The Examination of Schizophrenia

By Abimbola Farinde, PharmD –

What is schizophrenia?

Schizophrenia is considered to be a psychotic thought disorder that is characterized by a mixture of symptoms that involve perception, cognition, emotions, behavior, attention, concentration, motivation, and judgment (Dipiro et al., 2005).

The postulated hypothesis underlying the development of schizophrenia focuses on the hyperdopaminergic and hyerserotinergic hypothesis for the positive and negative symptoms that are associated with schizophrenia.

The positive symptoms typically consist of hallucination, delusions, disorganized speech, thought, and language while the negative symptoms consist of flat affect, alogia (poverty of speech), poor attention, loss of social interest, avolition (loss of motivation) and much more) but likely the development of typical and atypical antipsychotics and behavioral therapies have allowed many sufferers to have some semblance of a normal life.

The diagnostic criteria for schizophrenia is based on the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition, Fifth Revisions (DSM-V) which states that two or more active positive and negative symptoms must be present for 1 month or there must be continuous signs of illness for at least 6 months for an individual to meet the diagnostic criteria (American Psychiatric Association, 2013).

Journal Article Review

A journal article that addresses the treatment for schizophrenia is titled ‘Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia” released by Lieberman and colleagues in 2005. The use of antipsychotics has been considered to be the cornerstone for the treatment of schizophrenia. The use of first-generation or typical antipsychotic have long been recognized as the drug of choice based on their level of effectiveness against psychotic symptoms but they have a high rate of side effects such as tardive dyskinesia, dystonia, pseudoparkinsonism, and tremors (Lieberman et al., 2005).

The introduction of the second atypical antipsychotic in the early 1990s came with the promise of enhance efficacy and safety when compared to the first generation antipsychotics so the authors decided to conduct a double-blind, active control clinical trial sponsored by the National Institute of Health (NIMH) to compared the effectiveness of the older, typical antipsychotics to the newer, atypical antipsychotic drugs called the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study.

The study was conducted between January 2001 and December 2004 in which participants were randomly assigned to receive atypical antipsychotics, olanzapine (zyprexa®), quetiapine (seroquel®), risperidone (risperdal®), and typical antipsychotic perphenazine (trilafon®), and with ziprasidone (geodon ®) being approved after the study began it was added to the study in January 2002.

The proposed hypothesis for the study was that there would be significant differences in the overall effectiveness of olanzapine, quetipine, risperidone, ziprasidone, and perphenazine in treating schizophrenia with regards to efficacy and tolerability, and the primary outcomes measure for the study was the discontinuation of treatment for any cause and the secondary outcome being the specific reason for the discontinuation whether it was inefficacy, intolerability due to side effects, extrapyramidal signs, or sedation.

The study consisted of Phase 1 of the study with additional information from Phases (Phase IB, Phase 2, and Phase 3) being released.

From Phase I it was determined that the time to discontinuation for treatment was significantly longer with olanzapine than in the quetiapine (p<0.001) or risperidone (p=0.002) group but not in the perphenazine (p=0.021) group or ziprasidone (p=0.028) group but out of the 1432 individuals and the 1061 who received doses, 82% of those assigned to quetiapine discontinued treatment.

In terms of the secondary outcome the specific reason for discontinuation was related to intolerable side effect with olanzapine being associated with more discontinuation for weight and metabolic side effects ( increase in glucose and lipid metabolism) than any other antipsychotic and extrapyramidal side effects was the reason for more discontinuation of perphenazine.

From this Phase 1 study of the CATIE trial it was determined that the many of the participants assigned to each group discontinued as a result of inefficacy or intolerable side effects and olanazapine was found to be the most effective antipsychotic in terms of its rate of discontinuation (64% for olanzapine, 74% for risperidone, 75% for perphenazine, 79% for ziprasidone, and 82% for quetiapine) and the efficacy of the first generation antipsychotic (perphenazine) was found to be the same as the atypical antipsychotics which disproved the authors hypothesis of there being a significant difference among the antipsychotics.

Even though it has been stated that the atypical antipsychotics have superior efficacy when treating schizophrenia by reducing psychotic symptoms, the data has not been robust enough to support this theory, but if negative symptoms supersedes positive symptoms atypical antipsychotics can be used whereas the typical antipsychotics are effective for treating the positive symptoms of schizophrenia.

Conclusion

Lastly, a question that was triggered from reading this article is that whether the varying doses of the antipsychotics played a major role in the time to discontinuation and side effect development. The doses that were approved by the Food and Drug Administration (FDA) for quetiapine and ziprasidone were potentially below the optimal therapeutic doses but the participants were given the maximal doses while the dose of perphenazine was lower in order to minimize exrapyramidal side effects.

If the authors were allowed to go beyond the recommended daily doses of the antipsychotics would this have yielded different results and would there have been a significant difference in efficacy among the antipsychotics?

References

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author.

Dipiro, JT et al (2005). Pharmacotherapy: A Pathophysiologic Approach. 3^rd edition. New York: The McGraw-Hill

Companies, Inc.

Lieberman, J.A.,Stroup, S., McEvoy, J.P. et al (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. The New England Journal of Medicine, 353(12),1209-1223.

Abimbola Farinde, PharmD is a clinical pharmacy specialist who has gained experience in the field and practice of psychopharmacology/mental health, and geriatric pharmacy. She has worked with active duty soldiers with dual diagnoses of a traumatic brain injury and a psychiatric disorder providing medication therapy management and disease state management.