Atypical Antipsychotics: A Practical Review

Donna A. Wirshing, MD, William C. Wirshing, MD, Stephen R. Marder, MD, C. Scott Saunders, MD, Elizabeth H. Rossotto, PhD, Stephen M. Erhart, MD


Medscape Psychiatry & Mental Health eJournal. 1997;2(5) 

In This Article


Clozapine is the prototypic atypical antipsychotic agent. It clearly separates antipsychotic efficacy from neurotoxicity. The exact neurochemical mechanism by which clozapine exerts its atypical effect is unknown. It has complex receptor pharmacology, including antagonist activity at dopaminergic (D1, D2); serotonergic (5-HT2a, 5-HT2c, 5-HT3); adrenergic (alpha1, alpha2); histaminergic (H1); and muscarinic (M1) receptors (Table I). Its activity at D2 receptors is weak compared with conventional neuroleptics, and this characteristic probably accounts for its virtual absence of clinically pertinent EPS.

Although clozapine was not clinically available in the US until 1990, it actually was patented in 1960 and used in clinical trials in the 1960s and 1970s. It was clear from the earliest trials that clozapine was an effective antipsychotic without EPS. Unfortunately, its development in the US was brought to a near halt in 1975 when it was found to be associated with a substantial risk of agranulocytosis and death. In other parts of the world (eg, Scandinavia, Germany, China, and elsewhere), clozapine continued to be used to treat patients throughout the 1970s and 1980s. The cumulative experience with these patients (as well as a small cadre treated in the US under compassionate-use protocols) suggested that when patients are carefully monitored, clozapine could be administered safely, provided it was withdrawn when patients showed evidence of neutropenia or agranulocytosis.

Clozapine has a number of characteristics that make it unique. It appears to be more effective than conventional antipsychotics for schizophrenia patients who are severely psychotic and poorly responsive to the mechanism of action of conventional antipsychotic drugs. This finding was demonstrated in a convincing manner in the multicenter study[2] that led to clozapine's approval in the US for refractory patients. In this trial, severely ill inpatients with a history of poor responsiveness to at least 2 antipsychotics were assigned to a 6-week comparison trial of either clozapine or chlorpromazine with benztropine. Clozapine was significantly more effective on a broad range of psychopathology that included both positive and negative symptoms. Although only 30% of clozapine-treated patients met stringent improvement criteria, other studies have suggested that this percentage would have been substantially higher if the study had continued for a longer time. For example, a 16-week trial[3] found a 38%-improvement rate, and a more recent report[4] found that 60% of treatment-refractory patients treated with clozapine improved at the end of a 29-week trial.

Another important characteristic of clozapine is its spectrum of antipsychotic activity. In the study by Kane and colleagues,[2] clozapine-treated patients demonstrated improvements in items from the Brief Psychiatric Rating Scale (BPRS)[5] that are associated with negative symptoms. Although others[6,7] have not found that clozapine clearly improves negative symptoms, clinicians have reported that clozapine treatment in some individuals led to substantial gains in social and occupational adjustment. It is also unclear if clozapine's apparent effects on negative symptoms are actually due to its superior impact on positive symptoms (eg, social withdrawal improves because paranoia declines) or comparative lack of EPS (eg, improvement in akathisia leads, in turn, to less alogia).

A number of reports have indicated that clozapine is effective in psychotic disorders other than schizophrenia (Table II). This finding is parallel with the effectiveness of conventional antipsychotics for nearly any disorder that results in psychotic symptoms. Although no controlled double-blind studies have been performed, several open-label studies have demonstrated the efficacy of clozapine in treating bipolar and schizoaffective mania.[8,9,10,11] It appears to be particularly effective for managing mania; 9 published case reports indicated that clozapine is an effective antimanic agent.[12,13,14]

Clozapine may also be helpful for the management of psychosis in idiopathic Parkinson's disease. These patients can develop psychosis as part of the illness itself or as a secondary effect from dopamine agonist treatments (eg, L-dopa-induced psychosis). Several double-blind studies have confirmed that clozapine is highly effective for these patients when administered in low doses, sometimes below 100mg daily.[15,16] Unlike the traditional antipsychotics, clozapine does not worsen motor symptoms.[17,18,19] It can cause heightened sensitivity to sedation and orthostatic hypotension in parkinsonian patients.[16]

Clozapine also has been reported to be effective for some developmentally disabled patients,[20] for cases in which it appears to positively influence both psychosis and behavioral disturbances (eg, violence, self-injurious acts).[21] Other reports have suggested a role for clozapine in other childhood and adolescent schizophrenic illnesses[22,23] and in severe personality disorders.[24]

