Chlorprothixene

Psychosis, a major mental disorder that may be caused by organic or functional conditions, is typified by gross impairment of thought and behavior. It is often accompanied by delusions, hallucinations and/or inappropriate mood. A nonpsychiatric cause of psychosis should always be sought.[1]

Antipsychotic agents are among the drugs most commonly used to alleviate or eliminate specific signs and symptoms of psychosis. Indications for antipsychotic agents include hallucinations, delusions, combativeness (stemming from delusions or frightening hallucinations), disorganization of thought, and social withdrawal or apathy (stemming from psychosis). Antipsychotic agents are not used to ameliorate anxiety or depression unless these emotions are components of a syndrome characterized by psychosis.

The classification of some commonly used antipsychotic agents is given in Table l.[2] Knowing the classification of a specific agent may be helpful in predicting the properties of that drug, including its side effects. [TABULAR DATA 1 OMITTED]

A drug's side-effect profile and the clinician's previous experience with the use of that drug are among the most important considerations in the selection of an antipsychotic medication. The side-effect profiles of antipsychotic agents are fairly easy to predict on the basis of the relative capacities of these drugs to block dopamine and muscarinic or adrenergic receptors.

Receptor Blockade

DOPAMINE BLOCKERS

All antipsychotic agents block the effects of dopamine by directly binding to dopamine receptors. Dopamine-receptor blockade is thought to account for the efficacy of these drugs. The affinity of specific antipsychotic agents for dopamine receptors is positively correlated with their potency.[3] The antipsychotic agents marketed in the United States are both [D.sub.1]- and [D.sub.2],-dopamine-receptor antagonists, but all of these agents have a relatively high affinity for the [D.sub.2] receptor.

"Atypical" antipsychotic agents are drugs that either have a particularly high affinity for [D.sub.2] relative to [D.sub.1] receptors or have reduced potency as dopamine-receptor antagonists, combined with increased potency as serotonergic and adrenergic receptor antagonists. Clozapine (Clozaril) is the only atypical antipsychotic agent currently marketed in the United States. This agent is virtually free of extrapyramidal side effects. There have as yet been no confirmed reports of tardive dyskinesia induced by clozapine. The preferential effect of clozapine on limbic dopamine receptors relative to striatal dopamine receptors may account for its negligible effects on dopaminergic mechanisms governing movement. The nondopaminergic (e.g., serotonergic) actions of clozapine may be critical to its mode of action. The most important limitation of clozapine is its potential for causing agranulocytosis.

Some of the side effects of antipsychotic agents stem from their blockade of dopamine receptors in specific areas of the brain or the hypothalamus. The side effects associated with the blockade of dopamine receptors within these vulnerable areas are listed in Table 2.[2,4,5] [TABULAR DATA 2 OMITTED]

MUSCARINIC AND [ALPHA.sub.1]-ADRENERGIC BLOCKERS

Antipsychotic agents also bind to muscarinic receptors[6,7] and [alpha.sub.1]-adrenergic receptors.[7,8] The side-effect profiles of these agents are related to their affinity for these receptors. The probability that antipsychotic agents will produce extrapyramidal side effects increases in proportion to their affinity for dopamine receptors and decreases in proportion to their affinity for muscarinic receptors.

Side effects produced by blockade of muscarinic receptors include dry mouth, blurred vision, constipation, urinary hesitancy and tachycardia. Adverse effects that may be due to blockade of muscarinic receptors are dysphagia, urinary retention, paralytic ileus, fecal impaction, delirium and precipitation of narrow-angle glaucoma.

Blockade of [alpha.sub.1]-adrenergic receptors can result in severe orthostatic hypotension and syncope. Low-potency phenothiazines are most likely to produce these adverse effects.

Potency

LOW-POTENCY AGENTS

Chlorpromazine (Thorazine), thioridazine (Mellaril) and chlorprothixene (Taractan) are low-potency antipsychotic agents. Consequently, relatively high doses of these agents must be used to treat psychosis. These drugs all have a low affinity for dopamine receptors[3] and a high affinity for muscarinic receptors[6,7] and [alpha.sub.1]-adrenergic receptors,[7,8] compared with high-potency antipsychotic agents.

The antiadrenergic and antimuscarinic effects of low-potency antipsychotic agents necessitate that they be used with caution, especially in elderly patients. These drugs have relatively potent antimuscarinic effects, and they can produce severe orthostatic hypotension. Low-potency antipsychotic agents are contraindicated in patients with autonomic neuropathy, narrow-angle glaucoma, urinary hesitancy or diseases that interfere with the motility of smooth muscle.

HIGH-POTENCY AGENTS

Compared with the low-potency antipsychotic agents, the high-potency, low-dose antipsychotic agents, such as perphenazine (Trilafon), trifluoperazine (Stelazine), fluphenazine (Permitil, Prolixin) and haloperidol (Haldol), are more likely to produce extrapyramidal side effects but much less likely to produce orthostatic hypotension and antimuscarinic side effects.

