Decoding Schizophrenia

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Theories focusing largely on dopamine are problematic on additional grounds. Improper dopamine balance cannot account for why one individual with schizophrenia responds almost completely to treatment, whereas someone else shows no apparent response. Nor can it explain why positive symptoms respond so much better than negative or cognitive ones do. Finally, despite decades of research, investigations of dopamine have yet to uncover a smoking gun. Neither the enzymes that produce this neurotransmitter nor the receptors to which it binds appear sufficiently altered to account for the panoply of observed symptoms.

The Angel Dust Connection

If dopamine cannot account well for schizophrenia, what is the missing link? A critical clue came from the effects of another abused drug: PCP (phencyclidine), also known as angel dust. In contrast to amphetamine, which mimics only the positive symptoms of the disease, PCP induces symptoms that resemble the full range of schizophrenia's manifestations: negative and cognitive and, at times, positive. These effects are seen not just in abusers of PCP but also in individuals given brief, low doses of PCP or ketamine (an anesthetic with similar effects) in controlled drug-challenge trials.

Such studies first drew parallels between the effects of PCP and the symptoms of schizophrenia in the 1960s. They showed, for example, that individuals receiving PCP exhibited the same type of disturbances in interpreting proverbs as those with schizophrenia. More recent studies with ketamine have produced even more compelling similarities. Notably, during ketamine challenge, normal individuals develop difficulty thinking abstractly, learning new information, shifting strategies or placing information in temporary storage. They show a general motor slowing and reduction in speech output just like that seen in schizophrenia. Individuals given PCP or ketamine also grow withdrawn, sometimes even mute; when they talk, they speak tangentially and concretely. PCP and ketamine rarely induce schizophrenialike hallucinations in normal volunteers, but they exacerbate these disturbances in those who already have schizophrenia.

One example of the research implicating NMDA receptors in schizophrenia relates to the way the brain normally processes information. Beyond strengthening connections between neurons, NMDA receptors amplify neural signals, much as transistors in old-style radios boosted weak radio signals into strong sounds. By selectively amplifying key neural signals, these receptors help the brain respond to some messages and ignore others, thereby facilitating mental focus and attention. Ordinarily, people respond more intensely to sounds presented infrequently than to those presented frequently and to sounds heard while listening than to sounds they make themselves while speaking. But people with schizophrenia do not respond this way, which implies that their brain circuits reliant on NMDA receptors are out of kilter.

If reduced NMDA receptor activity prompts schizophrenia's symptoms, what then causes this reduction? The answer remains unclear. Some reports show that people with schizophrenia have fewer NMDA receptors, although the genes that give rise to the receptors appear unaffected. If NMDA receptors are intact and present in proper amounts, perhaps the problem lies with a flaw in glutamate release or with a buildup of compounds that disrupt NMDA activity.

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