Clozapine's side effects make it one of the most difficult drugs in psychiatry to administer (Table III). The most serious side effect is agranulocytosis, a potentially lethal effect that occurs in less than 1% of patients treated.[25] Some have noted that patients with an Ashkenazi Jewish background seem to be at greater risk for this complication.[26] Alvir and colleagues[25] looked at retrospective data on 11,555 patients who received clozapine in the US. In 1.5 years of monitoring white blood cell (WBC) counts, 73 (0.9%) patients developed agranulocytosis, 2 of whom died. The cumulative incidence of agranulocytosis was 0.80% at 1 year and 0.91% at 1.5 years. There have been several reports that treatment with granulocyte colony-stimulating factor (G-CSF) shortens the period of infectious risk after agranulocytosis develops.[27,28] Although a mandatory system of weekly monitoring of the WBC count makes the drug relatively safe, many patients find this requirement onerous to the point of medication refusal. The US Food and Drug Administration (FDA) is currently considering a proposal to decrease or even discontinue frequent monitoring after 6 or 12 months of treatment. Thus, in the future, this impediment to treatment may be lessened somewhat.

The most common side effect of clozapine is sedation. This is also the side effect that usually limits the dose and titration speed of clozapine. Other common side effects include sialorrhea, tachycardia, orthostatic hypotension, constipation, and weight gain. Seizures occur in 5% to 10% of patients treated with doses above 500mg.[29] The induction of seizures does not preclude continued use of clozapine, as most patients can be managed by reducing the dose and adding an anticonvulsant such as valproic acid. We recently examined electroencephalograms (EEG) pre- and post-clozapine or haloperidol treatment and noted an increase in nonseizure EEG abnormalities in the clozapine-treated group compared with the haloperidol-treated group. Some researchers have speculated that part of clozapine's efficacy is sustained through its seizure-inducing potential.[30,31,32]

The usual target range for clozapine is 400 to 700mg per day, and it is generally given in a divided dose schedule. Notably, the average European dose range is approximately one half its US counterpart. This more than likely reflects the US practice of reserving clozapine for the most densely unresponsive of schizophrenic syndromes. Such subjects typically, and predictably, require higher doses than more responsive patients. Because of clozapine's pronounced alpha1 blockade (inducing a marked decrease in peripheral vascular resistance with a reflex increase in cardiac output and possible clinically significant orthostatic hypotension) and H1 blockade (sedation inducing), it must be titrated very slowly over several weeks to this target dose range. Patients should, in general, be started at 12.5mg bid, with gradual titration to approximately 500mg by no more than 50-mg increments every 2 days. In addition to the required weekly monitoring of WBC counts, patients should have vital signs (with orthostatic changes) taken daily, if possible, during the first week of titration. Patients who demonstrate cardiovascular intolerance to the clozapine-induced decrease in peripheral vascular resistance (persistent, subjectively distressing orthostatic hypotension) should be titrated with extreme caution.[33] The predictable and occasionally severe constipation that occurs in two thirds of patients taking clozapine should be anticipated. Some clinicians automatically prescribe lactulose or Metamucil (psyllium husk fiber) to prevent this difficulty. Other common toxicities include weight gain (probably secondary to blockade of 5-HT2c)[34]; sedation (probably related to a combination of alpha1 and H1 blockade); and sialorrhea (secondary to increase in salivary output, the mediation of which is unclear). Sedation can, in general, be managed by slowing the titration and shifting the bulk of the daily dose to bedtime. Weight gain should be anticipated, and the usual behavioral strategies should be instituted before significant changes in weight occur. Once an increase in weight has been established, it is virtually impossible to get patients to return to their baseline as long as clozapine (indeed, any of the atypical antipsychotics) is continued. The sialorrhea is most problematic at night. It is generally dealt with by using "pillow towels" or adding anticholinergics or even clonidine.[35]

Provided that no untoward toxicities have emerged, the titration should be continued until either psychotic symptoms have begun to remit or a target dose of 500mg per day has been reached. If improvement has begun, several weeks of negligible clinical improvement should then be allowed to pass before the next higher dose is reached. In the absence of clinical improvement, once a dose of 500mg per day has been reached, a trough plasma level for clozapine should be drawn. If possible, at least 2 trough levels on consecutive days should be obtained because of the marked variability of this laboratory measure. Plasma levels of 250ng/mL or higher are highly predictive of optimal clinical outcome.[36] A plasma level below this measure should prompt an increase in dosing, while those above should signal the treating clinician to wait longer for clinical benefit to accrue.


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