Introducing the first step-by-step rehabilitation program for the PVD patient Major Side Effects of Antipsychotic Drugs

K. D. Charalampous, MD and G. A. Keepers, MD Houston, Texas

Since the introduction of phenothiazines into clinical practice in 1952, over 250 million people have received these drugs for the treatment of psychotic states. In addition to the phenothiazines, five other classes of neuroleptic medications are now in use: butyrophenones, thioxanthenes, dihydroin- dolones, diphenylbutylpiperidines, and dibenzoxazepines. Besides their use in the treatment of psychosis, these drugs have been used in the treatment of anxiety, depression, nausea, alcoholic withdrawal, and pain, and are often adminis­ tered in combination with other medications. Through the use of these drugs, many psychotic patients have been able to move back into the community, and the family physician is coming into contact with more patients on maintenance dos­ ages of neuroleptics. He/she may wish to prescribe these drugs or may, in the treatment of a medical problem, need to pre­ scribe other medication to an individual already receiving neuroleptics. It is important, therefore, for the family physi­ cian to be aware of the side effects of these drugs and of complications which can arise when neuroleptics are given in combination with other families of drugs.

The actions of neuroleptic agents are amazingly system and the autonomic nervous system. There ubiquitous and involve every organ system. Cen­ are a host of other actions including antiemetic, trally, they are dopamine-blocking agents, affect­ antihistaminic, and antipyretic. The antipsychot- ing neural transmission from the cortex to the ics, nevertheless, have a high therapeutic index brain stem and even hypothalamic control of and are remarkably safe agents. Death from pituitary function. Peripherally, they are both po­ an overdose is a rare event. Most known side ef­ tent alpha adrenergic-blocking agents and an­ fects are extensions of the pharmacological ac­ ticholinergic agents affecting the cardiovascular tions of these drugs, the most important being those on the central nervous system, endocrine system, and cardiovascular system. In addition, there are a few toxic and idiosyncratic effects un­ related to the antipsychotic actions or to the in­ teractions resulting from their concomitant pre­ From the Department of Psychiatry, Baylor College of Medicine, Houston, Texas. Requests for reprints should be scription with other medications. This article ex­ addressed to Dr. K. D. Charalampous, Department of Psy­ plores the major side effects of these drugs (Table chiatry, Texas Tech University School of Medicine, P.O. Box 4569, Lubbock, TX 79409. 1) and their interactions with other medications

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(Table 2) beginning with the central nervous sys­ are acute, and one—tardive dyskinesia—is tem. chronic. Haloperidol and the piperazine deriva­ tives of phenothiazines seem to produce the acute syndromes more frequently than other anti­ psychotics, while the dibenzoxazepines and thioxanthenes have the lowest incidence of these side effects. Severe extrapyramidal side effects Central Nervous System Effects sometimes delayed by several days, can also occur after depot phenothiazines; however, patients The totality of actions of the antipsychotic maintained on fluphenazine decanoate develop drugs within the central nervous system is not fewer extrapyramidal side effects than those on yet thoroughly understood. The antipsychotics fluphenazine enanthate. appear to affect all neurotransmitters but particu­ Parkinsonism is probably due to a functional larly influence levels of dopamine and norepineph­ dopamine deficiency. It may be indistinguishable rine. By blocking central dopaminergic trans­ from idiopathic parkinsonism. The most notice­ mission, secondary extrapyramidal side effects are able signs are tremor at rest and rigidity; “pill roll­ produced. Dopamine, norepinephrine, and other ing” movements are common; and there is a gen­ neurotransmitters are also implicated in the elec- eralized slowing of volitional movements and a troencephalographic (EEG) and psychobehavioral mask-like facies. The syndrome responds to re­ changes, but the mechanisms are less well under­ duction of dosage, to anticholinergic agents, and stood. according to a recent report, to amantadine.2 All phenothiazines other than promazine and The second acute type, akathisia, is not a spe­ prochlorperazine lower the seizure threshold. cific movement or symptom; it refers rather to an Haloperidol also lowers the seizure threshold and inability of the patient to remain quiescent. The its effects on the EEG are similar to those of the patient feels a compelling need to move, which he phenothiazines. These agents produce slowing of may find impossible to control, and this movement the EEG and increased occurrence of theta waves. may be mistaken for psychological agitation. The The variability of frequencies decreases, while cause of akathisia is not known. It has been shown voltage and burst activity increase. The piperazine that previous hyperthyroidism or hyper­ phenothiazines differ slightly in that they produce parathyroidism increases the risk of acquiring the increased alpha wave activity as well. disorder. Akathisia responds less frequently to In nonpsychotic individuals, the antipsychotics anticholinergics than other extrapyramidal side ef­ may impair vigilance on various psychomotor fects do; its treatment, therefore, may require re­ tests, may interfere with complex intellectual duction in antipsychotic dosage and the use of functions, and may reduce spontaneous motor ac­ diazepam. tivity. In psychotic patients, neuroleptic medica­ The third acute syndrome, dystonia, is a com­ tions produce psychomotor slowing, emotional mon side effect that may occur early during anti­ quieting, and affective indifference, termed the psychotic treatment. It is most often seen in chil­ neuroleptic activity by Delay and Deniker.1 Addi­ dren and young adults. Torticollis and facial tionally, many neuroleptics produce sedation, al­ grimacing are present and may be accompanied by though there is no correlation between the seda­ oculogyric crises. Dystonia is thought to be due to tive property and therapeutic effectiveness of the transient dopaminergic hyperactivity and is occa­ antipsychotic drugs. The sedative effect may be sionally mistaken for hysteria or seizures, but can useful in the treatment of anxious or agitated pa­ be readily differentiated from them by its response tients. Tolerance develops rapidly to the sedative to anticholinergic agents. The dystonia is self­ effects of these medications but not to the limited and will generally abate without treatment. neuroleptic effects. Mild withdrawal symptoms Severe symptoms may be treated with in­ can occur. tramuscular anticholinergics (eg, benztropine 1 to The administration of antipsychotic drugs may 2 mg), intravenous caffeine sodium benzoate (500 induce several neurological syndromes of which mg), or intramuscular diphenhydramine (50 mg). three—parkinsonism, akathisia, and dystonia— While clinical management for these three acute

