Schizophrenia Under Control

Switching from one antipsychotic drug to olanzapine is safe, study shows

Antipsychotic drugs, also known as neuroleptics, have been used as a major medication to treat schizophrenia, as well as agitation and psychosis associated with other psychiatric and organic disorders. Antipsychotics significantly improved the treatment of patients suffering from schizophrenia in spite of their potential side effects. Research in this field paved the way for the discovery of newer drugs that are both safe and effective in treating the clinical symptoms of schizophrenia.

    Recognizing the need to introduce better treatment alternatives, the Philippine Psychiatric Association and Eli Lilly Philippines Inc. recently held a dinner-symposium on two issues involving the treatment of schizophrenia. Dr. Bernardo Jorge Conde, associate professor and chair of the Department of Neurology and Psychiatry of the Sto. Tomas University Hospital, discussed the techniques of switching from previous antipsychotics to olanzapine. Dr. Frans August Korb, clinical research physician for neurosciences of Eli Lilly South Africa, tackled ways to get the most out of antipsychotic treatment.

To Switch and How to Switch

    Dr. Conde shared the results of the study "Switching From Previous Antipychotics to Olanzapine: A Regional Collaborative Multi-Center Trial Assessing Two Switching Techniques in the Asia-Pacific." The results were first presented during the May 2001 American Psychiatric Association Convention in New Orleans.

    The study compared the tolerability and efficacy of direct switch with start-taper switch in changing an Asian patient's medication from neuroleptics to olanzapine. It also evaluated the efficacy and safety of olanzapine using two different switch techniques as measured by the Positive and Negative Syndrome Scale (PANSS) and the CGI-Severity Scale (CGI-S).

    An open-label, randomized study, the research involved 108 patients diagnosed to have schizophrenia based on the DSM-IV criteria who were on a usual neuroleptic medication for a minimum of four weeks before the first visit.

    The first study period consisted of two main activities: screening and administration of the usual neuroleptic treatment. Patients continued to receive their usual neuroleptic medication for one week. The clinically stable patients were then qualified to enter Study Period II or the six-week open-label olanzapine treatment. The direct-switch group stopped taking their previous neuroleptic and started olanzapine therapy at 10 mg/day. The start-taper switch group received olanzapine (10 mg/day) and their usual neuroleptic treatment in decreasing doses over the first two weeks.

    A patient who successfully switched to olanzapine was defined as one who remained in the open-label therapy for at least six weeks without worsening symptoms as shown by two successively worse ratings from baseline on the CGI-S and without any exacerbation of extrapyramidal symptoms (EPS) as evidenced by an increase from baseline values in any post-baseline visit using the Simpson-Angus Scale total score.

Start-Taper or Direct Switch

    Seventy-four percent had a successful switch in the direct-switch group, 67.9 percent in the start-taper switch group. Dr. Conde said there was no significant difference between the two groups.

    The efficacy scales showed a marked improvement from baseline to endpoint, although there were no statistically significant differences between the two groups.

    Among the observed cases, the PANSS Total Score and the CGI-Severity Score showed a significant improvement of the patients' condition from the baseline over six weeks of olanzapine therapy. This was again true for both switching techniques. There was also a marked improvement of EPS scores (Figure 1), with the differences between the two switching techniques not statistically significant.

    Dr. Conde noted the following treatment-emergent adverse events in at least five percent of patients in either switch group: somnolence, headache, insomnia, akathisia, increased appetite, asthenia, agitation, weight gain, tremors, and diarrhea. Weight gain was significant in the direct-switch group, but a mean weight loss was observed in the start-taper group. For the direct-switch group, there were notable increases in pulse rates in both the standing and supine positions. The reverse was true in the start-taper group.

    While recommending that further controlled trials be carried out, Dr. Conde said the results of the study suggest that among Asian patients with schizophrenia, switching to olanzapine from another antipsychotic medication, directly or gradually, may be a safe and effective therapeutic option.

