This large NIMH-sponsored multicenter study sought to examine the safety and effectiveness of second generation antipsychotics (olanzapine, quetiapine, risperidone, and ziprasidone) and a first generation antipsychotic, perphenazine, in treating schizophrenic patients (Lieberman et al. 2005; Meyer et al. 2005). The primary outcome measure, time to discontinuation, served as an index of effectiveness and was remarkably short; only 26 % of subjects completed the 18-month trial on the medicine to which they were initially randomized. Subjects receiving olanzapine experienced a slightly longer time to discontinuation. Olanzapine showed greater effectiveness than the other agents despite its association with significant metabolic disturbance, especially weight gain. Perphenazine unexpectedly showed comparable levels of effectiveness and produced no more extrapyramidal side effects than the other agents. Despite modest prolactin elevation, risperidone was the best-tolerated medication. In Phase 2, clozapine demonstrated better effectiveness compared to other second generation antipsychotics (SGA) for subjects who discontinued their Phase 1 medication because of efficacy. Olanzapine and risperidone showed greater effectiveness in the tolerability pathway. Improvements in cognition were modest among all the agents in Phase 1, and perphenazine was no less effective in improving cognitive performance than the SGAs. Cost-effectiveness analysis revealed a significant advantage for perphenazine, due to the impact of the high-priced, brand-name SGAs on overall health care costs (Manschreck and Boshes 2007). Aripiprazole and ziprasidone are less implicated in weight gain and metabolic syndrome and are less sedating than other SGAs.

There is evidence that genetically informed personalized medication regimen may become efficacious in the use of antipsychotic medications (Liu et al. 2012).

Parkinsonism-like symptoms, for example, muscle rigidity, tremor, bradykinesia, dystonias, and akathisia, are associated with the dopamine antagonism of antipsychotic drugs. With first-generation antipsychotics, particularly haloperidol and fluphenazine, the incidence of extrapyramidal symptoms (EPS) may approach 90 %, particularly in young males. Acute dystonias, such as torticollis, may be treated with diphenhydramine 50–100 mg IV or benztropine 1–2 mg IM. Extrapyramidal symptoms are usually controlled with anticholinergic drugs such as benztropine or antihistaminics such as diphenhydramine. Akathisia may respond to beta-blockers, such as propranolol 20–40 mg t.i.d. or q.i.d.

Tardive dyskinesia, a side effect of prolonged use, particularly of first-generation antipsychotics, is characterized by choreoathetoid movements of the tongue, lips, and extremities. There is no effective treatment for this condition.

Neuroleptic malignant syndrome (NMS) is a potentially fatal syndrome associated with the use of dopamine-antagonist antipsychotics. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac dysrhythmia). Sialorrhea and incontinence may occur. There is often elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), leukocytosis, and acute renal failure. Extrapyramidal signs such as tremor, rigidity, and cogwheeling are common. Differential diagnoses include infection, anticholinergic toxicity, the serotonin syndrome (see Chap. 7), heat stroke, and central nervous system (CNS) disease (e.g., encephalitis).

If NMS is suspected, all antipsychotic drugs should be discontinued, and the patient should be intensively monitored and supportive treatment given. Pharmacotherapy may include dantrolene (a muscle relaxant, an inhibitor of calcium release from sarcoplasmic reticulum), 1–3 mg/kg IV initially, and then 10 mg/kg/day IV or po in divided doses. Dopamine agonists, such as bromocriptine, 2.5–10 mg t.i.d. po, gradually titrated, or levodopa/carbidopa (Sinemet) 25/250 t.i.d. or q.i.d., may be used. During the acute phase, for behavioral control, benzodiazepines should be used rather than antipsychotics. If antipsychotic treatment becomes necessary after the resolution of NMS, for at least two weeks, it should begin in low doses very cautiously with careful monitoring.

Metabolic syndrome or syndrome X, consisting of insulin resistance, impaired glucose regulation and type II diabetes mellitus, obesity, hypertension, hypertriglyceridemia, increased low-density lipoprotein (LDL), and low high-density lipoprotein (HDL) cholesterol levels, may be associated with second-generation antipsychotics. Appetite stimulation through the blockade of histamine H₁ and noradrenergic A₁ receptors seems to be the underlying mechanism (Zarate et al. 2004). Clozapine and olanzapine seem to be most associated with this syndrome (Hartling et al. 2012), risperidone and quetiapine may be intermediate in risk, and ziprasidone and aripiprazole seem to have minimal risk for this syndrome.

Patients receiving second-generation antipsychotics should be monitored for weight, body mass index, fasting glucose, and the lipid profile for possible development of the metabolic syndrome. If such development is suspected, switching to drugs less likely to cause the syndrome should be considered, and dietary and exercise programs should be initiated as well as possible medical intervention, including the use of weight loss medications such as sibutramine, orlistat, and rimonabant (Filippatos et al. 2008; Fujioka 2006).

Common Considerations

The sedative effect may be accentuated with concurrent use of other sedating agents including alcohol. Orthostatic hypotension may be potentiated with the use of other hypotensive agents. Most antipsychotics, due to the dopamine antagonist action, may antagonize the effects of levodopa and other dopamine agonists. Most antipsychotics are metabolized by the cytochrome P-450 enzyme systems in the liver; enzyme inducers such as carbamazepine decrease the antipsychotic blood levels, and enzyme inhibitors such as ketoconazole increase the blood levels. In general, antipsychotics do not necessitate changes in dosing of other medications.

Olanzapine

Drugs that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance; thus a dosage increase of olanzapine may be necessary. Inhibitors of CYP1A2 may inhibit olanzapine clearance. Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine and may result in a mean increase in olanzapine.

Olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

Risperidone

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone. Carbamazepine and other enzyme inducers may decrease the effective level of risperidone by 50 %. Coadministration of other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment. Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone 2.5- to 2.8-fold and threefold to ninefold, respectively.

Quetiapine

Enzyme inducers such as phenytoin, carbamazepine, barbiturates, rifampin, and glucocorticoids may increase the oral clearance of quetiapine up to fivefold, necessitating an increased dose. Caution should be exercised if phenytoin is withdrawn and replaced with a noninducer (e.g., valproate). Coadministration of quetiapine and divalproex increases the mean maximum plasma concentration of quetiapine by 17 % without affecting the extent of absorption or mean oral clearance. Thioridazine increases the oral clearance of quetiapine by 65 %. Cytochrome P-450 3A inhibitors (e.g., ketoconazole, itraconazole, fluconazole, and erythromycin) may reduce oral clearance of quetiapine and may result in a 335 % increase in maximum plasma concentration of quetiapine. Quetiapine reduces the oral clearance of lorazepam.