994 THE JOURNAL OF FAMILY PRACTICE, VOL. 6, NO. 5, 1978 ANTIPSYCHOTIC DRUGS

Table 1. Common Side Effects of Antipsychotic Drugs

Organ System Drug Family Side Effects

Autonomic All antipsychotics anticholinergic: dry mouth blurring of vision urinary retention constipation Phenothiazines perspiration

Neurologic Phenothiazines lowered seizure threshold Butyrophenones All antipsychotics extrapyramidal reactions: parkinsonism akathisia dystonia

All antipsychotics tardive dyskinesia

Endocrinous All antipsychotics hypothalamic susceptibility to hyperpyrexia and hypopyrexia appetite increase

All antipsychotics galactorrhea All antipsychotics amenorrhea or dysmenorrhea

Cardiovascular Phenothiazines ECG changes Phenothiazines arrhythmias Phenothiazines hypotension Phenothiazines cardiomyopathy

Dermatologic All antipsychotics skin rash Phenothiazines photosensitivity

y Phenothiazines pigmentation

Ocular Phenothiazines lens pigmentation Phenothiazines pigmentary retinopathy

Hematologic All antipsychotics leukopenia and agranulocytosis

Hepatic phenothiazines obstructive jaundice

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Table 2. Antipsychotic Drug Interactions

Antipsychotic Drug Other Medication Interaction

Phenothiazines Antiparkinsonian drugs Interference with antipsychotic efficacy Butyrophenones Thioxanthenes Increased risk of tardive dyskinesia Phenothiazines Anticholinergics Additive anticholinergic effects Butyrophenones Tricyclic antidepressants Aggravation of tardive dyskinesia Thioxanthenes

Phenothiazines Estrogens Increased plasma levels of antipsychotic drugs Butyrophenones Thioxanthenes Increased risk of extrapyramidal reactions Phenothiazines Barbiturates Reduced plasma levels of antipsychotic drugs Lithium

Phenothiazines Antihypertensives Additive hypotensive effect Butyrophenones Thioxanthenes

Chlorpromazine Guanethidine and false transmitter antihypertensives Rise in blood pressure Phenothiazines Sympathomimetics Pressor effect inhibited Butyrophenones Thioxanthenes

Phenothiazines Norepinephrine Retains hypertensive effect Butyrophenones Thioxanthenes

Phenothiazines CNS Depressants Additive CNS depression Butyrophenones Thioxanthenes

