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Optimizing Antipsychotic Drug Treatment

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS -49th Annual Meeting of the American College of Neuropsychopharmacology (ACNP)

Miami, Florida / December 5-9, 2010

In general, second-generation (atypical) antipsychotics are now used preferentially over traditional neuroleptics for schizophrenia. Many of these agents, which appear to be more versatile and better tolerated than the first-generation antipsychotic drugs, are also approved for use in controlling bipolar disease. While both typical and atypical agents offer activity at the D<sub>2</sub> dopamine (D2D) receptor (D2DR), the clinical efficacy of atypical agents relative to typical agents appears to be derived from more complex neurotransmitter activity, including a greater propensity for activity at the serotonin type 2 (5HT2) receptor. Increasingly, receptor activity is being used to predict clinical activity, including dosing.

Individualized Dosing

The most important recent example involves a series of studies with ziprasidone, an atypical agent associated with a low relative risk for weight gain that is approved for schizophrenia and bipolar disease. It is unclear whether its specific neurotransmitter activity accounts for its favourable benefit:risk profile, but it shares robust activity at the D2DR observed with other typical and atypical agents. New studies measuring this activity appear to be useful in defining the optimal dose of this therapy.

“We were interested in brain occupancy over a 24-hour period as opposed to plasma levels, where we know the half-life is relatively short,” stated Dr. Steven Potkin, Director of Clinical Research, Psychiatry, and Human Behavior, University of California, Irvine School of Medicine, who presented the results of the study. “Many clinicians use once-a-day dosing with ziprasidone, but this has not been studied formally as an effective dosing [scheme]. We wondered whether occupancy data would support this or not.”

In this study, 13 patients with schizophrenia were randomized to ziprasidone monotherapy 60 mg b.i.d., 80 mg b.i.d. or 120 mg b.i.d. All patients were maintained on therapy for at least 2 weeks. Brain imaging to evaluate receptor activity was performed with 18F-fallypride PET scans with a high-resolution camera at 5, 12 and 24 hours after the last dose to create a 24-hour time activity curve. Two reference tissue models were used to compute distributed volume ratio estimates from the graphic analysis of PET data to obtain receptor occupancies.

Using the Logan reference tissue method, D2DR occupancy in the caudate was 83% at 5 hours, 80% at 12 hours and 71% at 24 hours’ post last dose. Occupancy in the putamen was 81%, 78% and 69%, respectively. These results were similar in the thalamus and amygdala. Occupancies at corresponding time points in the nucleus accumbens were slightly lower than other areas (74%, 70% and 59%). The investigators obtained similar results using the multilinear reference tissue method.

“At the time when blood levels of ziprasidone are expected to be close to zero, occupancy in the brain is still substantial, which supports the idea of once-a-day dosing,” Dr. Potkin stated, noting no occupancy:dose relationship. “There is really no difference in per cent occupancy between 120 mg/day and 240 mg/day,” he told delegates. “It showed that some patients needed to have the same D2DR occupancy at 240 mg as other patients did at 120 mg/day, meaning that the dose has to be individualized. Some patients may need only 80 mg/day as a starting dose, but others will need even higher doses than currently recommended,” he suggested.

Disease State and Variable Side Effects

On the basis that neurotransmitter activity is the critical determinant of clinical benefit, the same approach is likely to be relevant to other antipsychotic drugs. Focusing on the central nervous system (CNS) activity of antipsychotic agents—as opposed to serum drug levels—is also likely to be relevant to predicting risks as well as benefits. This was suggested by a less sophisticated study that compared patients with schizophrenia, mania and bipolar depression. Although this study did not involve PET imaging, it demonstrated that the side effect profile of the same agent is different depending on the disease state. Although the antipsychotic employed in this study (ziprasidone) has demonstrated efficacy in all 3 psychiatric diseases, the differences in side effects are presumed to be at least partially mediated by activity at specific neurotransmitter receptors.

The relative risk for adverse events with these agents, such as extrapyramidal symptoms (EPS) or weight gain, varies across disease states, according to Dr. Keming Gao, Assistant Professor, Case Western Reserve University School of Medicine, Cleveland, Ohio. For example, “Patients with bipolar mania have a higher risk for EPS than those with schizophrenia when treated with haloperidol or atypical antipsychotics [while] the risk for discontinuation due to adverse events and reported somnolence using quetiapine vs. placebo was higher in patients with bipolar depression compared to schizophrenia or mania.”

In a study designed to evaluate specific risk profiles in patients with different diagnoses taking ziprasidone, data were collated from 9 double-blind, placebo-controlled, short-term trials that investigated ziprasidone monotherapy in doses ranging from 5 mg to 100 mg b.i.d. This included 2 trials that randomized more than 900 patients with bipolar depression, 3 involving more than 500 patients with bipolar mania, and 4 trials with more than 900 patients with schizophrenia.

The risk for somnolence was significantly higher for ziprasidone vs. placebo in bipolar depression and bipolar mania but this risk was only significantly increased at the highest dose (=80 mg) in patients with schizophrenia. Concerning risk for =7% weight gain, the researchers found no significant difference in bipolar depression or bipolar mania relative to placebo. In schizophrenia, the risk was moderately higher but not significantly different than placebo for the highest dose (100 mg).

The efficacy analyses of these trials support the current indications for ziprasidone, which include schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate. However, the differences in side effects associated with this atypical when employed in different types of psychiatric disorders encourage translation of neurotransmitter receptor activity into clinical activity. This may be relevant for individualizing care of patients according to their underlying diagnosis and their unique response to antipsychotic therapy.

Predicting Response

Indeed, new data identifying 5 distinct trajectories of response to antipsychotic therapy among patients with chronic schizophrenia support differences in neurotransmitter receptor activity. In this study, led by Dr. Virginia L. Stauffer, Zucker Hillside Hospital, New Hyde Park, New York, the 5 patterns of response were derived from 6 trials with olanzapine, ziprasidone, risperidone, quetiapine and aripiprazole that randomized 1990 patients.

When evaluated with growth mixture modelling, most patients (90.6%) were identified as Class 2, which is characterized by a moderate level of illness at baseline (Positive and Negative Syndrome Scale [PANSS] total=90), a mean improvement of 20% by week 4, and little further improvement. Patients in Class 1, characterized by severe illness at baseline (PANSS total=124) but rapid response by week 3 (51% reduction in mean PANSS total score), only represented 2.4%. Classes 3 and 4, which were both characterized by a minimal initial response or subsequent loss of response, represented only 3% of patients in total. Class 5, characterized by marked to severe illness at baseline (PANSS total=113), an initial delay in response (11% improvement over 8 weeks), but noticeable (28%) improvement in the remaining 4 weeks, represented 4.1% of patients.

The 5 classes differed significantly by gender, age, race, baseline illness severity, specific symptom types, weight, EPS and discontinuation rates (all P<0.05). Dr. Stauffer and colleagues offered that understanding these response patterns might be clinically useful. These patterns might also inform antipsychotic drug activity if they correspond to receptor activity profiling. Studies evaluating receptor activity in relationship to symptom control may be the next frontier in improved patient management.

Summary

It has long been predicted that neurotransmitter receptor activity will explain most benefits and some of the risks of antipsychotic therapy. New data with sophisticated imaging are beginning to look at dosing of therapies based on their activity in the CNS rather than on the basis of drug serum levels alone. Newer atypicals, particularly those that produce low risks of the most feared side effects, such as EPS and weight gain, provide an important avenue to pursue studies that will isolate drug mechanisms.

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