Schizophrenia researchers seek elusive ‘quantum leap’

May 12, 2017|Psychiatry

Mental health researchers like to say a half-century has passed since the last major advance in schizophrenia treatment came along. Gavin P. Reynolds, PhD, a schizophrenia researcher, says that’s wrong. In fact, he says, “it’s more like 60-plus!”

Yes, there have been advances in drug treatment since the early 1950s, when chlorpromazine (Thorazine) was introduced. Available are new types of antipsychotics, a whole bunch in fact, and they’ve helped many patients. “But these have been incremental, rather than the much-needed quantum leap,” said Dr. Reynolds in an interview. “We still need improved treatments. About one-third of patients do not respond to standard drug treatment. And of those who do respond, the negative symptoms and cognitive problems caused by schizophrenia may still be very limiting.”

Researchers have hardly been idle over the past 6 decades, however. They’ve been buzzing for years about a major role for the neurotransmitter glutamate in the treatment of schizophrenia, and at least one headline proclaimed that it’s “the next psychiatric revolution.”

That’s quite optimistic. The “revolution” hasn’t yet jumped from medical journals and clinical trials to prescription pads and drugstore shelves, and it’s not likely to do so any time soon. “This isn’t around the corner,” said Joshua T. Kantrowitz, MD, also a schizophrenia researcher. “But I can imagine a day where someone with schizophrenia will undergo a full genetic scan or a specific type of MRI or EEG, and we’ll then be able to recommend the drug they’d be able to use.” And he believes that a glutamate-based medication will be among the available options.

Thorazine: A pioneer with major limits

Like every person, each illness has a history. But schizophrenia’s past is fuzzier than that of many diseases, and this lack of clarity continues into the present as researchers try to understand exactly what it is – a single disorder? a collection of conditions? – and what it isn’t.

“Schizophrenia is a serious mental illness with a remarkably short recorded history. Unlike depression and mania, which are recognizable in ancient texts, schizophrenia-like disorder appeared rather suddenly in the early 19th century,” wrote R. Walter Heinrichs, PhD, a psychologist at Toronto’s York University (J Hist Behav Sci. 2003 Fall;39[4]:349-63). “This could mean that the illness is a recent disease that was largely unknown in earlier times. But perhaps schizophrenia existed, embedded and disguised within more general concepts of madness, and within the arcane languages and cultures of remote times,” he wrote.

As Dr. Heinrichs noted, schizophrenia’s history has spawned at least three theories: It’s a fairly new disease that just popped up in recent centuries. It has been around a long time but just didn’t get identified. It’s not a real disease but a product of modern thought.

Psychiatrists and researchers have rejected the latter possibility and its implications that psychotherapy could be the best treatment. Instead, they have tried to adjust the workings of the schizophrenic brain via medication.

The main breakthrough came in the 1950s through the development of the antipsychotic chlorpromazine. Its success “was instrumental in the reintegration of psychiatry with the other medical disciplines,” wrote Thomas A. Ban, MD, an emeritus professor at Vanderbilt University, Nashville, Tenn. “It turned psychiatrists from caregivers to full-fledged physicians who can help their patients and not only listen to their problems” (Neuropsychiatr Dis Treat. 2007 Aug; 3[4]:495-500).

Since chlorpromazine, however, medical treatment for schizophrenia has barely evolved, said Dr. Reynolds, professor emeritus at Queen’s University Belfast (Northern Ireland) and honorary professor at Sheffield (England) Hallam University. “The two most important developments have been the introduction of clozapine (Clozaril) for patients who don’t respond to other treatments and aripiprazole (Abilify), which has a somewhat different pharmacological action from other antipsychotics and thereby avoids some of the side effects.”

Negative symptoms fail to crumble

But, he said, side effects such as severe weight gain still can hamper the use of antipsychotics. And antipsychotics don’t fare well at treating the negative symptoms of schizophrenia.

As one overview puts it, “negative symptoms, e.g., social withdrawal, reduced initiative, anhedonia, and affective flattening, are notoriously difficult to treat.” Nonmedical treatments have shown some promise, the overview authors write: “Some positive findings have been reported, with the most robust improvements observed for social skills training. Although cognitive-behavior therapy shows significant effects for negative symptoms as a secondary outcome measure, there is a lack of data to allow for definite conclusions of its effectiveness for patients with predominant negative symptoms.”

As for medications, “antipsychotics have been shown to improve negative symptoms, but this seems to be limited to secondary negative symptoms in acute patients. It has also been suggested that antipsychotics may aggravate negative symptoms” (Schizophr Res. 2016 Jun 9. doi: 10.1016/j.schres.2016.05.015).

Dr. Kantrowitz, assistant professor of clinical psychiatry and director of the Lieber Schizophrenia Research Clinic at Columbia University in New York, put it this way: “Some people do quite well on your traditional antipsychotic drugs, and they go into remission. But the drugs don’t help the majority with all their symptoms, and most people are left with significant disability.”