Chlorpromazine Anticoagulants Potentiate anticoagulant activity

996 THE JOURNAL OF FAMILY PRACTICE, VOL. 6, NO. 5, 1978 ANTIPSYCHOTIC DRUGS conditions has been mentioned, the ideal treat­ In view of the undesirable properties of an­ ment for extrapyramidal symptoms is still uncer­ tiparkinsonian drugs, the recent studies of aman­ tain. In the past, antiparkinsonian agents were tadine are encouraging. Amantadine is a putative often coadministered with neuroleptics in an effort dopaminergic compound which has proven effec­ to prevent neurological side effects. Patients were tive in the treatment of idiopathic parkinsonism. It often maintained on these regimens for years. It is does not have any appreciable anticholinergic ac­ important to note, therefore, that numerous re­ tivity. Controlled studies found amantadine to be ports indicate only a minority of patients develop a comparable to standard antiparkinsonian agents recurrence of symptoms when the antiparkin­ (benztropine and trihexyphenidyl) but with fewer sonian agent is stopped. The relapse rate has var­ side effects.1,9 ied among studies: one reported a 10 percent In contrast to the acute syndromes of parkin­ rate,3 whereas, another reported a 27 percent sonism, akathisia, and dystonia, tardive dys­ rate.4 A recent study by McClelland and col­ kinesia is a late occurring neurological syndrome leagues in Britain5 of 100 inpatients found an ex­ which is associated with chronic administration of tremely low incidence (four percent) of the re­ phenothiazines. It is characterized by rhythmical currence severe enough to require reinstitution of involuntary administration of the tongue, face, antiparkinsonian agents. Other studies found no mouth, and jaw, sometimes accompanied by need for the chronic use of antiparkinsonian choreoathetoid movements of the extremities. The agents, even with depot phenothiazines.6 syndrome occurs more frequently in the elderly Furthermore, the antiparkinsonian agents are and in those with prior neurological deficit. Risk not benign. Undesirable anticholinergic effects are has been related to total intake of neuroleptics. relatively common and may combine with those Symptoms may be masked by increased dosage of caused by the phenothiazines to give a significant neuroleptics; after discontinuation of the incidence of blurred vision, gastric irritability, neuroleptic, however, symptoms may persist in­ dizziness, and lethargy. A toxic psychosis, a var­ definitely or even worsen. Antiparkinsonian iant of the “central anticholinergic syndrome,” agents worsen tardive dyskinesia and may in­ may result; and the antiparkinsonian agents may crease the incidence of this disorder when given interfere with the actions of the neuroleptics. concurrently with neuroleptics. Studies in 19727 showed that benztropine may re­ The production of tardive dyskinesia is related verse some of the therapeutic effects of to the activity of dopamine at certain striatal re­ haloperidol. Subsequent experiments have dem­ ceptor sites. By analogy with L-dopa-induced onstrated that trihexyphenidyl reduces the plasma dyskinesia and with Huntington chorea, it appears levels of chlorpromazine.8 that tardive dyskinesia may be produced by in­ The routine prescription of antiparkinsonian creased responsiveness of dopamine receptor sites agents with antipsychotic drugs is, therefore, to be as a result of neuroleptic-induced denervation avoided. Extrapyramidal side effects should be hypersensitivity. treated only when they are of clinical significance. Numerous pharmacological treatments of this The initial treatment approach consists of decreas­ condition have been attempted. The medications ing the dose of the offending neuroleptic drug, or tested include reserpine, tetrabenazine, pimozide, prescribing an alternate neuroleptic. These ap­ haloperidol, thiopropazate, perphenazine, lithium, proaches may not be practical in patients with un­ methyldopa, alpha methyl paratyrosine, aman­ controllable psychotic symptoms. The use of an tadine, papaverine, physostigmine, deanol, antiparkinsonian agent may then be unavoidable. pyridoxine, tryptophan, and 5-hydroxy- It should be remembered, however, that such tryptophan. No single drug has emerged as the treatment may increase the patient’s discomfort as agent of choice. Most clinicians, therefore, rec­ well as decrease the effectiveness of his anti­ ommend that patients on long-term anti­ psychotic management. Since there is a diminution psychotic therapy be carefully and frequently of extrapyramidal side effects after the first three examined so that this disorder can be detected as months of treatment, withdrawal of antiparkinson­ early as possible. Drug holidays may reduce the ian medication should be attempted after this risk of this disorder and may also reveal dys­ period. kinesia at an earlier stage. When the dyskinesia is

