Schizophrenia 2

7. Pharmacological Treatments of Schizophrenia (Schizophrenia Part 2)

7.1. Clozapine

Clozapine is a dibenzodiazepine and the prototype for most of the atypical antipsychotics (agents that may treat positive, negative, or cognitive symptoms of schizophrenia, have decreased liability for EPS and tardive dyskinesia, may be effective for a proportion of treatment nonresponsive patients, exhibit greater 5HT2 than D2 receptor antagonism, and do not cause hyperprolactinemia). Clozapine has a complex pharmacologic profile encompassing affinities for 5HT2A, 5HT2C, 5HT6, 5HT7, α1 and α2 adrenergic, M1 muscarinic, and histaminergic receptors. Clozapine exhibits inverse agonist activity at 5H2A and 5HT2C receptors, blocking constitutive activity of these receptors. The ratio of 5HT2A to D2 receptor affinities may signal the low EPS profile of clozapine.

Clozapine has been shown to be effective in treatment-resistant schizophrenia. This important study compared the efficacy of clozapine with chlorpromazine in 268 subjects with treatment-resistant schizophrenia (defined as having failed to respond to at least three previous antipsychotics). By 6 weeks, 30% of the clozapine-treated group but only 4% of the chlorpromazine-treated group responded to the respective medications. Thus, clozapine remains the only antipsychotic agent to date that is US Food and Drug Administration (FDA)-approved for treatment-resistant schizophrenia. Additionally, other studies have shown superiority of clozapine versus typical agents in the treatment of total psychopathology, EPS, and tardive dyskinesia and categorical response to treatment. Clozapine reduces positive, negative, and cognitive symptoms of schizophrenia without causation of EPS, tardive dyskinesia, or hyperpro-lactinemia. Additionally, clozapine has been shown to reduce depression and suicidality.

The dose range of clozapine varies from 150 to 600 mg/day for most patients. The initial dose of 25 mg/day must be titrated upward slowly (increments of 25 mg every 3 days) because of hypotensive and tachycardic side effects. The average dose is approximately 400 to 500 mg/day as a twice daily regimen. Plasma levels of 350 to 400 ng/ml have been associated with good clinical response.

Despite clozapine’s important clinical efficacy, several side effects must be considered as potentially significant and life threatening. Agranulocytosis occurs within the initial 4 to 18 weeks of treatment, necessitating monitoring of white blood cell (WBC) and neutrophil count every 2 weeks for the first 6 months, every 2 weeks for the next 6 months, and once monthly thereafter. If the WBC count falls below 3,000 cells/mm³ or the absolute neutrophil count below 1,500 cells/mm³, clozapine administration must be stopped. On diagnosis of agranulocytosis, administration of granulo-cyte colony stimulating factor (G-CSF) and hospitalization is warranted. The death rate from agranulocytosis is approximately 1 per 10,000 patients. Other side effects of cloza-pine include sedation, weight gain, seizures, OCD symptoms, hypersalivation, tachycardia, hypotension, hypertension, stuttering, neuroleptic malignant syndrome, urinary incontinence, myocarditis, constipation, hyperglycemia, leukocy-tosis, eosinophilia, and fever. Seizures can be treated with valproic acid or lamotrigine supplementation.

7.2. Risperidone

Risperidone is a member of the benzisoxazole family of atypical agents and the second FDA-approved antipsychotic agent classified as atypical to be marketed in the USA. Several studies suggest that risperidone may be more effective than typical antipsychotics in acute and maintenance treatment of schizophrenic subjects. Although risperidone may be superior to typical agents in treatment-resistant patients, it is not considered as effective as clozapine in this vulnerable group of schizophrenic patients.

The recommended dosage of risperidone is 2 to 8 mg/day. Risperidone causes higher occupancy of D2 receptors than does clozapine and may cause mild EPS even at a 2 to 4 mg/day dosage range. Additionally, risperidone causes hyperprolactinemia. Other side effects include akathisia, weight gain, sexual dysfunction, decreased libido, and galactorrhea (7). Risperidone is available in depot form for injection.

