day orally). 34 No effective treatment is available for the dementia. Hemiballismus is characterized by unilateral flailing movements of an extremity and is caused by a vascular lesion of the contralateral subthalamic nucleus. This disorder frequently decreases spontaneously after 8

7 Mayo Clin Proc, November 1985, Vol 60 ANTIPSYCHOTIC AGENTS 783 weeks; thus, no treatment may be needed. The movements have reportedly lessened with use of perphenazine (4 mg orally three times daily) or haloperidol (2 mg orally daily). 35 Chorea associated with rheumatic fever is usually selflimiting and needs no intervention. In severe cases that are unresponsive to diazepam or other benzodiazepines, the movements can be diminished by using haloperidol (2 to 4 mg/day orally). 36 Treatment should be of limited duration and should be discontinued as soon as the chorea subsides. Patients with this disorder are young and must be closely monitored for extrapyramidal reactions, especially acute dystonia. Choreiform movements related to systemic lupus erythematosus can also be lessened by using haloperidol in daily doses up to 10 mg orally. 37 This movement disorder may remit if the underlying condition is controlled. Spasmodic torticollis is a limited dystonia that results in intermittent recurring contractions of the neck muscles. Gilbert 38 reported that haloperidol (2 to 12 mg/day) has successfully alleviated the symptoms. Meige's syndrome 39 is an idiopathic disorder that consists of blepharospasm and oromandibular dystonia; it seems to be due to excessive dopamine activity in the brain. 40 Haloperidol (1.5 to 15 mg/day orally) has been used to lessen the symptoms of this syndrome but will not induce a remission. 39 OTHER CONDITIONS Although anxiety caused by nonpsychotic disturbances has been treated with antipsychotic agents, we do not recommend use of these drugs for this condition because of the potential side effects especially tardive dyskinesia. 41 For short-term drug therapy for anxiety, benzodiazepines are safe and effective. If chemical dependency is an issue, hydroxyzine may be used. Any antipsychotic agent except thioridazine can be used for the treatment of nausea and vomiting. 18 In adults with nausea, prochlorperazine (15 to 120 mg/day orally or intramuscularly) is most widely used. Administration of this drug should be discontinued when the nausea resolves permanently. Many patients who receive antipsychotics for nausea, however, are debilitated or are receiving other medications, which can lead to complications and drug interactions. In such patients, antipsychotics should be used cautiously if at all. In the treatment of children with nausea, antipsychotics especially prochlorperazine should be avoided because of the high incidence of severe dystonic reactions in these patients. Painful peripheral diabetic neuropathies have been treated with a combination of a tricyclic antidepressant and a neuroleptic, usually amitriptyline (75 to 150 mg orally daily and fluphenazine 1 mg orally three times daily). 42 Intractable hiccup, caused by brainstem disorders, uremia, or extensive burns or of an idiopathic nature, have been eliminated by using haloperidol (5 mg orally three times daily). 43 Valproic acid also may be effective. 44 SIDE EFFECTS Most of the side effects associated with neuroleptics are caused by receptor antagonism (Table 1). Of the adverse reactions, those caused by dopamine D-2 receptor blockade and those of an idiosyncratic or dose-related nature will be emphasized in the following discussion. Early Onset. Acute Dyskinesia. Acute dyskinesias (dystonic reactions) are common early-onset side effects of neuroleptic treatment that can be life-threatening for the patient. This reaction is characterized by abrupt onset of torticollis, grimacing, labored breathing, and involuntary muscle movements. Patients with dyskinesias often act bizarrely and may be misdiagnosed as having seizures, tetanus, or hysteria. Subtypes of acute dyskinesias include laryngeal and pharyngeal dystonia, in which spasms of the larynx and pharynx cause gagging, cyanosis, respiratory distress, and asphyxia; respiratory dyskinesias with alarming and serious dyspnea; and oculogyric crisis with upward rotation or lateral deviation of the eyes associated with blepharospasm. The first two sub-types can be life-threatening, and the third type is often painful. About 12% of all patients treated with neuroleptics have a dystonic reaction. Men are affected twice as often as are women, and these side effects occur most commonly in patients who are 5 to 45 years old. Most cases of acute dyskinesia develop within the first 4 days after onset of drug therapy. The reaction is most frequently associated with drugs that have high D-2 antagonism and low antimuscarinic activity. If acute dyskinesia develops, the drug regimen can be changed to chlorpromazine, mesoridazine, or thioridazine (Table 3). Features that support a diagnosis of acute dyskinesia include recent ingestion of an antipsychotic agent, repeated spasms with hypertonicity between attacks, relatively painless spasms, and rapid reversal of the condition after administration of anticholinergic agents. 45,46 Intravenous or intramuscular administration of benztropine, biperiden, or diphenhydramine produces rapid reversal of these syndromes. Diazepam has also been successfully used to treat these side effects. 45,47 With time, through a process of tolerance, the dystonic reactions become less frequent. Therefore, patients with dystonic reactions may not need indefinite treatment with antimuscarinic agents.