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first recognized, the antipsychotic drug should be neuroleptics due to interference with the pituitary discontinued. If further pharmacological manage­ regulatory sex hormones. ment is required for psychotic behavior, a change to a drug with few extrapyramidal side effects should be considered. This approach will lead to the resolution of symptoms in at least some cases. If this approach is unsuccessful, it might then be appropriate to challenge patients with different categories of drugs including cholinomimetic Cardiovascular Effects drugs and dopamine-blocking agents. The results Effects on the cardiovascular system have been from such a therapeutic regimen could then be reported with all antipsychotics though more fre­ used to plan a longer, more extensive course of quently with the phenothiazines. Complex, in­ therapy. completely understood effects are produced through direct actions on the heart and blood ves­ sels and through responses mediated by au­ tonomic reflexes and the central nervous system. The most important mechanisms of action are alpha adrenergic blockade and a direct depressant action on the myocardium. Prolonged ventricular repolarization is observed frequently in patients Endocrinous and Metabolic Effects receiving high doses of thioridazine. Fasting and Most antipsychotic medications have metabolic potassium administration reverse this change or endocrinous effects. Chlorpromazine’s actions while oral glucose load exacerbates it. Prolonged have been the most thoroughly explored, but it is repolarization can lead to reentry arrhythmias, a presumed that other antipsychotics produce simi­ cause of sudden death in treated patients. Re­ lar effects. The alterations in endocrine function ported clinical effects of the antipsychotics on the are mediated through the drug’s action on the cardiovascular system include acute hypotension, hypothalamus. ECG changes, arrhythmia, infarction, car­ Miscellaneous and complex side effects are diomyopathy, and cardiac failure. These effects produced by the actions of antipsychotic drugs on are dose dependent, more frequent with the al­ the hypothalamus. These agents may affect iphatic phenothiazine derivatives, more likely to hypothalamically controlled temperature regula­ occur with chronic administration (except for tion, rendering patients vulnerable to hypother­ hypotension), and more apt to occur in patients mia or hyperthermia. Disturbances in the hy­ susceptible to or having cardiovascular disease. pothalamic control of appetite are likely re­ Additionally, cardiovascular toxicity is more sponsible for the weight gain seen in some patients likely to occur with acute overdosage and with taking neuroleptics. Chlorpromazine and other polypharmacy. antipsychotics decrease the secretion of growth While the parenteral administration of hormone, an effect which has been utilized in the phenothiazines may cause an acute drop of 40 treatment of acromegaly. Serum prolactin levels mmHg or more in blood pressure, the average fall have been shown to be elevated three- to fourfold in blood pressure is much smaller and shock is a in patients receiving neuroleptics. This elevation is rarity. When it occurs it indicates a preexisting believed to result from the inhibition of dopamine circulatory lability and should prompt a search for receptors in the hypothalamopituitary axis, pre­ pheochromocytoma. Reports of sudden death due venting dopamine-mediated inhibition of prolactin to coronary thrombosis during phenothiazine release. Some progress has been made in the treatment have been attributed to this effect. treatment of the resultant galactorrhea with Moderate hypotension can usually be managed by brom-ergocryptine.10 Administered in the dosage keeping the patient prone and by elevating the of 5 mg/day, this drug significantly reduces galac­ legs. Severe phenothiazine hypotension can be torrhea. Amenorrhea and dysmenorrhea may also treated with norepinephrine or dopamine and be produced in a significant portion of women on should not be treated with epinephrine, since