7.3. Olanzapine

Olanzapine is a thienobenzodiazepine agent and the third FDA-approved atypical agent, marketed in the USA in the late 1990s. This novel agent exhibits nanomolar affinity at several receptor sites, including D1-D4, 5HT2, 5HT3, 5HT6, muscarinic M1–5, α1 adrenergic, and H1 histaminergic sites. Additional novel findings show that olanzapine causes modulation of several important brain genes such as Reelin, insulin, RGS2, pyruvate kinase, calbindin, and homer 1 after chronic administration in rats. Furthermore, olanzapine was shown to increase glucogenesis in brain via multiple pathways, potentially linking its ability to produce glucose for energy consumption in brain to its metabolic side effect profile in the treated subjects. Olanzapine also downregulates the soluble isoform of COMT in the frontal cortex of rats, helping upregulate the levels of dopamine in this important brain area.

Olanzapine has several characteristics of an atypical agent, such as low EPS propensity, chemical structural similarity to clozapine, lack of hyperprolactinemic side effect, broad efficacy, and ability to treat negative symptoms of schizophrenia. Multiple studies have shown olanzapine to have some efficacy over typical agents in the acute and maintenance treatment of schizophrenia and in treatment of refractory patients. The dose range for olanzapine is 10 to 30 mg/day. Despite olanzapine’s beneficial effects, several side effects, including weight gain, metabolic disturbances, sedation, dizziness, and transient liver transaminase elevations should be watched for.

7.4. Quetiapine

Quetiapine is a member of dibenzothiazepine family of atypical agents with high affinity for 5HT2A, α1 adrenergic, and H1 histaminergic receptors. Quetiapine also exhibits a moderate affinity for D2 and a low affinity for M1 muscarinic receptors. The dose range of quetiapine is 300 to 800 mg/day, with similar efficacy to typical agents. Quetiapine is associated with low EPS propensity and low prolactin elevation. The most common side effects include sedation, dry mouth, agitation, constipation, and orthostatic hypotension.

7.5. Ziprasidone

Ziprasidone is a benzothiazolyl piperazine with high affinity for serotonergic (5HT1A, 5HT2A, 5HT2C, 5HT1D) and dopaminergic (more D3, less D2) receptors. It has weak affinities for muscarinic and histaminergic receptors. Recent data indicate that ziprasidone has similar antipsychotic efficacy to haloperidol, and is associated with minimal weight gain, sedation, or prolactin elevation. The dose range is 120 to 200 mg/day. Despite initial concerns for ziprasidone causing QT-interval changes, such as torsade de pointes, the FDA does not require ECG acquisition before treatment and no published reports indicate any cardiotoxic effects.

7.6. Aripiprazole

Aripiprazole is the first FDA-approved partial dopamine D2 agonist, marketed in 2002, with partial agonist activity at the 5HT1A receptor and 5HT2A antagonism. Aripiprazole has low EPS propensity, and a low liability for hyperpro-lactinemia and weight gain. The dose range is 10 to 30 mg/day. Aripiprazole is effective in short- and long-term treatment of schizophrenia. Side effects may include activation and nausea.

7.7. Paliperidone

The newest atypical agent, approved by FDA in 2007, is paliperidone, which is a major metabolite of risperidone with pharmacological activity at monoamine receptors analogous to risperidone. The terminal half-life is less than 24 hours. Paliperidone does not undergo significant hepatic metabolism and has a dose range of 3 to 15 mg/day once daily. A recent study shows efficacy and safety of paliperidone-ER in an acute and a 14-week trial treatment of schizophrenia.

7.8. Typical Antipsychotics

Results of CATIE trials indicated that there may not be significant differences between several atypical agents (cloza-pine, olanzapine, ziprasidone, aripiprazole, and risperidone) and a typical agent (perphenazine) regarding efficacy in treatment of schizophrenic positive symptoms. Indeed, introduction of chlorpromazine and later antipsychotic agents such as haloperidol in the 1950s revolutionized the treatment of schizophrenia. These agents clearly treated positive symptoms in 60 to 70% of patients and enabled many patients to leave hospitals for the first time in decades. The early hypotheses suggested that the actions of typical antipsychotics in ameliorating the positive symptoms of schizophrenia were caused by their dopaminergic antagonism. Recent genetic and microarray studies have revealed that most, if not all, antipsychotic agents probably treat schizophrenic symptoms by modulating a large number of brain genes whose chronic upregulation or repression may lead to stabilization of positive, negative, and cognitive deficits in schizophrenia. Thus, it seems that modulation of major neuro-transmitters like dopamine, serotonin, glutamate, GABA, and acetylcholine by various antipsychotic agents may only be part of a larger array of brain genes and proteins that may be involved in treatment of schizophrenia.