8 784 ANTIPSYCHOTIC ACENTS Mayo Clin Proc, November 1985, Vol 60 Parkinsonism. Neuroleptic-induced parkinsonian treatment. 45 The high-potency antipsychotic agents are symptoms are early-onset side effects that occur in about most likely to cause akathisias. Patients in whom akathisia develops may benefit from a change to chlorproma- 13% of all patients who take these drugs. Drug-induced parkinsonism is common in patients of all ages and zine, loxapine, mesoridazine, or thioridazine therapy affects women twice as often as it affects men. Most cases develop within the first 72 days after institution of antipsychotic (Table 3). Although akathisia sometimes responds to antiparkinsonian agents, many of these patients are unre therapy. 45 This side effect is apparently caused sponsive. Lipinski and associates 50 recently described by blockade of nigrostriatal postsynaptic D-2 receptors. the use of propranolol (10 mg three times daily) to control The incidence is highest among patients who are receiving akathisia. Reducing the dose of the neuroleptic or giving high-potency neuroleptics with low antimuscarinic a small dose of a short-acting barbiturate or diazepam has activity in high doses intramuscularly. Antimuscarinic agents such as benztropine, biperiden, diphenhydramine, and trihexyphenidyl are effective in combating this drug-induced parkinsonism. Recently, amantadine, also been effective in controlling this side effect. 45 As in drug-induced parkinsonism and acute dyskinesias, tolerance to this side effect may occur, and the dose of the drug used to control the akathisia may be tapered. which increases receptor levels of dopamine, has frequently Variable Onset. Neuroleptic Malignant Syn been used because it produces fewer side effects drome. The neuroleptic malignant syndrome is a life- than the antimuscarinic agents. 48 In a controlled study, threatening side effect of antipsychotic therapy. The syndrome is characterized by hyperpyrexia (up to 42 C), however, amantadine had a slower onset of action and may not have been as effective in controlling rigidity as altered consciousness, muscular rigidity, perspiration, benztropine. 49 Because parkinsonian symptoms do not hypotension or hypertension, and laboratory abnormalities develop in all patients on antipsychotic therapy, concomitant prophylactic use of an antiparkinsonian drug is including leukocytosis, myoglobinuria, elevated se rum creatine kinase, serum transaminases, lactic dehydrogenase, and alkaline phosphatase The mortality unnecessary. In addition, some patients who do have this side effect require decreased doses of antiparkinsonian rate ranges from 12 to 20%; death is usually due to drug with time. respiratory, renal, or cardiovascular complications. 52 The disorder can occur anytime during neuroleptic treatment and with use of any neuroleptic agent, although high-potency neuroleptics and especially haloperidol are the most commonly associated agents. Patients with this side effect frequently are examined by internists or emergency room physicians. Rapid diagnosis and effective intervention should reduce the morbidity and mortality associated with this side effect. Persistent drug-induced parkinsonism can be a lateonset side effect of antipsychotic drug use as well. Normally, drug-induced parkinsonism clears 10 to 60 days after use of the drug has been discontinued. Some reports, however, have described patients with parkinsonism that failed to clear years after discontinuation of neuroleptic therapy. 45 In such cases, determining whether idiopathic parkinsonism has developed or whether this disorder is a side effect of antipsychotic therapy has been impossible. Akathisia. Akathisia is a condition of motor restlessness that occurs early during treatment with neuroleptics or after an increase in the dose of the drug. Patients complain of feeling jittery, are literally unable to sit or stand still, and have a subjective feeling of inner tension. The disorder may resemble anxiety. Psychotic patients who complain of restlessness that was not present before neuroleptic therapy and who have psychotic symptoms that fail to remit may actually have akathisia. When the akathisia is controlled, the psychotic symptoms may be reduced. Patients with akathisia are often misdiagnosed as having agitation related to their psychosis and are given higher doses of neuroleptics, which worsen their restlessness. Akathisia develops in about 20% of all patients who receive neuroleptics, and women are affected twice as frequently as men. Patients of any age can be affected. Most cases occur within the first 73 days of Dantrolene sodium, a drug used in the treatment of malignant hyperthermia, has reportedly been effective in the neuroleptic malignant syndrome. 