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epinephrine administration in the presence of chlorpromazine. The major reactions of this type these alpha adrenergic-blocking agents lowers affect the skin, eyes, bone marrow, and liver. The blood pressure. effects on these organ systems are thought to be Chlorpromazine and other neuroleptics can due to hypersensitivity to the particular neurolep­ produce a variety of ECG alterations, including T tic; often switching to a drug from a different class wave blunting, ST depression, and Q-T segment results in disappearance of symptoms. lengthening. It has been proposed that these ECG Four types of dermatological reactions occur abnormalities are a benign disturbance of with neuroleptic medications. About five percent myocardial repolarization correctable by adminis­ of the patients treated develop a hypersensitivity tration of a potassium salt. Nonetheless, several reaction between the first and fifth week of treat­ cases of ventricular arrhythmia and sudden death ment, which may be urticarial, edematous, pete­ have been reported in patients treated with anti- chial, or maculopapular. Withdrawal of medication psychotics. Third-degree heart block with ventricu­ produces clearing, and the condition may not lar tachycardia has been reported in several pa­ reoccur upon reinstitution of therapy. Photosen­ tients taking high doses of thioridazine; sudden sitivity is another problem that may develop, death in patients taking chlorpromazine has been necessitating an effective sunscreen, such as those reported by several authors. A review by Leetsma containing para-aminobenzoic acid. Others receiv­ and Koenig in 1968 of 54 cases of sudden death ing high doses of phenothiazines administered for during phenothiazine treatment suggested that a long time have developed abnormal skin pigmen­ drug-induced arrhythmia rather than ath­ tation. While chlorpromazine has been reported as erosclerotic heart disease was responsible for producing this reaction most frequently, other death.11 Autopsy studies have shown some ab­ phenothiazines have also been implicated. The normalities in the myocardium, suggesting a pos­ skin in this condition is pigmented grayish blue in sible mechanism for arrhythmias. Hollister and exposed areas and the dermis contains melanin Kosek12 have reported pigment deposition in the deposits throughout the corium. Finally, contact myocardium, and Alexander and coworkers13 dermatitis may develop in personnel who handle have reported pigmentation as well as changes in antipsychotics, especially phenothiazines. the arterioles of patients who die of phenothiazine Eye changes are a common side effect and have overdosage. been extensively documented in retrospective The weight of the evidence indicates that the studies. In combined series totaling some 1,554 phenothiazines, especially the aliphatic and patients without any skin hyperpigmentation, ap­ piperidine derivatives, can have cardiotoxic ef­ proximately 30 percent of the patients had drug- fects. It is essential, therefore, that physicians related eye lesions. Both lenticular opacities, prescribing these drugs periodically evaluate their which are granular deposits in the axial portion of patients’ cardiac status. If ECG abnormality or the anterior capsule, and corneal changes were cardiomegaly is found, the physician should reas­ seen. In most patients no impairment of visual sess the patient’s psychiatric status to determine if acuity resulted. However, some patients on very continued drug treatment provides sufficient ben­ high doses of chlorpromazine for a number of efit to outweigh the risk involved. years have a reduction of visual acuity due to cataracts, which one group14 found to be revers­ ible if the patient was switched to another drug and was treated with d-penicillamine. Pigmentary ret­ inopathy has also been found in patients with pigmentary lesions of the lens and cornea. This condition has been a problem particularly with high doses (greater than 800 mg/day) of Idiosyncratic and Toxic Effects thioridazine; however, there are reports of its oc­ Toxic and idiosyncratic reactions have been re­ currence with other phenothiazines as well. ported with all antipsychotic drugs. The most Prien and his colleagues15 have addressed this complete information, however, comes from problem in a well-controlled prospective study of studies of the phenothiazines and particularly of 120 schizophrenic patients treated with chlor-

