The seminal work of Delay and Deniker (1952) provided a phar-macological strategy that would forever change the face of schiz-ophrenia. The implementation of chlorpromazine became the turning point for psychopharmacology. Patients who had been institutionalized for years were able to receive treatment as out-patients and live in community settings. The road was paved for the deinstitutionalization movement, and scientific understand-ing of the pathophysiology of schizophrenia burgeoned. The in-troduction of clozapine started the era of antipsychotic agents be-ing referred to as either “typical” (conventional or traditional) or “atypical” (or novel) antipsychotic drugs. If chlorpromazine started the first revolution in the psychopharmacological treat-ment of schizophrenia, then clozapine ushered in the second and more profound revolution whose impact is felt beyond schizo-phrenia and its full extent is yet to be realized. Moreover, cloza-pine has invigorated the psychopharmacology of schizophrenia and rekindled one of the most ambitious searches for new antip-sychotic compounds by the pharmaceutical industry. There are now five novel antipsychotics in the USA: risperidone, olanzap-ine, quetiapine, ziprasidone and aripiprazole.
Double–blind, controlled studies demonstrated the superior clin-ical efficacy of clozapine compared with standard neuroleptics, without the associated extrapyramidal symptoms. It is clearly superior to traditional neuroleptics for psychosis. Approximately 50% of patients with chronic and treatment-resistant schizophre-nia derive a better response from clozapine than from traditional neuroleptics. Its effect on negative symptoms is somewhat con-troversial and has started an intense and a passionate debate as to whether the efficacy of the medication is with primary or secondary negative symptoms or both (Meltzer, 1989a). There is substantial evidence that clozapine decreases relapses, improves stability in the community, and diminishes suicidal behavior. There have also been reports that clozapine may cause a gradual reduction in preexisting tardive dyskinesia.
Unfortunately, clozapine is associated with agranulocyto-sis and, because of this risk, it requires weekly white blood cell testing. Approximately 0.8% of patients taking clozapine and re-ceiving weekly white blood cell monitoring develop agranulocy-tosis. Women and the elderly are at higher risk than other groups. The period of highest risk is the first 6 months of treatment. These data has led to monitoring of white cell counts less frequently after first 6 months to every other week if a person has a history of white cell counts the within the normal range in the preceding 6 months. Current guidelines state that the medication must be held back if the total white blood cell count is 3000/mm3 or less or if the absolute polymorphonuclear cell count is 1500/mm3 or less. Patients who stop clozapine treatment continue to require bloodmonitoring for at least 4 weeks after the last dose according to current guidelines. Other side effects of clozapine include orthos-tatic hypotension, tachycardia, sialorrhea, sedation, elevated tem-perature and weight gain. Furthermore, clozapine can lower the seizure threshold in a dose-dependent fashion, with a higher risk of seizures seen particularly at doses greater than 600 mg/day.
Clozapine has an affinity for dopamine receptors (D1, D2, D3, D4 and D5), serotonin receptors (5-HT2A, 5-HT 2C, 5-HT6 and 5-HT7), alpha-1- and alpha-2-adrenergic receptors, nicotinic and muscarinic cholinergic receptors and H1 histaminergic receptors. As clozapine has a relatively shorter half-life, it is usually admin-istered twice a day.
The superior antipsychotic efficacy of clozapine has in-spired an abundance of research in the field of modern psychop-harmacology for the treatment of schizophrenia. Clozapine and the other novel compounds have an array of biochemical profiles, with affinities to dopaminergic, serotoninergic and noradrener-gic receptors. Research on the atypical antipsychotic compounds has led to a greater understanding of the biochemical effects of antipsychotic agents, leaving the basic dopamine hypothesis of schizophrenia insufficient to explain schizophrenic symptoms. Clozapine shows selectivity for mesolimbic neurons and does not increase the prolactin level. Binding studies have shown it to be a relatively weak D1 and D2 antagonist, compared with traditional neuroleptics (Farde et al., 1989). Clozapine shares the property of higher serotonin 5-HT2A to dopamine D2 blockade ratio reported to impart atypicality. The noradrenergic system may also have a role in the mechanism of action of clozapine (Breier, 1994). Clozapine, but not traditional neuroleptics, causes up to fivefold increases in plasma norepinephrine. Moreover, these increases in norepinephrine correlated with clinical response.