53,54 Bromocriptine, a dopamine agonist, has also produced excellent results in doses ranging from 7.5 to 60 mg daily. 55 Although antimuscarinics, amantadine, levodopa, and carbidopa have been used to treat the neuroleptic malignant syndrome, little convincing evidence supports their efficacy. 55 The use of anticholinergics should be discouraged because they interfere with perspiration and may worsen the hyperthermia. Hyperprolactinemia. Neuroleptics notably elevate prolactin levels and thereby can produce breast tissue hypertrophy and, occasionally, lactation.' 3 Hyperprolactinemia can also cause amenorrhea. After testing the patient for pregnancy, these conditions should be treated by decreasing or discontinuing use of the drug or changing the regimen to an agent with lower dopamine D-2 antagonism, such as chlorpromazine, loxapine, meso-

9 Mayo Clin Proc, November 1985, Vol 60 ANTIPSYCHOTIC AGENTS 785 ridazine, molindone, or thioridazine (Table 3). Late Onset. Late-onset side effects of neuroleptics are usually not life-threatening conditions but may be unremitting and disfiguring. These disorders occur after long-term administration (usually more than 3 months) of antipsychotics. 45,56 Although these syndromes can begin during neuroleptic therapy, they more frequently ensue after the dose has been reduced or the therapy has been discontinued. Tardive Dyskinesia. Tardive dyskinesia is a hyperkinetic movement disorder that consists of choreiform movements of the mouth, tongue, and lips. The patient may have associated choreiform movements of the limbs and trunk. The symptoms fluctuate in severity with time, become transiently worse during episodes of anxiety, and disappear during sleep. Recent studies indicate that tardive dyskinesia develops in 27 to 35% of patients who receive long-term treatment with neuroleptics. 57 All antipsychotics can cause this disorder, and the frequency of occurrence is similar no matter which neuroleptic agent is used. In a recent 2-year follow-up study of patients with tardive dyskinesia, 66% showed no change, 16% worsened, and 18% improved. 58 Medication variables, however, made this study difficult to interpret. Although the symptoms frequently are not distressing to the patient, before treatment both the patient and the family should be informed about the possibility of development of severe forms of the disorder that may be disfiguring. Patients with affective disturbances who received neuroleptics seem to be at increased risk for the development of tardive dyskinesia. 59 The incidence of this disorder is highest among female patients who are older than 50 years of age. The pathogenesis of tardive dyskinesia is unclear. One speculation is that when dopamine receptors of the nigrostriatal system are chronically antagonized by antipsychotic drugs, asupersensitivity and proliferation of dopamine receptors occur. This outcome may lead to a relative overactivity of the nigrostriatal dopaminergic system, which may result in the symptoms of tardive dyskinesia. Currently, no definitely effective treatment for tardive dyskinesia is available. Antimuscarinic agents worsen the symptoms. Cholinergic agents such as deanol 60 and physostigmine 61 have not been consistently effective. Increasing the dose of the offending neuroleptic effectively diminishes the dyskinesia but further worsens the underlying disorder of receptor dysfunction. Agonists of γ-aminobutyric acid such as baclofen, sodium valproate, and benzodiazepines may be of some benefit, but these drugs should be studied further. Levodopa and dopamine agonists such as apomorphine may be beneficial only after transient worsening of symptoms. 