New Generation Antipsychotics and Bipolar Disorder

Thomas A. M. Kramer, MD


May 16, 2003


New generation, or atypical, antipsychotics -- medications that were initially developed for the treatment of psychosis in general and schizophrenia in particular -- are being used increasingly in the treatment of bipolar disease. Medications such as olanzapine, which has a formal indication for bipolar disease from the US Food and Drug Administration, clozapine, quetiapine, and risperidone have become important tools for the clinician in helping to stabilize acutely ill bipolar patients and preventing them from becoming ill again. These medications may have efficacy beyond being simply antimanic agents, but may have utility as true mood stabilizers; they may actually help prevent mood fluctuations that interfere with social and occupational functioning.

It is important to note that these medications have a utility beyond simple efficacy. Many medications are effective antimanic agents. Chlorpromazine and haloperidol, for example, have been shown to be effective in the treatment of acute mania. We do not use them routinely because their side effect profile makes them less desirable and because they appear to have no other efficacy besides their antimanic properties in bipolar disease. They may treat mania, but they do not stabilize mood, and they are ineffective as antidepressants. What makes new generation antipsychotic medications so potentially important in the treatment of bipolar disease is that they may have all 3 of these properties, to a greater or lesser extent, desirable in a medication for bipolar disease. Equally important is the fact that these medications are usually quite well tolerated. This becomes crucial because mood stabilizers, for the most part, are medications that the patient will take indefinitely. As such, if they are unpleasant to take, they are essentially ineffective.

There is no question that medications that block the D2 receptor will treat acute mania. What is considerably more speculative are the other properties of these medications that make them useful mood stabilizers. For some possible answers to that question, we can look at their other major common pharmacodynamic action, their blockade of postsynaptic serotonin receptors, specifically the 5HT2A receptor. Blockade of this receptor inhibits a reverse feedback loop in the prefrontal cortex in which serotonin decreases dopaminergic tone, so that when these drugs block these receptors, dopaminergic tone increases in the prefrontal cortex. In the treatment of psychotic disorders and, in particular, schizophrenia, this effect serves to, at the very least, limit the side effect of cognitive dulling that occurs with D2 blockers and may even help to treat the negative symptoms of schizophrenia. The effect that these drugs have in patients with bipolar disease is considerably less clear.

Dopamine is a crucial neurotransmitter in the prefrontal cortex, so an increase in dopaminergic tone in that area essentially means greater activity in the prefrontal cortex. This is thought to be the "executive" area of the brain, in which decision making, judgment, and impulse control reside. If these functions are enhanced, it may help bipolar patients control their behavior in useful ways. Similarly, enhancement of these functions may also help treat depression and may explain why new generation antipsychotics have proven to be so useful as augmenting agents for major depression. We do know that these medications do enhance cognition in schizophrenics, and current thinking is that this is due to enhanced activity in the prefrontal cortex. There is no reason to believe the same is not true for bipolar patients.

It is also important to note that, for the most part, these medications are extremely safe. The risk of tardive dyskinesia, always a major concern with older generation antipsychotics, is considerably less with these newer drugs. Even the presence of extrapyramidal symptoms, which was virtually a given with older generation high potency antipsychotics, is considerably less common with new generation drugs. This is probably because their inhibition of the serotonin dopamine feedback loop described above allows us to block less D2 receptors in the prefrontal cortex and the extrapyramidal system, where the side effects from D2 blockade occur and where the increased dopaminergic tone caused by the blockade of the feedback loop creates more competition for dopamine receptors between the drug and the increased amount of dopamine, causing less D2 blockade. Conversely, this feedback loop does not operate in the mesolimbic system -- where we believe a hyperdopaminergic state causes symptoms of either schizophrenia or bipolar disease -- so we can block more D2 receptors where we want to block them.

Finally, it is important to reiterate that this generation of antipsychotic medications is quite different from the previous one, and does not represent merely an improvement of a whole new class of medications. As such, we need to look beyond the indications for the previous generation -- mostly schizophrenia and psychotic disorders -- and continue to explore other uses that may be beneficial to our patients.


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