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promazine. An increased incidence of corneal and neuroleptic is discontinued, recovery occurs in lens changes was found among patients on high two weeks. doses of chlorpromazine as compared to patients Diagnosis has been attempted by some, with on low doses or on placebo. There was a high weekly white counts in all patients receiving correlation between the development of photo­ neuroleptics. Pisciotta obtained 37,500 white sensitivity and eye changes, but none of the study blood cell counts in 6,300 inpatients and found patients developed any deterioration in visual only five cases of agranulocytosis.18 Litvak and acuity over the nine-month period of the study. A Kaelbling19 obtained 40,000 white blood cell similar study of trifluoperazine failed to disclose counts in 11,407 patients and found only five pa­ any significant eye changes. tients with counts of 2,000 white blood cells or less Rasmussen’s team16 studied patients on chlor­ during the 15-year duration of their study. Only promazine over 372 years to determine if there three of these patients ever developed any signs of was any progression of pigmentary lesions either infection. Clearly, the yield from routine white in the chlorpromazine group, the thioridazine blood cell counts is minute, so if routine counts are group, or the control group. Visual acuity declined to be made, they should be used only in suspected equally in both the experimental and control high-risk and older patients receiving chlor­ groups due to age. The authors concluded that eye promazine or thioridazine, and should be extended changes with moderate dosage of chlorpromazine for no more than a few months. The best and most and thioridazine do occur but pose no threat to feasible way of preventing the consequences of patients’ eyesight. agranulocytosis is to warn everyone: nursing staff, Another complication of neuroleptic treatment patients, and relatives to report sore throats and which is rare but very serious is agranulocyto­ fevers immediately and then to get emergency sis. It appears more frequently with aliphat­ white blood cell counts. For comparison purposes ic phenothiazine derivatives and perhaps more it is mandatory to have a baseline white blood cell with clozapine than with other drugs, but has count. been reported with all phenothiazine s, thioxan- Treatment of this disorder consists of the im­ thenes, butyrophenones, and dibenzoxazepines. It mediate withdrawal of the offending agents. A is thought to be due to suppression by the careful check of the patient’s other medication for neuroleptic of DNA synthesizing enzymes in agents known to affect hematopoiesis should also granulocyte precursors. In general, the risk of a- be made and these should also be discontinued. It granulocytosis decreases with a rise in milligram must be remembered that this complication carries potency of the phenothiazine. Data compiled by a grave prognosis. Vigorous and aggressive the American Medical Association Council on therapy is indicated. Cultures should be obtained, Drugs between 1957 and 1967 indicated that sus­ sensitivities should be tested, and infective agents ceptibility to agranulocytosis also increases with should be treated with appropriate antibiotics. age and that age is an important factor in recovery. Finally, the last of the idiosyncratic or toxic Of the 147 patients who developed agran­ reactions, jaundice, occurs in less than one per­ ulocytosis, none under the age of 30 died, but cent of patients, usually those on chlorpromazine. one third of those over 30 died. Race, too, seems Clinically, the condition presents within the first to be a factor since no blood dyscrasias were two to four weeks of therapy. The urine may be found in black patients in several studies; dark; the alkaline phosphatase and serum bilirubin moreover, one of the studies17 indicated that are elevated, but signs of hepatitis (fever, obesity and chronic physical disability appear to anorexia, hepatic tenderness) are usually not pres­ increase the risk. ent though they may precede the onset of jaun­ Agranulocytosis presents clinically with dice. Pathologically, the jaundice is of the symptoms of infection unless it is discovered early obstructive type. Biopsy specimens show cen- by hematologic surveillance. Fever, sore throat, trilobular cholestasis with little parenchymal dam­ and weakness are seen along with marked lym­ age. It is thought that the occurrence of jaundice is phopenia and leukopenia. The marrow appears a- a hypersensitivity reaction. Eosinophilia with plastic. Infection during this period is life threaten­ eosinophilic infiltration of the liver is always ob­ ing; however, if infection is avoided and the served in these cases. Jaundice subsides when the

