Antipsychotics—Overview
Essential Concepts
All antipsychotics share varying degrees of dopamine-2 (D2) blockade as the presumed main mechanism of action. Primary symptom targets of antipsychotics are positive symptoms (disorganization, delusions, and hallucinations) and agitation, with questionable efficacy for negative symptoms.
Antipsychotics are grouped into first-generation antipsychotics—typical or conventional antipsychotics, which are all characterized by extrapyramidal symptom (EPS) liability—and second-generation antipsychotics (with reduced EPS risk, hence “atypical” antipsychotics). However, the second-generation antipsychotics (currently, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone) should not be considered interchangeable, as patients might respond differently to each drug in this class.
The main risks for first-generation antipsychotics are neurologic side effects (dystonias, akathisia, parkinsonism, and tardive dyskinesia); for most second-generation antipsychotics, metabolic problems (weight gain, dyslipidemia, and hyperglycemia) have emerged as major problems in management.
First- and second-generation antipsychotics are about equally effective for nonrefractory patients with schizophrenia. For more refractory patients, olanzapine and, in particular, clozapine have shown the best efficacy.
Clozapine has minimal to no EPS liability and is the most effective antipsychotic. However, its clinical use is limited to refractory patients because of serious side effects, including metabolic problems and agranulocytosis [which requires mandated white blood count (WBC) monitoring].
“The greater the ignorance, the greater the dogmatism.”
—Sir William Osler, Father of Modern Medicine, 1849-1919
All currently marketed antipsychotics block D2 receptors, albeit with different affinities. Side-effect differences can be predicted from the degree of D2 is blockade (the more tightly bound to D2 is the antipsychotic, the higher the risk for EPS) and the selectivity (histamine receptor binding is associated with sedation and weight gain, anticholinergic receptor binding with anticholinergic side effects, and adrenergic blockade with orthostatic hypotension). Clozapine and quetiapine are the antipsychotics with the least “tightness” of binding to D2 (i.e., fastest dissociation from the receptor) and hence are the least likely to cause EPS, even at high doses (Kapur and Seeman, 2001). All antipsychotics are full D2 antagonists with the exception of aripiprazole, which is a partial agonist at D2.
One word on nomenclature: First-generation (or conventional) antipsychotics (FGAs) are old medications that were approved in the 1950s and 1960s. All are effective, and all cause EPS. FGAs are also referred to as “typical” antipsychotics to differentiate them from the “atypical” antipsychotic, clozapine, which was the first antipsychotic that did not cause EPS, hence “atypical.” Its value was only recognized and proved in a seminal trial in 1988 when Kane showed superior efficacy in treatment-refractory patients over typical antipsychotics. Since then, other atypicals (or second-generation antipsychotics, SGAs) have been marketed, beginning with risperidone in 1994. Antipsychotic is the term preferred over neuroleptic.
KEY POINTA broad definition of “atypicality” denotes the absence of extrapyramidal side effects. More narrow definitions include the absence of hyperprolactinemia and broadened efficacy for negative symptoms. A neuroleptic is considered typical if it causes EPS at usual clinical doses (which is what you would expect from a “neuroleptic”—a “neuron-grabber”).
For most antipsychotics, once-a-day dosing would be appropriate with regard to efficacy because the serum half-life of the antipsychotic does not reflect drug action on the brain. Ziprasidone is nevertheless usually administered twice daily (it is also the only antipsychotic that should be taken with food). Quetiapine, olanzapine, and clozapine are sometimes given more than once a day because of tolerability (or to take
advantage of their sedating properties in acute settings), but nightly dosing works for most patients. The safe starting dose and the rapidity of titration depend on the clinical situation (e.g., age, gender, ethnicity, first-episode vs. multiepisode patient, acute vs. maintenance treatment phase). As a rule of thumb, start at the low end of the dose range for outpatients and increase the dose slowly. More aggressive dosing is possible in supervised inpatient settings.
advantage of their sedating properties in acute settings), but nightly dosing works for most patients. The safe starting dose and the rapidity of titration depend on the clinical situation (e.g., age, gender, ethnicity, first-episode vs. multiepisode patient, acute vs. maintenance treatment phase). As a rule of thumb, start at the low end of the dose range for outpatients and increase the dose slowly. More aggressive dosing is possible in supervised inpatient settings.
FIRST-GENERATION ANTIPSYCHOTICS
The FGAs can be broadly classed into low-potency antipsychotics, medium-potency antipsychotics, and high-potency agents. The prototype of a low-potency FGA is chlorpromazine (brand name Thorazine), the first antipsychotic approved by the Food and Drug Administration (FDA) in 1954. Low-potency FGAs are not selective for the dopamine receptor; sedation, orthostatic hypotension, and anticholinergic side effects, as well as metabolic problems, are problematic. Haloperidol and fluphenazine are high-potency agents, which are highly selective for the D2 receptor; predictably, side effects are largely restricted to the motor system. The medium-potency FGA, perphenazine, has a side-effect profile that falls in-between chlorpromazine and haloperidol with regard to EPS and sedation. Perphenazine has returned as an interesting antipsychotic choice after its good efficacy and tolerability were demonstrated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE; see Chapter 14 for more information on the seminal CATIE trial) in which it was chosen as the FGA comparator medication.
KEY POINTFor antipsychotic efficacy, about 65% of (striatal) D2 receptors need to be blocked. Pushing the dose of tightly bound antipsychotics, such as all FGAs, beyond this point will not increase efficacy but will merely lead to EPS once a threshold of 80% occupancy is exceeded (Farde et al., 1988).
There is no advantage to switch between FGAs for better efficacy since they all share the same mechanism of D2 blockade. The dosing of FGAs (Table 11.1; but not of SGAs) can be
based on chlorpromazine equivalents (CPZ-Eq) as a guideline. Pushing the dose of FGAs reliably increases EPS but does not translate into further efficacy; it is not a good strategy to increase FGAs beyond recommended CPZ-Eq. Instead, use the “neuroleptic threshold,” which is the point at which you just begin to see EPS (and which corresponds to 80% D2 occupancy), to determine the optimal dose; exceeding the patient’s neuroleptic threshold does not increase efficacy (McEvoy et al., 1991). The major long-term morbidity concern with FGAs is tardive dyskinesia. Haloperidol and fluphenazine have the advantage of being available as long-acting depot injections (the only other antipsychotic available as a long-acting injectable in the United States is risperidone); Table 11.2 presents dosing equivalencies.
based on chlorpromazine equivalents (CPZ-Eq) as a guideline. Pushing the dose of FGAs reliably increases EPS but does not translate into further efficacy; it is not a good strategy to increase FGAs beyond recommended CPZ-Eq. Instead, use the “neuroleptic threshold,” which is the point at which you just begin to see EPS (and which corresponds to 80% D2 occupancy), to determine the optimal dose; exceeding the patient’s neuroleptic threshold does not increase efficacy (McEvoy et al., 1991). The major long-term morbidity concern with FGAs is tardive dyskinesia. Haloperidol and fluphenazine have the advantage of being available as long-acting depot injections (the only other antipsychotic available as a long-acting injectable in the United States is risperidone); Table 11.2 presents dosing equivalencies.
TABLE 11.1. Dosing of Selected First-Generation Antipsychotics | ||||||||||||||||||||||||||||||
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