A high-potency neuroleptic such as haloperidol is the antipsychotic agent of choice in patients with delirium or dementia. High-potency neuroleptic agents have minimal affinity for muscarinic receptors; this is important, because muscarinic-receptor blockade can further compromise cognitive function.[9-11] These drugs are also less likely to produce severe orthostatic hypotension, which in elderly patients can pose major problems, such as injuries from falls.

EFFECTIVE DOSES

The effective doses of antipsychotic agents vary greatly. A 1- to 2-mg dose of a high-potency agent, administered once daily, may be effective in demented patients with psychotic features. However, the management of acute, severe psychosis may require the equivalent of 20 to 40 mg of haloperidol per day.

Side Effects

The risk of antipsychotic-induced dystonic reaction, parkinsonism or akathisia is greatest in men under 40 years of age,[12] but extrapyramidal side effects occur in as many as 70 percent of patients treated with these drugs.[13,14] Consequently, many physicians administer an antiparkinsonian agent prophylactically, especially early in the treatment of psychosis.[15] Benztropine (Cogentin) and trihexyphenidyl (Artane) are the antiparkinsonian agents most commonly used for this purpose in the United States. These antiparkinsonian-antimuscarinic drugs are not only muscarinic-receptor antagonists but also inhibitors of dopamine uptake.[16]

An antiparkinsonian agent should be given intravenously to treat severe dystonia (tonic contraction of a major group of muscles). Some clinicians use diphenhydramine (Benadryl), an antihistamine with antimuscarinic properties. A dystonic reaction can usually be aborted by intravenous infusion of 1 to 2 mg of benztropine or 50 mg of diphenhydramine.

Akathisia is characterized by an uncomfortable sense that one must keep moving.[17] Patients with this side effect appear restless or anxious and sometimes seem to "walk in place," even when they are sitting. Akathisia can be quite resistent to treatment and may create the false impression that a patient's condition is deteriorating. A physician may conclude that the patient is not adequately medicated and may inappropriately increase the antipsychotic dosage. Akathisia is often relieved with oral administration of propranolol (Inderal).

Photosensitivity induced by a phenothiazine, especially chlorpromazine, is apt to bring patients to the attention of family physicians during the summer. In such patients, the skin that is exposed to the sun initially becomes tan or golden-brown; the skin later becomes gray, then blue, and finally purple.

Relatively rare side effects of antipsychotic drugs are listed in Table 3.

TARDIVE DYSKINESIA

Tardive dyskinesia is an irreversible hyperkinetic disorder of movement produced by the long-term administration of antipsychotic agents. It has been estimated that 20 percent of patients who receive chronic antipsychotic drug therapy develop this disorder.[18,19] Puckering of the lips, extrusion of the tongue, and hyperkinesis of the mandible and eyelids are among the most common movement abnormalities in tardive dyskinesia. Excessive movements and dystonia of the extremities are also frequently observed. Involvement of the diaphragm and intercostal muscles may interfere with breathing.

Prevention is the best treatment for tardive dyskinesia. There is no proven therapy. If the antipsychotic medication can be discontinued, some patients will improve gradually.

NEUROLEPTIC MALIGNANT SYNDROME

Neuroleptic malignant syndrome is an uncommon but potentially lethal effect of antipsychotic drug therapy. The syndrome is characterized by hyperthermia, rigidity and confusion.[20-22] Hypertension, tachycardia, tachypnea and orthostatic hypotension may also be present. In nine published reports, the incidence of neuroleptic malignant syndrome was 0.23 percent among 16,016 patients treated with antipsychotic drugs.[20] Neuroleptic malignant syndrome is a medical emergency and has a 10 percent mortality rate.

The hyperthermia in neuroleptic malignant syndrome results from the generation of heat by the continuous contraction of agonist and antagonist skeletal muscles (the cause of rigidity) in the context of the blockade of a central dopaminergic mechanism required for the dissipation of heat. Elevation of the creatine kinase level and myoglobinuria occur because of the destruction of skeletal musculature. It is critical to screen urine for the presence of myoglobin, since the accumulation of this macromolecule within nephrons can produce renal failure.

There is no specific treatment for neuroleptic malignant syndrome. Management includes discontinuation of all medication, careful medical evaluation and supportive care, including hydration and cooling. The dopamine agonist bromocriptine (Parlodel), benzodiazepines and the muscle relaxant dantrolene (Dantrium) may occasionally be effective.[21-23]

Withdrawal Symptoms

The withdrawal of antipsychotic agents may precipitate syndromes attributable to cholinergic or dopaminergic rebound in discrete areas of the brain or in the autonomic nervous system. Components of the four syndromes that may occur are (1) anorexia, nausea, emesis, diarrhea, diaphoresis, myalgias, malaise, headache, chills, fatigue and anxiety; (2) insomnia accompanied by vivid dreams; (3) anxiety, agitation, restlessness and insomnia, and (4) a transient hyperkinetic dyskinesia indistinguishable from tardive dyskinesia.[24,25]

The severity of withdrawal symptoms can be minimized by slowly discontinuing the antipsychotic drug. The syndrome comprised of anxiety, agitation, restlessness and insomnia is particularly ominous, because these symptoms are indistinguishable from those that may presage the recurrence of psychosis. The occurrence of this syndrome may justify increasing the dosage of the antipsychotic agent. Once the patient is free of symptoms, the drug may be discontinued at a slower rate.