Treatment Options

    Antipsychotic treatment has changed over the years. Today's antipsychotics are either typical or atypical. Also known as conventional antipsychotics, the typical drugs have limitations in efficacy, safety, and tolerability, being unable to correct primary disorders of thought. They are not as effective in alleviating negative symptoms or associated depression, and fail to arrest disease progression. They cause extrapyramidal symptoms (EPS) or tardive dyskinesia (TD), sedation and cognitive impairment, and serum prolactin elevation. They also induce undesirable effects on the cardiovascular system, blood components, and sexual function. Approximately 50 percent of patients on conventional antipsychotics do not respond adequately.

    Atypicals have lower incidence of EPS, broader efficacy profile, and minimal effect on prolactin levels. But not all atypicals are the same. Dr. Korb said they are classified into three sub-groups based on their binding profiles: the D2 antagonists sulpiride and amisulpiride; D2/5-HT2/a1 antagonists risperidone, ziprasidone, and sertindole; and the multi-receptor antagonists clozapine, olanzapine, and quetiapine. Dr. Korb said the psychiatrist's choice of agent and dosage should result in maximal therapeutic benefit with minimal side effects.

Weighing the Risks and Benefits

    The key to effective and safe treatment lies in the control of EPS (dystonia, Parkinsonism, akathisia, and dyskinesia) and other potential side effects. Dr. Korb said atypicals are associated with lower risk of acute EPS than conventional antipsychotics, and they are as effective as conventional antipsychotics across all psychotic disorders.

    He said this has been proved in many studies, among them the Naturalistic Antipsychotic Drug Study that measured spontaneous adverse events per COSTART glossary comparing atypicals olanzapine and risperidone with typical haloperidol. Haloperidol caused the most number of adverse events and EPS while olanzapine had the least (Figure 2). With low EPS risk, patients comply better, improve their cognition, and experience less negative symptoms, dysphoria, motor side effects and tardive dyskinesia.

    Weight gain is also common among patients on antipsychotic medication. Dr. Korb cited three theories to explain this phenomenon. Sedation, mostly mediated by H1 and a1 receptors, decreases the basal metabolic rate (BMR); constant caloric intake results in increased adiposity. Another theory highlights the role of 5-HT2C affinity, which may cause an increased "set" point, the reason why the patient starts putting on weight. On the other hand, H1 affinity can cause failure of satiety. "Patients do not feel that they have eaten enough," Dr. Korb explained. "They don't feel full so they overeat."

    The last theory has something to do with the dysregulation of the leptin NPY system. A study determined the magnitude of weight gain during treatment with different antipsychotics. Clozapine caused the most weight gain while olanzapine and thioridazine ranked second.

    Dr. Korb said behavioral intervention helps prevent weight gain as shown by Wirshing's study in which he suggested the following modes of intervention:

    o Weigh the patient at one to four weeks intervals

    o Discuss lifestyle interventions with the patient

    o Ask the patient to maintain a diary of food intake

    o Refer the patient to a nutritionist and to a "wellness clinic" where an exercise and diet program is made

    o Control the patient's diet if confined in a hospital.

    Dr. Korb also pointed out that weight gain tends to plateau, citing studies with olanzapine used alone or in combination with nizatidine or amantadine.

    Some antipsychotic drugs have also been known to cause clinically significant cardiac events because they prolong the QT interval. Dr. Korb advised psychiatrists to watch out for symptoms like dizziness, palpitations, syncope, and ventricular tachyarrhythmias.

    QT interval is the length of time it takes the electrical system in the heart to depolarize and repolarize. In study 054, it was noted that thioridazine and ziprasidone caused QTC change of 60 msec in 29 percent and 21 percent of patients, respectively. Individual QTC changes = 60 msec from baseline measures raise clear concerns about the potential risk of a medication in inducing arryhthmias.

    Summing up, Dr. Korb stressed the role of other services and support systems. "If we can minimize side effects and maximize psychotherapy and social support systems, we can hopefully get better compliance from our patients," he said. "This will lead to better symptom control and ultimately to a better quality of life."