Atypical Antipsychotics Enhancing Mood and Cognition

Researchers find no single antipsychotic drug stands out in treating symptoms of schizophrenia.

Although some patients may respond to one agent better than another, no one atypical antipsychotic has proven consistently superior in treating cognitive or affective symptoms in schizophrenia. Investigators have found preliminary evidence that all atypical antipsychotics improve cognitive and affective symptoms in schizophrenia and are superior to conventional neuroleptics in this regard. For all atypical antipsychotics, onset of cognitive and affective symptom improvement appears delayed compared to improvement in positive symptoms. These observations were made at the 157th Annual Meeting of the American Psychiatric Association by researchers from the Neuroscience Education Institute in San Diego.

"All physicians have seen some patients respond to one atypical and not another. The class actions of the agents explain why they are similar. The differential pharmacology potentially can explain why they are different. This is actually predicted from pharmacology," said Stephen M. Stahl, MD, PhD.

Atypicals Are Typical in Target

An "interest in expanding the relationship between pharmacologic mechanism of action and clinical actions of atypical antipsychotics" led Dr. Stahl and Darius K. Shayegan, BS,

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to investigate the receptor-binding properties of those agents, according to Dr. Stahl, who is Chairman of the Neuroscience Education Institute and Professor of Psychiatry at the University of California, San Diego.

A literature review profiled the portfolio of receptor-binding actions for each of the five first-line atypical antipsychotics risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify). All antipsychotic agents target the key hypothetical neurochemical disturbance in psychosis excessive dopamine neurotransmission at dopamine-D2 receptors in the mesolimbic pathway of the brain - presumably responsible for the positive symptoms of schizophrenia. All atypical antipsychotic agents are serotonin-2A (5-HT2A)/ dopamine-D2 antagonists or D2 partial agonists, properties that contribute to reduced motor side effects, the investigators noted. Interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors, as well as with serotonin and norepinephrine reuptake sites in human brain tissue, predicts cognitive improvement, heightened negative symptom relief, and enhanced modulation of mood. Affinity for α1-adrenoceptors, histamine H1 receptors, and muscarinic M1 receptors predicts orthostatic hypotension, sedation, cognitive disturbance, or weight gain. Receptor-binding properties other than 5-HT2A/D2 receptor occupancy, the researchers suggested, may explain cognitive and affective symptom improvement associated with atypical antipsychotic therapy.

All Are Not Equal

Varying outcomes are commonly observed for different patients treated with different atypical antipsychotics, the investigators said. "Although it is true that no one agent is clearly superior in large clinical trials, it is not true that all are equal for every individual. Some patients respond quite differently to one agent than another, and that is why it is important for formularies to keep all the options open and for prescribers to try every agent in this class if the patient does not have a satisfactory response," said Dr. Stahl. According to the researchers, it is theoretically possible that variable treatment outcomes may be due to differential sensitivities of a patient's neurobiologic machinery, as enabled via individual genotype, and to pharmacologic differences inherent within individual drugs.

For this reason, the investigators believe that receptor- binding properties other than 5-HT2A/D2 occupancy may explain cognitive and affective symptom improvement associated with atypical antipsychotic therapy. The researchers based this conclusion on their review of the literature, which demonstrated that differences in clinical efficacy among atypical antipsychotics may be related to variances in 5-HT2A/D2 receptor relative affinity ratios, the degree of D2 receptor blockade, and sensitivity of an individual's cortical neuronal architecture to increasing dopamine, norepinephrine, or acetylcholine subsequent to establishing potent 5-HT2A antagonism. These receptor-binding properties might enhance the ability of an atypical antipsychotic to improve affect and cognition, it has been theorized.

"Most physicians already recognize that individual patients respond differently to different atypical antipsychotics, and these findings may help them understand why and encourage them to try some of the agents they do not use as frequently, in the hope of attaining a better result in some individuals," said Dr. Stahl.

Understanding the receptor-binding properties of atypical antipsychotics may also help physicians select which treatments to combine for patients who are not responding to monotherapy. According to Dr. Stahl, "pharmacologic properties may explain synergy in combination with other classes of drugs, such as mood stabilizers."

Dosing Differences?

It was demonstrated that improvement of cognitive and affective symptoms observed with atypical agents was delayed compared to improvement of positive symptoms. The investigators suspect this implies the likelihood of a delayed biochemical process such as changing gene expression that may underlie cognitive and affective improvement.

Immediate biochemical events such as increasing cortical neurotransmitters may trigger the events leading to cognitive and affective behavior. It is not known if potent 5-HT2A/D2 antagonism is a prerequisite to establishing procognitive or antidepressant effects. However, many atypical antipsychotics possess additional receptor pharmacology that may contribute to increasing cortical monoamines when dosed optimally in patients.

"We continue to look for explanations for how dosing may be different for different patients, especially bipolar II patients versus acute mania and schizophrenia. Pharmacology may help explain why different patients with different diagnoses require different doses of different atypicals," Dr. Stahl said.

Source: Neuropsychiatry Reviews, October 2004

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