Risperidone is a benzisoxazol compound with a high affin-ity for 5-HT2A and D2 receptors and has a high serotonin dopamine receptor antagonism ratio. It has high affinity for alpha-1-adren-ergic and H1 histaminergic receptors and moderate affinity for alpha-2-adrenergic receptors. Risperidone is devoid of significant activity against the cholinergic system and the D1 receptors. The efficacy of this medication is equal to that of other first-line atypi-cal antipsychotic agents and is well tolerated and can be given once or twice a day. It is available in a liquid form as well. The most common side effects reported are drowsiness, orthostatic hypotension, lightheadedness, anxiety, akathisia, constipation, nausea, nasal congestion, prolactin elevation and weight gain. At doses above 6 mg/day EPS can become a significant issue. The risk of tardive dyskinesia at the regular therapeutic doses is low.
Olanzapine, a thienobenzodiazepine compound, has an-tagonistic effects at dopamine D1 through D5 receptors and sero-tonin 5-HT2A, 5-HT2C and 5-HT6 receptors. The antiserotonergic activity is more potent than the antidopaminergic one. It also has affinity for alpha-1-adrenergic, M1 muscarinic acetylcholinergic and H1 histaminergic receptors. It differs from clozapine by not having high affinity for the 5-HT7, alpha-2-adrenergic and other cholinergic receptors. It has significant efficacy against positive and negative symptoms and also improves cognitive functions. EPS is minimal when used in the therapeutic range with the ex-ception of mild akathisia. As the compound has a long half-life, it is used once a day and as it is well tolerated, it can be started at a higher dose or rapidly titrated to the most effective dose. It is available as a rapidly disintegrating wafer form, which dis-solves immediately in the mouth, and as an intramuscular form. The major side effects of olanzapine include significant weight gain, sedation, dry mouth, nausea, lightheadedness, orthostatichypotension, dizziness, constipation, headache, akathisia and transient elevation of hepatic transaminases. The risk of tardive dyskinesia and NMS is low. Though used as a once-a-day medi-cation, it is often administered twice a day with the average dose of 15 to 20 mg/day. However, doses higher than 20 mg/day are of-ten used clinically and are thus being evaluated in clinical trials.
Quetiapine, a dibenzothiazepine compound has a greater affinity for serotonin 5-HT2 receptors than for dopamine D2 recep-tors; it has considerable activity at dopamine D1, D5, D3, D4, se-rotonin 5-HT1A, and alpha-1-, and alpha-2-adrenergic receptors. Unlike clozapine, it lacks affinity for the muscarinic cholinergic receptors. It is usually administered twice a day due to a short half-life. Quetiapine is as effective as typical agents and also appears to improve cognitive function. Among 2035 patients enrolled in seven controlled studies, quetiapine at all doses used did not have an EPS rate greater than placebo. This is in contrast to olanzapine, risperi-done and ziprasidone, where there were dose related effects on EPS levels. The rate of treatment emergent EPS was very low even in high at-risk populations such as adolescent, parkinsonian patients with psychosis and geriatric patients. Major side effects include somnolence, postural hypotension, dizziness, agitation, dry mouth and weight gain. Akathisia occurs on rare occasions. The package insert warns about developing lenticular opacity or cataracts and advises periodic eye examination based on data from animal stud-ies. However, recent data suggest that this risk may be minimal.
Ziprasidone has the strongest 5-HT2A receptor binding rela-tive to D2 binding amongst the atypical agents currently in use. Interestingly, ziprasidone has 5-HT1A agonist and 5-HT1D antago-nist properties with a high affinity for 5-HT1A, 5-HT2C and 5-HT1D receptors. As it does not interact with many other neurotransmit-ter systems, it does not cause anticholinergic side effects and pro-duces little orthostatic hypotension and relatively little sedation. Just like some antidepressants, ziprasidone blocks presynaptic reuptake of serotonin and norepinephrine. Ziprasidone has a rela-tively short half-life and thus it should be administered twice a day and along with food for best absorption. Ziprasidone is not completely dependent on CYP3A4 system for metabolism, thus inhibitors of the cytochrome system do not significantly change the blood levels. Ziprasidone at doses between 80 and 160 mg/ day is probably the most effective agent for treating symptoms of schizophrenia. To assess the cardiac risk of ziprasidone and other antipsychotic agents a landmark study was designed to evaluate the cardiac safety of the antipsychotic agents, given at high doses alone and with a known metabolic inhibitor in a randomized study involving patients with schizophrenia. This was done to replicate the possible worst-case scenario (overdose or dangerous combina-tion treatment) in the real world. All antipsychotic agents studied caused some degree of QTc prolongation, with the oral form of ha-loperidol associated with the least and thioridazine with the great-est degree. Major side effects reported with the use of ziprasidone are somnolence, nausea, insomnia, dyspepsia and prolongation of QTc interval. Dizziness, weakness, nasal discharge, orthostatic hypotension and tachycardia occur less commonly.