7.9. Multiple Phases of Pharmacologic Treatment

In the acute phase treatment, patients with florid psychotic symptoms are generally admitted to a hospital setting and given short-acting antipsychotic agents (ziprasidone, olanzapine, or haloperidol) alone or in combination with benzo-diazepines and/or anticholinergics. The clinical decision to begin antipsychotic treatment is dependent on several factors, including side effect profile, history of response to medications, and patient preference (Table 6). The order of antipsychotic agents of choice based on low propensity for metabolic side effects, EPS, and tardive dyskinesia may be aripipra-zole, quetiapine, risperidone/paliperidone, ziprasidone, olan-zapine, and haloperidol. In cases of noncompliance, depot medications, such as long-acting risperidone, haloperidol, or fluphenazine may be administered.

In the continuation-phase treatment, the patient’s response to the antipsychotic agent, and the side effect profile, tolerability, and compliance will be monitored carefully. It is generally expected that optimal response to most agents will be achieved by 4 to 6 weeks, however, longer periods of therapy may be necessary in certain individuals. In some patients, residual constellations of positive, negative, or cognitive symptoms may remain. In some cases, one antipsychotic agent may be switched with another medication. Alternatively, and specifically in treatment nonresponsive patients, clozapine alone or in combination with other agents, such as valproate, benzodiazepines, antidepressants, or lithium, may be necessary to treat various symptoms.

In the maintenance-phase treatment, patients who have responded well to various agents should be treated indefinitely to prevent relapse and worsening of the disease process. In treatment-refractory cases, clozapine seems to be the only drug with proven efficacy.

Table 6. Commonly used antipsychotic drugs.

Class and drug name	Dosage range (mg)	Chlorpromazine equivalents (mg/day)	Parenteral dosage	Galenic formsa
Typical drugs
Chlorpromazine	300-1000	100	25-50 mg	O, L, I, S
Fluphenazine	5-20	2	1.25-2.25 mg	O, L, I
Fluphenazine decanoate	—	—	12.5–50 mg every 1–4 weeks	—
Fluphenazine enanthate	—	—	12.5–50 mg every 1–4 weeks	—
Haloperidol	5-20	2	5-10 mg	O, L, I
Haloperidol decanoate	—	—	25–100 mg every 1–4 weeks	—
Loxapine	30-100	10	25 mg	O, L, I
Mesoridazine	150-400	50	25 mg	O, L, I
Molindone	30-100	10	NA	O, L
Perphenazine	16-64	10	5-10 mg	O, L, I
Pimozide	0.5-2	2	NA	O
Thioridazine	300-800	100	NA	O, L
Thiothixene	15-50	5	2-4 mg	O, L, I
Trifluoperazine	15-50	5	1-2 mg	O, L, I
Atypical drugs
Aripiprazole	10-30	4b	NA	O, L
Clozapine	150-600	50-100	NA	O
Olanzapine	10-30	4	NA	O, I, OD
Paliperidone	3-15	NA	NA	O
Quetiapine	300-800	100	NA	O
Risperidone	2-8	1	NA	O, L, I, OD
Risperidone microspheres	—	—	25–50 mg every 2 weeks	—
Ziprasidone	120-200	40	10 mg	O, L, I

O, oral; L, liquid; I, injection; S, suppository; OD, oral disintegrating form. Meltzer et al., 2008 (29). Adapted with permission from the International

Psychopharmacology Algorithm Project (IPAP) algorithm for the treatment of schizophrenia, available at www.ipap.org.

^aMeltzer and Fatemi, 2000 (7).

^bDrug Information Handbook for Psychiatry, 6th ed. Fuller MA, Sajatovic M, eds. Lexi-Comp, 2007 (175).

