Pharmacotherapy in the Treatment of People With Schizophrenia

By | February 4, 2015

The pharmacological agents most primarily associated with treatment of schizophrenia are grouped in a large and heterogeneous family, the antipsychotics. Recently, this family has been subdivided into the typicals, or neuroleptics, and the atypicals (see Tables Selected Typical Antipsychotic Drugs and Their Characteristics and Atypical Antipsychotics: Relative Potencies and Side Effects). The neuroleptics are so named because they all produce side effects suggestive of neurotoxicity. Until the late 1980s there was only one known antipsychotic that was not a neuroleptic: clozapine. In early trials, clozapine was observed to cause a potentially lethal side effect — agranulocytosis, a suppression of white blood cell (WBC) production — in an unacceptably high proportion of individuals. For that reason, clozapine was not approved for use in the United States until 1990. However, clinical use in Europe increasingly suggested that clozapine has important advantages over neuroleptics, and it was eventually made available in the United States, under a strict regimen of continuous monitoring. Shortly thereafter, additional atypical antipsychotics began to appear, and they continue to proliferate. They have little in common, except that whereas the neuroleptics all appear to work through strong blockade effects on the D2 receptor of the neurotransmitter dopamine, the new ones affect other neurotransmitter systems and some show little or no D2 blockade (see Table Atypical Antipsychotic Receptor-Binding Profiles). This inspired the categorical distinction between the “typical” neuroleptic D2 blockers and the atypicals. Today the development and marketing of ever safer and more effective atypical antipsychotic agents has become a major activity in the pharmaceutical industry.

Table Selected Typical Antipsychotic Drugs and Their Characteristics

Chemical name Trade name Dose (mg), usual range Potency *
Phenothiazines
Aliphatic
Chlorpromazine Thorazine 400-800 100
Piperazine
Fluphenazine Prolixin 4-20
Trifluoperazine Stelazine 6-20 5
Thioridazine Mellaril 200-600 100
Butyrophenone
Haloperidol Haldol 8-32 2
Thioxanthene
Thiothixene Navane 15-30 5
Dihydroindolone
Molindone Moban 40-200 10
Dibenzoxazepine
Loxapine Loxitane 20-250 15

* Potency is expressed as the proportionate dosage required for an antipsychotic effect, with chlorpromazine set at 100. Thus a potency of 50 indicates a drug is twice as potent as chlorpromazine.

Table Atypical Antipsychotics: Relative Potencies and Side Effects

Drug Potency(mg/day) Sedation Side effects autonomic EPS Relative clinical dose (CPZ equivalent)
Clozapine 200-600 + + + + + + ( + ) 1
Quetiapine 300-900 + + + + + 1
Risperidone 2-8 + + + + + 80
Olanzapine 10-25 + + + (+) 20
Ziprasidone 80-200 + + + + + + 2

Note. Plus signs represent semiquantitative estimates of the degree of side effects based on the available, relatively limited literature. Parentheses indicate very minimal effect. CPZ = chlorpromazine; EPS = extrapyramidal symptoms.

Table Atypical Antipsychotic Receptor-Binding Profiles

Drug Dl D2 5-HT2 Alpha 1 Cholinergic Histaminergic
Clozapine + + + + + + + + + + + + + +
Quetiapine (+) + + + + + +
Risperidone + + + + + + + + +
Olanzapine + + + + + + + + + + + + + +
Sertindole + + + + + +
Ziprasidone + + + + + + + + +

Note. Plus signs represent semiquantitative estimates of the degree of side effects based on the available, relatively limited literature. Parentheses indicate very minimal effect. D = dopamine; 5-HT = 5-hydroxytryptamine

Changing Views of Schizophrenia and Antipsychotic Agents

Schizophrenia: Strategies for Optimal Use of Antipsychotics

Considerations in the Choice of an Antipsychotic Agent

Ultimately, the best choice of antipsychotic agent must be determined empirically for each individual. Little is currently known about factors that may facilitate the choice of a candidate before the empirical trial. The choice of drug is influenced as much by side-effects considerations and circumstantial factors as by antipsychotic efficacy. Generally, the lower potency antipsychotics have more sedating action, so these get earlier consideration when agitation is part of the clinical picture. Sedation is often aversive, especially to individuals who do not need it, so the higher potency antipsychotics are preferred when sedation is not needed. However, the higher potency antipsychotics are more likely to produce extrapyramidal side effects (the high-potency atypicals are an exception to this). Two agents, haloperidol (Haldol) and fiuphenazine (Prolixin), are available in an injectable slow-release medium that eliminates the need for daily dosing. This is advantageous when psychoeducation and skill training are insufficient to establish adherence to a regimen (or until those modalities have time to work).

Also, new understanding about subtypes of schizophrenia may influence drug choices. For example, it may be that the hypothesized neurodevelopmental subtype of schizophrenia responds best to atypicals because the multiple actions of the atypicals address the pervasive dysregulation of brain systems that inspired the neurodevelopmental model. In other subtypes, symptoms and other impairments may be more focally influenced by dopamine systems and consequently more responsive to specific dopamine blockade.