62 Bromocriptine is currently being studied in several medical centers. Lithium may be effective in the treatment of tardive dyskinesia in depressed patients. 63 Tetrabenazine (not currently available in the United States), a drug that has pharmacologic properties similar to those of reserpine and depletes stores of dopamine, has also been described as useful but may induce episodes of depression. 64 Clearly, the best approach to this problem is prevention. Neuroleptics should be used only when absolutely indicated; when they are indicated, they should be used in the lowest effective dose, and treatment should be discontinued as soon as possible. Recent studies indicate, however, that in chronic psychiatric conditions that necessitate long-term treatment, continuous use of a neuroleptic may be preferred to intermittent treatment. In this situation, discontinuation of antipsychotic therapy may precipitate a relapse, which ultimately results in exposure of the patient to higher doses of the neuroleptic and in an increased risk of developing tardive dyskinesia. 21 Tardive Dystonia. Tardive dystonia is characterized by sustained or slow involuntary twisting movements that affect the limbs, trunk, neck, or face. This condition is related to tardive dyskinesia and may coexist with it. The disorder can be focal, segmental, or generalized. Burke and associates 65 reported that patients with this disorder range in age from 5 to 89 years (mean, 34 years). In that study, the mean duration of exposure to neuroleptics before development of this side effect was 3.7 years. A third of the patients had abnormalities at birth or during development. Whether this side effect occurs with all neuroleptics, as in tardive dyskinesia, is unknown. Increased doses of a neuroleptic will diminish the tardive dystonia but probably will eventually intensify the underlying disorder. In a report by Burke and associates, 65 improvement was noted in 68% of patients who were given tetrabenazine (presently unavailable in the United States) and in 39% of patients who received anticholinergics. Rabbit Syndrome. The rabbit syndrome is a focal, perioral tremor, similar to perioral tremors occasionally seen in patients with Parkinson's disease. This syndrome may occur late during treatment with antipsychotic agents 66 and, unlike tardive dyskinesia, responds well to antiparkinsonian agents. Idiosyncratic or Dose-Related. Agranulocytosis. Agranulocytosis is the most severe idiosyncratic side effect associated with the use of neuroleptics. 67 It may occur during use of any phenothiazine and usually is noted within the first 8 weeks of treatment. The mortality rate among affected patients is about 30%. The incidence of this side effect is very low, and no accurate data are available. 16 If fever and sore throat develop in patients

10 786 ANTIPSYCHOTIC AGENTS Mayo Clin Proc, November 1985, Vol 60 who are taking phenothiazines, a complete blood count should be done. If Ieukopenia is revealed, the patient should be hospitalized, appropriate cultures should be studied, and vigorous treatment with antibiotics should be initiated if indicated. Use of the offending drug should be discontinued and phenothiazines should be avoided, but other classes of antipsychotic agents can be tried cautiously. Cholestatic Jaundice. Cholestatic jaundice occurs in about 1 in 10,000 patients treated with chlorpromazine and can occur as well in patients treated with fluphenazine, prochlorperazine, thioridazine, or triflupromazine. Jaundice occurs 1 to 5 weeks after initiation of phenothiazine therapy and is preceded (for 1 to 7 days) by malaise, abdominal pain, fever, nausea, vomiting, and diarrhea. Treatment consists of discontinuation of use of the drug. 68 Ophthalmologic Changes. After long-term, highdose chlorpromazine treatment (1- to 3-kg lifetime accumulation), eye changes, including white-brown, granular deposits in the anterior lens and posterior cornea, can occur. These opacities, which do not impair vision, are seen most frequently in patients who also have bluegray metallic discoloration of the skin that is associated with high-dose chlorpromazine. Thiothixene has also been found to cause these skin and eye changes. 