Ziprasidone should not be used in combination with other drugs that cause significant prolongation of the QTc interval. It is also contraindicated for patients with a known history of signifi-cant QTc prolongation, recent myocardial infarction, or symp-tomatic heart failure. Ziprasidone has low EPS potential, does not elevate prolactin levels and causes approximately 1 lb weight gain in short-term studies.
At present, with respect to efficacy, it does not appear that any one of the novel antipsychotic agents (except clozapine) isbetter than another one in treating schizophrenia. The randomized controlled trials suggest that, on average, these antipsychotic agents are each associated with 20% improvement in symptoms. However, clozapine is the only new antipsychotic agent that is more effective than haloperidol in managing treatment resistant schizophrenia. Unfortunately, its potential for treatment-emergent agranulocytosis, seizures and the new warning of myocarditis, precludes its use as a first line agent for schizophrenia. A major difference amongst the newer antipsychotic agents is the side effect profile and its effect on the overall quality of life of the patient.
In last few years, the use of novel antipsychotics has surpassed the use of typical ones in the management of acute phase symptoms of schizophrenia, except for the use of parenteral and liquid forms of antipsychotics where typical antipsychotic agents still hold an upper hand. However, this trend will most likely change once the injectable preparations of the novel antipsychotics enter the market. The primary goal of acute treatment is the ameliora-tion of any behavioral disturbances that would put the patient or others at risk of harm. Acute symptom presentation or relapses are heralded by the recurrence of positive symptoms, including delusions, hallucinations, disorganized speech or behavior, se-vere negative symptoms or catatonia. Quite frequently, a relapse is a result of antipsychotic discontinuation, and resumption of an-tipsychotic treatment aids in the resolution of symptoms. There is a high degree of variability in response rates among individuals. When treatment is initiated, improvement in clinical symptoms can be seen over hours, days, or weeks of treatment.
Studies have shown that although typical neuroleptics are undoubtedly effective, a significant percentage (between 20 and 40%) of patients show only a poor or partial response to tradi-tional agents. Furthermore, there is no convincing evidence that one typical antipsychotic is more efficacious as an antipsychotic than any other, although a given individual may respond better to a specific drug. Once an informed choice has been made between using a novel or typical antipsychotic medication by the patient and the clinician, selection of a specific antipsychotic agent should be based on efficacy, side-effect profile, history of prior response (or nonresponse) to a specific agent, or history of response of a family member to a certain antipsychotic agent. (For a pharmacotherapy decision tree based on Texas Medication Algorithm Project, see Figure 45.3.) Amongst the typical antipsychotic medications, low-potency, more sedating agents, such as chlorpromazine, were long thought to be more effective for agitated patients, yet there are no consistent data proving that high-potency agents are not equally useful in this context. The low-potency antipsychotics, however, are more associated with orthostatic hypotension and lowered sei-zure threshold and are often not as well tolerated at higher doses. Higher potency neuroleptics, such as haloperidol and fluphena-zine, are safely used at higher doses and are effective in reducing psychotic agitation and psychosis itself. However, they are more likely to cause EPS than the low potency agents.
The efficacy of novel antipsychotic drugs on positive and negative symptoms is comparable to or even better than the typi-cal antipsychotic. The significantly low potential to cause EPS or dystonic reaction and thus the decreased long-term consequences of TD has made the novel agents more tolerable and acceptable in acute treatment of schizophrenia. Other significant advantages adding to the popularity of novel antipsychotics include their ben-eficial impact on mood symptoms, suicidal risk and cognition. The selection of the first line treatment with novel antipsychotic
(and occasionally typical antipsychotic agent) also depends on the circumstances under which the medications are started, for example, extremely agitated or catatonic patients would require intramuscular preparation of the antipsychotic agents which would limit the choice. Except for clozapine, which is not con-sidered first line treatment because of substantial and potentially life threatening side effects, there is no convincing data support-ing the preference of one atypical over the other. However, if the patient does not respond to one, a trial with another atypical an-tipsychotic is reasonable and may produce response.