As the atypicals have proliferated, there has been increasing discussion of whether there is now an antipsychotic drug of first recourse. Clozapine would not be a candidate, despite its superior antipsychotic properties, because of the problems associated with agranulocytosis (discussed later). On the basis of lower risk of side effects and greater antipsychotic efficacy, any of the three recently introduced atypicals — olanzapine, quetiapine, and risperidone — should be given priority over any typical. Within the next few years, one atypical, or perhaps more than one, may emerge as the first choice for different subtypes or clinical pictures. Of course, even after a first-recourse agent is identified on safety and efficacy grounds, cost and other factors could further influence its use.

Adjunctive Pharmacotherapy and Related Issues

An Algorithm for Treatment and Rehabilitation of Schizophrenia

In a preliminary differential diagnosis, rule out the presence of other conditions as possible causes of psychotic behavior.

• intoxication

• febrile delirium

• acute neuropathy

• known chronic or progressive neurological conditions

bipolar disorder

• psychotic depression

• factitious report of symptoms malingering

• transient periods of psychoticlike behavior associated with extreme stress, anxiety, depression, or severe personality disorder

• psychotic-like behavior associated with cultural or sociological circumstances (e.g., spiritual, religious, or political beliefs associated with identifiable groups or ideologies that appear bizarre to other groups).

Proceed with the algorithm if, after ruling out or resolving these causes, a clinical picture of schizophrenia or other severe, adult-onset psychiatric condition persists, including continuous or episodic psychotic symptoms when untreated and significant compromise of personal and social functioning (the functional deficits need not be attributable to the psychotic symptoms).

1. Begin functional assessment and rehabilitation counseling to identify problems and treatment goals.

2. Does historical or current behavioral-observational data indicate problems in adherence to treatment and rehabilitation regimens or an inability to give informed consent to treatment? If yes, assess thoroughly and take action as indicated to protect individuals at risk and engage treatment (these actions must be continuously re-evaluated as recovery permits greater participation and less restriction and restores legal competence).

• Establish means of appropriate substitute decision making (e.g., appointment of guardian, civil commitment, judicial supervision of treatment) when necessary.

• Provide environmental structure sufficient to ensure safety at lowest possible level of restriction (e.g., hospitalization, crisis respite, supervised residential services).

• Negotiate contingency management programs sufficient to establish engagement in treatment and rehabilitation at the lowest possible level of restriction.

3. (Under most circumstances, this step is conducted simultaneously with Step 2.) Do history and presentation suggest that the affected individual is currently experiencing an acute psychotic episode? If yes, take action to resolve acute episode.

• Provide crisis intervention as circumstances demand.

• Begin clinical trial of antipsychotic drug, beginning with first-recourse selection; titrate dose upward or select alternative as indicated by treatment response.

• Administer adjunctive drug to control side effects as necessary.

• Provide psychosocial interventions to enhance resolution of acute psychosis (e.g., specialized CBT) and suppress dangerous or unacceptable behaviors (e.g., time-out-from-reinforcement contingency management programs).

4. (When the antipsychotic used in resolving acute psychosis is a neuroleptic) is there evidence of residual negative symptoms, deficit states, side effects, or psychophysiological or affective dysregulation for which an atypical antipsychotic would be more beneficial? If yes, begin controlled trial of an atypical antipsychotic (under most circumstances, the switch should be gradual and staggered). Proceed to the next step when data indicate that the acute episode is stabilized as much as possible, that is, psychotic symptoms, related behaviors, and acute cognitive impairments are not expected to respond to further adjustments in drug or more time in the therapeutic milieu. Is there evidence of residual negative symptoms, deficit states, or psychophysiological or affective dysregulation for which adjunctive pharmacotherapy may be beneficial? If yes, begin controlled trial of adjunctive pharmacotherapy targeting specific residual problems (e.g., antidepressant drug if residual state is suspected to be depression related, anticonvulsant for agitation or aggression).

Does assessment reveal residual neurocognitive impairments sufficient to compromise personal or social functioning or response to rehabilitation? If yes, provide neuropsychological intervention.

• Begin trial of cognitive-rehabilitative intervention (e.g. Integrated Psychological Therapy, Cognitive Enhancement Therapy).

• Provide supportive and prosthetic environmental conditions for residual impairments that limit functioning and are not eliminated by treatment.

Is there evidence of residual symptoms, affective dysregulation, or other persistent condition for which psychosocial treatment may be effective? If yes, begin trial of psychosocial treatment targeting specific problem (e.g., CBT for symptom control or depression, relapse prevention for substance abuse). (This step is usually conducted simultaneously with Step 7.) Does functional assessment reveal deficits in key skill areas needed to achieve the affected individual’s full potential, live in the least restrictive possible environment, and enjoy a satisfactory quality of life? If yes, begin psychosocial rehabilitation targeting specific skill deficits.

Does progress in rehabilitation allow titration of antipsychotic dose to maintenance level, discontinuation of adjunctive pharmacotherapy, reduction or discontinuation of restrictive environmental supports, or contingency management programs? If yes, adjust regimen accordingly.

Is recovery proceeding as expected, toward measurable goals identified by the entire treatment team (including identified patient and relevant family)? If no, identify barriers to progress, reformulate the treatment and rehabilitation plan, and recycle the entire algorithm.