1000 THE JOURNAL OF FAMILY PRACTICE, VOL. 6, NO. 5,1978 ANTIPSYCHOTIC DRUGS drug is stopped and will recur if the same drug is psychotics by a mechanism which is thought to in­ restarted. Often, switching to another neuroleptic volve inhibition of the hepatic microsomal sys­ medication will terminate the jaundice. Thus, tem.20 It was noted above that the symptoms of many authorities believe that the occurrence of tardive dyskinesia worsen with a decrease in jaundice is not a contraindication to continued neuroleptic dose and transiently improve with an treatment. increase in dose. Hence, the physician must be aware that the effect of a tricyclic antidepressant on phenothiazine plasma level may lead to a level of the latter high enough to cause but also to mask Interaction of Antipsychotic Drugs and tardive dyskinesia, until the antidepressant is Other Drugs withdrawn and a plasma level decrease in The mentally ill patient on antipsychotic medi­ neuroleptic follows. The antipsychotics, in turn, cation will often be exposed to other drugs from raise the plasma levels of tricyclic antidepressants. prescriptions by physicians or from self- This elevation may increase the antidepressant medication. Antipsychotics interact with many activity of the drug, since therapeutic efficacy drugs, and such interactions may alter the efficacy bears some relationship to plasma drug levels. It of therapy and possibly endanger the patient’s should also be noted that the antipsychotic-tricy­ safety or comfort. It is essential, therefore, that clic combination increases the risk of agranulocyto­ the family physician be aware of the more impor­ sis, an expected effect whenever an antipsychotic tant drug interactions. is combined with other agents that suppress Because of anticholinergic activity, anti­ hematopoiesis. psychotics can interact with other anticholinergic Several other medications can affect the plasma agents producing a variety of symptoms, eg, levels of the antipsychotics. Estrogens have been glaucoma, xerostomia, ileus, hypotension, urinary shown to increase the serum concentrations of an­ retention, and cardiac irregularities. Additive ef­ tipsychotics when given concurrently.21 Barbitu­ fects from antiparkinsonian and other an­ rates in contrast may decrease the serum levels of ticholinergic agents may also produce the “ central antipsychotics,22 as may lithium.23 The mecha­ anticholinergic syndrome” which has been previ­ nisms of these interactions are not known. ously mentioned. It is a toxic confusional state The combination of antipsychotics and anti­ produced by the superimposition of an atropine­ hypertensive agents almost always produces addi­ like psychosis upon the primary psychiatric disor­ tive hypotension. An important exception is der. Characteristically, its onset is heralded by the guanethidine. Fann and his associates24 found that worsening of psychotic symptoms, disturbance of the addition of chlorpromazine to guanethidine in immediate memory, disorientation, visual halluci­ hypertensive patients produced an increase in nations, and peripheral anticholinergic signs. The their diastolic blood pressures. Chlorpromazine incidence of these reactions increases with age. inhibits the neuronal uptake of guanethidine and Because they possess the highest anticholinergic prevents its hypotensive effect by blocking access activity of the antipsychotics, mesoridazine, to its site of action. If chlorpromazine and false- thioridazine, and chlorpromazine are most often transmitter antihypertensive agents are used to­ implicated in the production of unwanted atropinic gether, the patient’s blood pressure should be effects. It should also be reiterated for emphasis carefully monitered. that the antiparkinsonian agents along with other Due to alpha adrenergic-blocking activity, all anticholinergic compounds reduce neuroleptic antipsychotics interact with sympathomimetic levels in plasma, possibly reducing therapeutic ef­ agents, inhibiting the pressor effects. Norepineph­ ficacy.8 The mechanism of this action is not rine, however, retains its ability to raise the known. blood pressure in combination with antipsychot­ Tricyclic antidepressants, which themselves ics. Chlorpromazine may potentiate the warfarin possess anticholinergic properties, can also aggra­ anticoagulants. Finally, an adverse interaction of vate the atropinic effect of antipsychotics. Unlike lithium and haloperidol was reported but is now antiparkinsonian agents, however, tricyclic an­ believed to have been a coincidental true infec­ tidepressants may raise the plasma levels of anti- tious encephalitis.25