17,69 Thioridazine in doses that exceed 800 mg/day has been associated with visual impairment produced by a retinitis pigmentosa-like syndrome. After use of the drug has been discontinued, the condition of mildly affected patients may remit. A progressive retinopathy, however, may develop in these patients. 70 This side effect has rarely been reported when the dose of thioridazine has been less than 800 mg/day. 17 Allergic and Cutaneous Conditions. Allergic dermatitis and contact dermatitis are most frequently associated with use of low-potency phenothiazines. In an estimated 3% of patients, photosensitivity develops during treatment with chlorpromazine. Other phenothiazines may also cause photosensitivity. 17,69 Effects on the Fetus. The effects of neuroleptics on the fetus are unknown. Antipsychotics have not been proved to cause birth defects, but recent data suggest the possibility of a slightly increased risk of occurrence of birth defects when the fetus is exposed to these drugs during the first trimester. 71,72 In addition, studies have suggested that use of these drugs in pregnant women may be associated with the risk of producing behavior disorders in infants and children. 73 The dilemma in managing pregnant psychotic women arises from the fact that these patients suffer emotional turmoil and increased fetal loss if left untreated. In such cases, what is best for the mother must be weighed against what is best for the child. Certainly, it is preferable to avoid exposure of the fetus to drugs during the critical first trimester. If electroconvulsive therapy is available, it should be considered in the treatment of pregnant psychotic women because it provides an alternative to neuroleptic management in some 74 cases. DRUG INTERACTIONS Pharmacodynamic. The combination of a neuroleptic and any depressant produces at least an additive depressant effect. Thus, care should be exercised when antipsychotic agents are taken in conjunction with sedatives, hypnotics, antihistamines, opiates, or alcohol, particularly in patients with compromised respiratory function. Even though neuroleptics are not respiratory depressants, they can increase the respiratory depression caused by other drugs. When neuroleptics are used with any other antimuscarinic agent such as tricyclic antidepressants or antiparkinsonian drugs, the combination can have a powerful anticholinergic effect. All neuroleptics are weak blockers of a 2 -adrenergic receptors. They should not interfere with clonidine, guanabenz, or a-methyldopa in the treatment of hypertension. Chlorpromazine, loxapine, mesoridazine, and thioridazine have the strongest affinity for c^ -receptors and may potentiate the antihypertensive effects of prazosin and monoamine oxidase inhibitors. Some neuroleptics may reduce the efficacy of guanethidine by interfering with its uptake into the presynaptic neuron. When epinephrine is given to a patient who is receiving a neuroleptic, severe hypotension may ensue. 75 This outcome is caused by ατ-adrenergic blockade by the neuroleptic, which allows unopposed ß-adrenergic stimulation by the epinephrine. Lithium, when given in combination with a neuroleptic and particularly haloperidol, has very rarely caused irreversible neurotoxicity with a clinical picture similar to that of the neuroleptic malignant syndrome. Most reported cases have been associated with the use of high therapeutic doses of lithium and high doses of a neuroleptic, but apparently this adverse effect can occur even if serum levels of lithium are in the therapeutic range. 76,77 The use of midtherapeutic serum levels of lithium and low to intermediate doses of a neuroleptic is the best prevention for this drug interaction. The combination of lithium and a neuroleptic may worsen druginduced parkinsonism, but the reason for this result is unknown at this time. Pharmacokinetic. Antacids diminish the absorption of antipsychotics from the gut. Any agent that slows the absorption of an antipsychotic, including long-acting

