Schizophrenia researchers seek elusive ‘quantum leap’

Looking to dopamine... and beyond

One solution to the vexing schizophrenia treatment gap is to develop a new medication that does a better job of adjusting the brain’s processing of dopamine.

Some researchers have found evidence that dopamine levels rise in the brains of people with schizophrenia, potentially explaining why chlorpromazine – which blocks receptors that process dopamine – is so effective. There also are signs that genes linked to dopamine play a role in schizophrenia.

But chlorpromazine is not effective enough to help many patients. Some gain no benefit, while others only see improvement in positive schizophrenia symptoms, those that are considered to be brought on – added – such as hallucinations and delusions.

And chlorpromazine isn’t believed to improve cognitive symptoms of schizophrenia like disorganized thoughts and concentration difficulties.

Atypical antipsychotics like clozapine (Clozaril) and risperidone (Risperdal), add the blocking of serotonin receptors to their dopamine focus. But they have serious limitations just like chlorpromazine.

The conclusion to take from the failure of dopamine-based drugs to fully combat schizophrenia, Dr. Kantrowitz and a colleague wrote, is that “dopaminergic dysfunction appears to account for only a part of schizophrenia’s symptomatic and neurocognitive profile.” Something else must be going on.

Enter the neurotransmitter known as glutamate.

The angel dust connection

Children who grew up in the 1970s and 1980s were flooded plenty of media messages about the dangers of illegal drugs. But one drug, “angel dust,” also known as phencyclidine or PCP, stood apart from the rest.

Using PCP, television shows and films suggested, led to consequences that could be deadly in ways that were entirely unlike the usual causes of death by drug use – a car accident, say, or a heroin overdose. Taking PCP, it seemed, was tied to crazed misadventure.

Consider a 1982 TV movie, “Desperate Lives,” starring a young actress named Helen Hunt. In a startling scene, she takes the drug and promptly jumps through a second-story window before screeching and cutting herself with jagged glass. The portrayal of PCP users as vividly unhinged – detached from reality and willing to hurt themselves or others – reflected a real phenomenon. As scientists had discovered, angel dust could made people act as if they were psychotic.

In the 1960s, “people started observing that drugs like PCP and ketamine produced schizophrenia-like symptoms,” Dr. Kantrowitz said. “But these observations were mostly ignored until the 1980s and 1990s.”

That’s when scientists started looking into the connections between these drugs and the psychotic states that they could induce. “These drugs can mimic, in animals and humans, the negative and cognitive symptoms as well as the positive symptoms of schizophrenia,” Dr. Reynolds said. “Combined with postmortem evidence of changes in various indicators of glutamate neurotransmission in the brain, these findings provide the basis for the glutamate hypothesis.”

The hypothesis theorizes that disruptions in the brain’s processing of glutamate are crucial to schizophrenia. Specifically, scientists believe the key lies in the N-methyl-D-aspartate (NMDA) receptor in nerve cells.

“Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors,” writes Daniel C. Javitt, MD, professor of psychiatry and director of schizophrenia research at the Nathan Kline Institute for Psychiatric Research at Columbia University. “Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain.

“Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction.” (Isr J Psychiatry Relat Sci. 2010;47[1]:4-16).

There’s even more to the story, said Dr. Reynolds, who cautions that the term “glutamate hypothesis” is misleading, because it misses the whole picture.

“The original research identifying the importance of the NMDA receptor highlighted how these receptors were actually on GABA neurons, reflecting the close interaction and interdependence of the two transmitter systems,” he said. (GABA receptors respond to the neurotransmitter gamma-aminobutyric acid, or GABA.)

“Subsequently, it has been established that there is a dysfunction, if not a deficit, of a subgroup of GABA neurons in schizophrenia,” Dr. Reynolds said, “and these neurons, which are important in the control of glutamate neuronal activity, are also a focus of current research.”

Challenges on the drug development front

Earlier findings linking glutamate to schizophrenia “have been strengthened by recent large genetic studies identifying that variability in some genes involved in glutamate’s action is a risk factor for schizophrenia,” Dr. Reynolds said, “while in animal models, some drugs influencing glutamate transmission have shown promise as potential treatments.”