REFERENCES

[1.] Dilsaver SC. Differentiating organic from functional psychosis. Am Fam Physician 1992; 45:1173-80. [2.] Baldessarini RJ. Chemotherapy in psychiatry: principles and practice. Cambridge, Mass.: Harvard University Press, 1985:22. [3.] Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976;192:481-3. [4.] Gold MS, Lydiard RB, Carman JS. Advances in psychopharmacology: predicting and improving treatment response. Boca Baton, Fla.: CRC Press, 1984:208-16. [5.] Appleton WS. Practical clinical psychopharmacology. 3d ed. Baltimore: Williams & Wilkins, 1988:58-76. [6.] Snyder S, Greenberg D, Yamamura HI. Anti-schizophrenic drugs and brain cholinergic receptors. Affinity for muscarinic sites predicts extrapyramidal effects. Arch Gen Psychiatry 1974;31:58-61. [7.] Richelson E. Neuroleptics and neurotransmitters. Psychiatr Ann 1980; 10: 21-6. [8.] Peroutka SJ, U'Prichard DC, Greenberg DA, Snyder SH. Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain. Neuropharmacology 1977; 16:549-56. [9.] Sunderland T, Tariot PN, Cohen RM, Weingartner H, Mueller EA 3d, Murphy DL. Anticholinergic sensitivity in patients with dementia of the Alzheimer type and age-matched controls. A dose-response study. Arch Gen Psychiatry 1987;44:418-26. [10.] Tune LE, Strauss ME, Lew MF, Breitlinger E, Coyle JT. Serum levels of anticholinergic drugs and impaired recent memory in chronic schizophrenic patients. Am J Psychiatry 1982;139: 1460-2. [11.] Miller PS, Richardson JS, Jyu CA, Lemay JS, Hiscock M, Keegan DL. Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients. Am J Psychiatry 1988;145:342-5. [12.] Moleman R, Janzen G, von Bargen BA, Kappers EJ, Pepplinkhuizen L, Schmitz PI. Relationship between age and incidence of parkinsonism in psychiatric patients treated with haloperidol. Am J Psychiatry 1986;143:232-4. [13.] Donlon PT, Hopkin JT, Tupin JP, Wicks JJ, Wahba M, Meadow A. Haloperidol for acute schizophrenic patients. An evaluation of three oral regimens. Arch Gen Psychiatry 1980;37: 691-5. [14.] Singh H, Levinson DF, Simpson GM, Lo ES, Friedman E. Acute dystonia during fixed-dose neuroleptic treatment. J Clin Psychopharmacol 1990;10:389-96. [15.] Bianchine JR. Drugs for Parkinson's disease, spasticity, and acute muscle spasms. In: Gilman AG, et al., eds. Goodman and Gilman's The pharmacological basis of therapeutics. 7th ed. New York: MacMillan, 1985:484-6. [16.] Modell JG, Tandon R, Beresford TP. Dopaminergic activity of the antimuscarinic antiparkinsonian agents. J Clin Psychopharmacol 1989;9:347-51. [17.] Van Putten T, May PR, Marder SR. Akathisia with haloperidol and thiothixene. Arch Gen Psychiatry 1984;41:1036-9. [18.] Kane JM, Smith JM. Tardive dyskinesia. Prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry 1982;39:473-80. [19.] Hyman SE, Cassem NH. Psychopharmacologic therapies. In: Rubenstein E, Federman DD, eds. Scientific American Medicine. Vol 3. New York: Scientific American, 1991: chap 13, pt 8. [20.] Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry 1987;22:1004-20. [21.] Guze BH, Baxter LR Jr. Current concepts. Neuroleptic malignant syndrome. N Engl J Med 1985;313:163-6. [22.] Kaufman CA, Wyatt RJ. Neuroleptic malignant syndrome. In: Meltzer HY, et al., eds. Psychopharmacology: the third generation of progress. New York: Raven, 1987:1247-8. [23.] Khan A, Jaffe JH, Nelson WH, Morrison B. Resolution of neuroleptic malignant syndrome with dantrolene sodium: case report. J Clin Psychiatry 1985;46:244-6. [24.] Dilsaver SC. Heterocyclic antidepressant, monoamine oxidase inhibitor and neuroleptic withdrawal phenomena. Prog Neuro-Psychopharmacol Biol Psychiatry 1990;14:137-61. [25.] Dilsaver SC, Alessi NE. Antipsychotic withdrawal symptoms: phenomonology and pathophysiology. Acta Psychiatr Scand 1988;77: 241-6.

STEVEN C. DILSAVER, M.D. is professor of psychiatry and behavioral sciences and director of research at the Harris County Psychiatric Center at the University of Texas Medical School at Houston. Dr. Dilsaver received his medical degree from the University of California, San Diego, School of Medicine and completed a psychiatry residency in the research track at the University of Michigan, Ann Harbor.

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