Once the decision is made to use an antipsychotic agent, an appropriate dose must be selected. Initially, higher doses or re-peated dosing may be helpful in preventing grossly psychotic and agitated patients from doing harm. In general, there is no clear evidence that higher doses of neuroleptics (more than 2000 mg chlorpromazine equivalents per day) have any advantage over standard doses (400–600 chlorpromazine equivalents per day).
Some patients who are extremely agitated or aggressive may benefit from concomitant administration of high-potency benzodiazepines such as lorazepam, at 1 to 2 mg, until they are stable. Benzodiazepines rapidly decrease anxiety, calm the person, and help with sedation to break the cycle of agitation. They also help decrease agitation due to akathisia. The use of these medications should be limited to the acute stages of the ill-ness to prevent tachyphylaxis and dependency. Benzodiazepines are quite beneficial in treatment of catatonic or mute patients but the results are only temporary though of enough duration to help with body functions and nutrition.
There is by now a great deal of evidence from long-term follow-up studies that patients have a higher risk of relapse and exacerbations if not maintained with adequate antipsychotic regimens. Noncom-pliance with medication, possibly because of intolerable neu-roleptic side effects, may contribute to increased relapse rates. Indouble-blind, placebo-controlled study of relapse rates, 50% of patients in a research ward demonstrated clinically significant ex-acerbation of their symptoms within 3 weeks of stopping neurolep-tic treatment. It is estimated that two-thirds of patients relapse af-ter 9 to 12 months without neuroleptic medication, compared with 10 to 30% who relapse when typical neuroleptics are maintained. Long-term outcome studies showed that persistent symptoms that do not respond to standard neuroleptic therapy are associated with a greater risk of rehospitalization. Nonpharmacological interven-tions may help decrease relapse rates (discussed later).
Long-term treatment of schizophrenia is a complex issue. It is clear that the majority of patients require maintenance medi-cation. Some patients do well with stable doses of neuroleptics for years without any exacerbations. However, many patients who are maintained with a stable neuroleptic dose have episodic breakthroughs of their psychotic symptoms. The difficulty in tol-erating neuroleptic side effects often results in noncompliance with medication. It is therefore prudent to assess patients for medication compliance when signs of relapse are suspected. Pro-dromal cues may be present before an exacerbation of psychotic symptoms. For example, any recent change in sleep, attention to activities of daily living, or disorganization may be a warning sign of an impending increase in psychosis.
For patients for whom compliance is a problem, long-act-ing, depot neuroleptics are available in the USA for both tradi-tional and novel antipsychotics. This form of medication deliv-ery guarantees that the medication is in the system of the person taking it and eliminates the need to monitor daily compliance. This alternative should be considered if noncompliance with oral agents has led to relapses and rehospitalization. With these patients, maintenance treatment using long-acting preparations should begin as early as possible. Depot antipsychotic drugs are effective maintenance therapy for patients with schizophrenia.
Many studies have investigated appropriate maintenance doses of standard antipsychotics. Effective maintenance treatment is defined as that which prevents or minimizes the risks of symp-tom exacerbation and subsequent morbidity. A series of interest-ing dose-finding studies were performed by Kane and colleagues (1983, 1985) to determine the minimal dosage required to prevent relapse and to reduce the risk of extrapyramidal symptoms and tardive dyskinesia. This group found that the relapse rate (56%) of patients treated with lower doses of fluphenazine decanoate (1.25– 5 mg every 2 weeks) was significantly greater than the relapse rate (14%) of patients receiving standard doses (12.5–50 mg every 2 weeks). Other investigators have found that this low dosage range may appear to prevent relapse for a certain period (Marder et al., 1984) but fails to do so if patients are followed up for more than 1 year (Marder et al., 1987). Unfortunately, no specific dosage reliably prevents relapse, and there is no way to predict future relapse. This is true for the novel antipsychotic agents as well.