11 Mayo Clin Proc, November 1985, Vol 60 ANTIPSYCHOTIC AGENTS 787 pharmaceutical preparations, decreases the bioavailability ofthe drug. Cimetidine may decrease antipsychotic bioavailability by reducing gastric acidity. 78 Neuroleptics may decrease blood levels of warfarin sodium, presumably by increasing the action of hepatic enzymes. Neuroleptics and tricyclic antidepressants decrease the metabolism of each other; thus, plasma concentrations of each of these drugs are increased when they are used in combination. Neuroleptics, especially thioridazine, may prevent metabolism of phenytoin and thereby cause toxic blood levels of this anticonvulsant. 79 Smoking may decrease blood levels of antipsychotic agents by increasing the activity of drug-metabolizing enzymes. When trifluoperazine or chlorpromazine is given to patients who are receiving propranolol, blood levels of both drugs may increase. 75 TREATMENT OF OVERDOSES Because antipsychotic drugs have a wide therapeutic range, overdoses are usually nonlethal. Most deaths due to an overdose of a drug in the phenothiazine class occur in children. The exceptions are thioridazine and mesoridazine, which can cause fatal cardiac arrhythmias. 11 After ingestion of an overdose, patients become drowsy and may become comatose. They may be agitated or delirious. Physical signs include twitching, dystonic movements, convulsions, miotic pupils, diminished deep tendon reflexes, tachycardia, hypotension, hypothermia, or hyperthermia. Cardiotoxicity from thioridazine may cause supraventricular tachycardia, heart block, refractory ventricular tachycardia, and prolongation of the Q-T interval, which can be observed on electrocardiographic recordings. 11 Torsades de pointes, a type of ventricular tachycardia-fibrillation that may be caused by thioridazine, may respond to infusion of isoproterenol or atrial or ventricular pacing. 80 Up to several hours after ingestion of an overdose of a neuroleptic, gastric lavage should be attempted because these drugs slow gastric motility. Activated charcoal should be given next, followed by cathartics. General supportive measures, such as those used in any overdose situation, should be implemented. Convulsions are treated with intravenously administered diazepam or phenytoin, but the patient must be carefully observed for respiratory depression. Heating blankets may be used for hypothermia. Appropriate cultures should be prepared in febrile patients, and a chest roentgenogram should be obtained if aspiration pneumonitis is suspected. Antibiotics should be withheld unless available evidence indicates an infectious cause. The treatment of hypotension may be difficult. Epinephrine may cause hypotension when given in conjunction with neuroleptics. 75 Intravenous fluids may not produce a sufficient increase in blood pressure, and patients with cardiac complications may not tolerate administration of intravenous fluids. Dopamine is frequently used in patients who are suffering from shock, but the peripheral action of this drug is probably mediated by D-1 or D-2 receptors, which are blocked by neuroleptics. 81 At the present time, neuroleptic overdoses in patients with severe hypotension should be treated empirically. CONCLUSIONS Antipsychotic agents have revolutionized the treatment of psychosis but are also used to treat many nonpsychiatric conditions. 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12 788 ANTIPSYCHOTIC AGENTS Mayo Clin Proc, November 1985, Vol Schyve PM, Smithiine F, Meltzer HY: Neuroleptic-induced prolactin level elevation and breast cancer: an emerging clinical issue. Arch Gen Psychiatry 35: , Miller RJ, Hiley CR: Anti-muscarinic properties of neuroleptics and drug-induced parkinsonism. Nature 248: , Mendez MF, Cummings JL, Benson DF: Epilepsy: psychiatric aspects and use of psychotropics. Psychosomatics 25: , Davis J, Janicak P, Linden R, Moloney J, Pavkovic I: Neuroleptics and psychotic disorders. In Neuroleptics: Neurochemical, Behavioral and Clinical Perspectives. Edited by JT Coyle, SJ Enna. New York, Raven Press, 1983, pp Hollister LE: Clinical Pharmacology of Psychotherapeutic Drugs. Second edition. New York, Churchill Livingstone, 1983, pp Byck R: Drugs and the treatment of psychiatric disorders. In The Pharmacological Basis of Therapeutics. Fifth edition. Edited by LS Goodman, A Gilman. 