8. Antipsychotic-Related Side Effects

One of the major reasons for the choice of new second-generation antipsychotics relates to the high frequency of several side effects that are more prevalent with typical agents. For example, EPS, such as dystonias (repetitive involuntary skeletal muscle contractions [Fig. 6]), dyskinesias (slow or tardive dyskinesias or severe involuntary choreiform, athetoid, or rhythmic muscular contractions that may involve the face, neck, tongue, hands, trunk, and legs (Fig. 5)), pseudoparkin-sonism, rabbit syndrome, and akathisias occur secondary to the use of high-potency typical antipsychotics. All of these side effects, except for tardive dyskinesia, can be treated by judicious use of anticholinergics, benzodiazepines, or propra-nolol, or by reduction in dose of the antipsychotic agents or by switching to an atypical agent. There are no proven treatments for tardive dyskinesia. Nonneurologic side effects may include hyperprolactinemia, gynecomastia, impotence, amenorrhea, weight gain, hematologic effects, jaundice, and cardiac effects.

9. ECT Treatment of Schizophrenia

ECT treatment (6–12 treatments) may be an adjunct in treatment-refractory patients and when required in rapid control of excited catatonia and severe agitation. Long-term use of ECT in treatment of schizophrenia is not supported by the current literature

Figure 5. A psychotic woman treated with numerous neuroleptic drugs for at least 15 years developed typical orofacial–buccolingual tardive dyskinesia (reprinted with permission from Blackwell Scientific Publications).

Figure 6. OCG with torticollis and tongue protrusion (reprinted with permission from Blackwell Scientific Publications)

10. Psychosocial Treatment

Several psychosocial treatment modalities, such as cognitive– behavioral therapy, personal therapy, compliance therapy, acceptance and commitment therapy, as well as supportive psychotherapy, have been found to help patients and their families to deal with the disease process, noncompliance issues, and improvement of patients’ living and work functioning. Application of case management, token economy, reduction of expressed emotion by patients’ family, and assertive community treatment, social skills training, and cognitive rehabilitation strategies can all help patients with schizophrenia to have a better outlook on life and to improve their compliance with the medication regimen.

11. Time Course of Schizophrenia

Disease onset is highly variable. The prodromal phase consists of a period during which the patient may experience social withdrawal, decreased motivation, poor cognition, increasing odd behavior, and restricted affective range. During the active phase (first psychotic break), patients exhibits florid psychotic symptoms either in response to life stressors or after substance abuse. In the residual phase, some schizophrenic symptoms remain that persist despite treatment.

12. Prognosis and Course of Illness

The modern concept of the prognosis of schizophrenia is based on multiple outcome measures. Four types of outcome measures have been identified: psychopathology, work function, social function, and rehospitalization. These measures could vary independently in schizophrenia, and, although they are central to evaluating outcome in schizophrenia, other measures, such as cognitive function, general health, and suicide are also important.

Table 7. Predictors of course and outcome in schizophrenia. (click image to view)

Key: 1, clinical; 2, diagnosis; 3, environment; 4, treatment; 5, genetic. Meltzer and Fatemi, 2000 (7); Meltzer et al., 2008 (29); Perkins et al., 2006 (171).

Outcome in schizophrenia can be predicted partially by age at onset and by the nature of the prodrome and first episode (Table 7). Early age at onset (e.g., 14–18 years) is often associated with a worse outcome than is later age at onset. An insidious rather than an abrupt onset is also associated with a poor outcome. If the initial clinical presentation is characterized mainly by negative symptoms, the outcome is likely to be poor, both in the short and long term. Conversely, florid psychosis and an abrupt onset are both likely to be associated with a good prognosis because antipsychotic drugs are much more effective against positive symptoms and disorganization than they are against negative symptoms and cognitive disturbance.

Results from several long-term reports studying outcome in schizophrenia show that, during a 15-year period, several disease courses may emerge: 1) 9 to 38% of patients will have a sustained recovery; 2) 10% of the patients will have a persistent unremitting course; 3) 67% of patients will have a good outcome; 4) 32% of patients will have a poor outcome; and 5) 10% will die by suicide. Generally, the overall prognosis of schizophrenia is more favorable now than before neurolep-tics were introduced, mostly because of improvements in pharmacologic therapies and, to some degree, changes in psychosocial treatment strategies. The increased mortality in patients with schizophrenia today is the result of suicide, accidents, and diseases (e.g., infections, type II diabetes, heart disease, and in women, breast cancer).

Acknowledgements.

The work of the author is supported by NIH grants 1R01HD046598-0142 and 1R01HD052074-01A2 and the Stanley Medical Research Institute grant # 06R-1406.