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The various side effects and interactions of the elderly, though more complex than treatment neuroleptic drugs are nowhere more evident than of other age groups, may be successfully accom­ in the geriatric patient population. The deploy­ plished. ment of antipsychotic medications for the elderly patient requires special knowledge, experience, References and care, particularly since this patient may be 1. Delay J, Deniker P: Trente-huit cas de psychoses traitees par la cure prolongee et continue de 4560 RP Le receiving several other medications. A variety of Congres des Al et Neurol de Langue Fr. In Compte rendudu factors leads to an increase in both clinical activity Congres. Paris, Masson et Cie, 1952 2. DiMascio A, Bernardo DL, Greenblatt DJ, et ah A and side effects of the drug. The amount of drug controlled trial of amantadine in drug-induced extrapyra- midal disorders. Arch Gen Psychiatr 33:599, 1976 ' bound to plasma protein, as well as hepatic drug 3. Anath JV, Hprodesky S, Lehmann HE, et al: Effect of metabolism, may be reduced. The ratio of fat to withdrawal of antiparkinsonian medication on chronically hospitalized psychiatric patients. Lava Med 41:934, 1970 parenchymal tissue is increased in the elderly, and 4. Stratas NE, Phillips RD, Walker PA, et al: A study of lipophilic compounds including many neuroleptics drug-induced parkinsonism. Dis Nerv Syst 24:180, 1963 tend to accumulate in fatty tissues. Thus, total 5. McClelland HA, Blessed G, Bhate S, et al: The a- brupt withdrawal of antiparkinsonian drugs in schizophrenic body clearance of drug is slowed. In addition, the patients. Br J Psychiatr 124:151, 1974 6. Idzorek S: Antiparkinsonian agents and sensitivity of the central nervous system to drugs fluphenazine decanoate. Am J Psychiatr 133:80, 1976 is usually increased. 7. Singh M M , Smith JM: Reversal of sorpe therapeutic effects of an antipsychotic agent by an antiparkinsonian These factors increase the likelihood of side ef­ drug. J Nerv Ment Dis 157:50, 1973 fects from neuroleptic agents. The elderly patient 8. Rivera-Calimlim L, Castaneda L, Lasagna L: Effects of mode of management on plasma chlorpromazine in psy­ shows increased susceptibility to neurological and chiatric patients. Clin Pharmacol Ther 14:978, 1973 cardiac side effects, and increased propensity for 9. Fann WE, Lake CR: Amantadine versus trihexyphenidyl in the treatment of neuroleptic-induced depression, paradoxical excitement, delirium, and parkinsonism. Am J Psychiatr 133:940, 1976 assaultiveness. These side effects are frequently 10. Beumont P, Bruwer J, Pimstone B, et al: Brom- ergocryptine in the treatment of phenothiazine-induced the result of the anticholinergic properties of an- galactorrhoea. Br J Psychiatr 126:285, 1975 tipsychotics, and are often worsened by the in­ 11. Leestma JE, Koenig KL: Sudden death and phenothiazines. Arch Gen Psychiatr 18:137, 1968 judicious administration of antiparkinsonian 12. Hollister LE, Kosek JC: Sudden death during treat­ agents. The latter should not be given prophylacti- ment with phenothiazine derivatives. JAMA 192:1035,1965 13. Alexander S, Shader R, Grinspoon L: Electrocar­ cally but only as needed, in small amounts, and diographic effects of thioridazine hydrochloride (Mellaril). only for as long as target symptomatology re­ Lahey Clinic Found Bull 16:207, 1967 14. Forrest FM, Snow HL: Prognosis of eye complica­ quires. Allergic reactions to antipsychotics, eg, tions caused by phenothiazines. Dis Nerv Syst 29(3) agranulocytosis, also occur in greater frequency in (suppl):26, 1968 15. Prien RF, Delong SL, Cole JO, et al: Ocular changes older patients. Thus, the physician must monitor occurring with prolonged high dose chlorpromazine the geriatric patient closely for evidence of any therapy. Arch Gen Psychiatr 23:464, 1970 16. Rasmussen K, Kirk L, Faurbye A: Deposits in the undesirable drug effects. lens and cornea of the eye during long-term chlor­ Neuroleptic drugs should be prescribed in low promazine medication. Acta Psychiatr Scand 53:1, 1976 17. Mandel A, Gross M: Agranulocytosis and dosages for elderly patients. Usually 30 percent of phenothiazines. Dis Nerv Syst 29:32, 1968 the dose for a young adult should be prescribed 18. Pisciotta AV: Agranulocytosis induced by certain phenothiazine derivatives. JAMA 208:1862, 1969 initially. Increase should be gradual and divided 19. Litvak R, Kaelbling R: Agranulocytosis, leukopenia, doses are preferable. Polypharmacy should be and psychotropic drugs. Arch Gen Psychiatr 24:265,1971 20. El-Yousef MK, Manier DH: Tricyclic antidepressants avoided. Absorption from the gastrointestinal and phenothiazines. JAMA 229:1419, 1974 tract may be altered in the elderly and the physi­ 21. El-Yousef MK, Manier DH: Estrogen effects on phenothiazine derivative blood levels. JAMA 2 28:827,1974 cian, after trying a liquid preparation, might well 22. Curry SH, Davis JM, Janowsky DS, et al: Factors try the parenteral route but with reduced doses. affecting chlorpromazine plasma levels in psychiatric pa­ tients. Arch Gen Psychiatr 22:209, 1970 The titration of a new pharmacological regimen 23. Lasagna L: Adverse interactions with other drugs. may be better achieved in an inpatient setting. Presented at the 15th Annual Meeting of American College of Neuropsychopharmacology, New Orleans, December Treatment should be monitored with frequent 17, 1976 physical, mental status, and laboratory evalua­ 24. Fann WE, Janowsky DS, Davis JM, et al: Chlor­ promazine reversal of the antihypertensive action ot tions, and persons in the patient’s natural habitat guanethidine. Lancet 2:436, 1971 should be educated as to the specific drugs given, 25. Shader R, Greenblatt D: Autonomic side effects. Presented at the 15th Annual Meeting of American College the therapeutic objectives, and probable side ef­ of Neuropsychopharmacology, New Orleans, December fects. In this manner, antipsychotic treatment of 17, 1976

1002 THE JOURNAL OF FAMILY PRACTICE, VOL. 6, NO. 5, 1978