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13 Mayo Clin Proc, November 1985, Vol 60 ANTIPSYCHOTIC AGENTS Tarsy D, Leopold N, Sax DS: Physostigmine in choreiform 71. movement disorders. Neurology (Minneap) 24:28-33, Smith RC, Tamminga CA, Haraszti J, Pandey GN, Davis JM: Effects of dopamine agonists in tardive dyskinesia. Am J Psychiatry 134: , Rosenbaum AH, Maruta T, Duane DD, Auger RG, Martin DK, Brenengen EE: Tardive dyskinesia in depressed patients: success- 73. ful therapy with antidepressants and lithium. Psychosomatics 21: , Asher SW, Aminoff M): Tetrabenazine and movement disorders. Neurology (NY) 31: , Burke RE, Fahn S, Jankovic J, Marsden CD, Lang AE, Gollomp S, llson ): Tardive dystonia: late-onset and persistent dystonia 76. caused by antipsychotic drugs. Neurology (NY) 32: , Tarsy D: Neuroleptic-induced extrapyramidal reactions: classification, description, and diagnosis. Clin Neuropharmacol 6 Suppl 78 1:S9-S26, Shaw RK, Raitt JW, Glazener FS: Agranulocytosis associated with thioridazine administration. JAMA 187: , Hollister LE: Allergic reactions to tranquilizing drugs. Ann Intern 7g Med 49:17-29, Hollister LE: Complications from psychotherapeutic drugs Clin Pharmacol Ther 5: , Miller FS III, Bunt-Milam AH, Kalina RE: Clinical-ultrastructural study of thioridazine retinopathy. Ophthalmology 81 89: , 1982 Goldberg HL, DiMascio A: Psychotropic drugs in pregnancy. In Psychopharmacology: A Generation of Progress. Edited by MA Lipton, A DiMascio, KF Killam. New York, Raven Press, 1978, pp Edlund MJ, Craig TJ: Antipsychotic drug use and birth defects: an epidemiologic reassessment. Compr Psychiatry 25:32-37, 1984 Galenberg AJ: Psychotropic drugs and the fetus. Biol Ther Psychiatry 7:13-14, 1984 Nürnberg HG, Prudic J: Guidelines for treatment of psychosis during pregnancy. Hosp Community Psychiatry 35:67-71, 1984 Gaultieri CT, Powell SF: Psychoactive drug interactions. J Clin Psychiatry 39: , 1978 Cohen WJ, Cohen NH: Lithium carbonate, haloperidol, and irreversible brain damage. JAMA 230: , 1974 Spring G, Frankel M: New data on lithium and haloperidol incompatibility. Am J Psychiatry 138: , 1981 Howes CA, Pullar T, Sourindhrin I, Mistra PC, Capel H, Lawson DH, Tilstone WJ: Reduced steady-state plasma concentrations of chlorpromazine and indomethacin in patients receiving cimetidine. Eur J Clin Pharmacol 24:99-102, 1983 Vincent FM: Phenothiazine-induced phenytoin intoxication. Ann Intern Med 93:56-57, 1980 Kemper AJ, Dunlap R, Pietro DA: Thioridazine-induced torsade de pointes: successful therapy with isoproterenol. JAMA 249: , 1983 Schmidt M, Imbs JL, Giesen EM, Schwartz J: Blockade of dopamine receptors in the renal vasculature by isomers of flupenthixol and sulpiride. J Cardiovasc Pharmacol 5:86-89, 1983 Aleksei Nikolaevich Bach: Soviet Chemist and Politician Robert A. Kyle, M.D., and Marc A. Shampo, Ph.D. Aleksei Nikolaevich Bach was born in Zolotonosha, Ukraine, Russia, on Mar. 17,1857. He studied chemistry at Kiev University but was expelled and exiled for 3 years because of his political activities. When he returned to Russia, he continued the political struggle and published one of the first statements of Marxist economic theory in Russian, an accomplishment that resulted in his move to France in At the College de France, he studied the assimilation of carbon by plants. In 1891, he traveled to the United States to introduce into Chicago's distilleries an improved method of fermentation. In 1894, Bach moved to Geneva, Switzerland, and began the studies on oxidation that constitute his major contribution to science. He concluded that oxygen formed during photosynthesis was the oxygen derived from water and not from carbonic acid. Bach extended the peroxide theory to processes of biologic oxidation and thus stimulated Otto Warburg's search for the enzymes responsible for oxidation. Bach also conducted fundamental investigations in industrial biochemistry, which resulted in improved methods for baking bread and for drying and preserving grain and flour. In addition, he contributed to new techniques for processing tea, wine, and tobacco. Bach returned to Russia after the revolution in Resuming political activities, he served as a member of the Central Executive Committee. He was a prominent figure in chemical research in the Soviet Union and was awarded the Lenin Prize. Bach died in Moscow on May 13, Russia honored him on a stamp issued in 1957, the centennial of his birth.