Dr. Corcoran is Assistant Professor of Clinical Psychiatry and Director, Center of Prevention and Evaluation, New York State Psychiatric Institute; Dr. Malaspina is the Anita Steckler and Joseph Steckler Professor of Psychiatry and Chairman of the Department of Psychiatry, New York University School of Medicine.

The more we learn about stress, the more we understand how great a role it plays in a wide range of diseases and conditions. Not surprisingly, this is especially true of psychiatric problems such as psychosis, affective illness (a category that includes manic-depression and major depression) and alcoholism.

Stress seems to be particularly harmful for those suffering from the psychiatric disorder schizophrenia. For a patient with schizophrenia, the death of a parent or other loved one, a change in therapist, moving from one apartment to another; these events can trigger acute anxiety, depression and psychotic episodes, which may lead to hospitalization. Even seemingly mildly stressful events such as a job interview or a date can have a devastating effect.

For a patient with schizophrenia, the death of a parent or other loved one, a change in therapist, moving from one apartment to another; these events can trigger acute anxiety, depression and psychotic episodes.

This increased susceptibility to stress fits the current thinking that schizophrenia is fundamentally related to a combination of difficulty in filtering out what is happening in the outside world and misattribution of internal thoughts and feelings, along with an inability or lessened ability to interpret social cues, all of which make it difficult for individuals with schizophrenia to cope. This is backed up by research showing that patients with schizophrenia are more affected by stress physically as well as emotionally; for instance they show different changes in heart rate under stress and a greater overall risk of cardiovascular disease.

Schizophrenia Is a Group of Disorders
Schizophrenia is best understood not as a single disease, but rather as a group of related psychiatric disorders. Each of these is characterized by various combinations of the following symptoms:
  1. "positive" or psychotic symptoms such as hallucinations and delusions;
  2. "negative" symptoms such as apparent lack of emotion ("flat affect") and motivation (" passivity");
  3. cognitive impairments such as problems with working and short-term memory.

Individuals with schizophrenia may sit quietly, make little or no eye contact and speak very little, or conversely may be agitated or suffer from elaborate hallucinations and delusions.

The causes of schizophrenia have been shown to be as varied as its symptoms. Genetic abnormalities, environmental factors and interactions of the two have all been implicated. A strong hereditary component for schizophrenia has been confirmed in scores of family, twin and adoption studies, although no particular gene has yet been identified as a cause.

The same studies have demonstrated the role of environmental factors; for example, if one identical twin has schizophrenia, the other twin will develop schizophrenia only about half of the time. Among the environmental factors that have been implicated as risk factors for schizophrenia are exposure to infection while in the womb, problems during delivery, adversity in childhood and brain injury. These exposures may cause illness directly, but they also appear to interact with some genetic vulnerability.

Understanding the environmental risk factors for schizophrenia is key for both prevention and treatment. While little can be done at present to treat purely genetic causes, environmental factors may be modified and individuals may be taught strategies to manage stress. For instance, if stress can cause or worsen schizophrenia, measures can be taken to protect those at risk and to better manage those who are already ill. This would include reducing exposure to stress as well as countering the effects of stress by training in stress management and social skills, fostering positive relationships, increasing social support and encouraging exercise.

The "Two-hit" Theory of the Origin of Schizophrenia
The leading theory about the origins of schizophrenia is that the disease results, in part, from abnormal early development. Evidence for this theory comes from studies showing the existence of structural brain abnormalities long before the appearance of any psychiatric symptoms; and an increased incidence of certain minor physical anomalies (for example, high arched palate, multiple hair whorls, abnormal head circumference, asymmetrical ears, curved fifth finger, webbed toes) in people with schizophrenia.

However, many individuals who have these abnormalities do not go on to develop schizophrenia. This has led to the so-called "two-hit" hypothesis of schizophrenia: that genetic vulnerability or problems in the womb set the stage for schizophrenia, but that a second event in adolescence or early adulthood leads to the development of schizophrenia. This "second hit" may be a major life event or episode of stress.

A Diverse Illness
Given similar treatments, some patients with schizophrenia recover completely; some are able to work and have families. However, more than half experience some degree of disability throughout their lives, while an additional 25% require lifelong care. It is not clear what accounts for these differences. One answer may be stress. Researchers suspect that stress worsens the course of illness by increasing the body's production of a substance called cortisol, which can damage an area of the brain called the hippocampus.

There is a growing body of evidence supporting the idea that stress and schizophrenia are closely linked. One groundbreaking study found that 46% of patients who experienced their first bout of schizophrenia underwent some stressful life event in the preceding three months.

The Effects of Stress on the Body and on the Brain
Medical scientists have demonstrated that stress can cause physical damage to the brain. Although schizophrenia is not the only illness that is connected to stress, the so-called "stress cascade" appears to play an important role in schizophrenia.

The stress cascade begins with the release of certain hormones in the brain. This release, in turn, triggers physiological effects that make your heart work more, shunt blood away from the digestive system and set up the "fight or flight" reaction, a state of high arousal, increased vigilance and excessive levels of cortisol.

Combat veterans with PTSD suffer a loss of hippocampal volume. In fact, there is a direct link between how these veterans perform on standard memory tests and the size of their hippocampus.

Stress and cortisol have been shown to damage -- and even destroy -- nerve cells in the hippocampus, which plays an important role in memory. These elements of the stress cascade -- excessive cortisol production, damage to the hippocampus and impairment in certain types of memory related to the hippocampus, all occur commonly in patients with schizophrenia.

Research has shown that patients with schizophrenia have smaller hippocampal volumes than people without the disease.

This is backed up by studies that have found that individuals with schizophrenia suffer from problems in areas of brain functions that are associated with the hippocampus, such as memory and the ability to coordinate and carry out tasks.

Stress, Cortisol, Memory and the Hippocampus
A number of studies in the last several years have confirmed a strong connection between stress, high cortisol levels, damage to the hippocampus and memory. This connection shows up across a wide range of human medical conditions, including post-traumatic stress disorder (PTSD), Cushing's disease, overexposure to steroid drugs, aging and depression.

For example, combat veterans with PTSD suffer a loss of hippocampal volume. In fact, there is a direct link between how these veterans perform on standard memory tests and the size of their hippocampus. Adult survivors of childhood abuse also have both smaller hippocampi and impaired memory. Problems regulating cortisol production ("cortisol dysregulation") and small hippocampal size are also common in depression.

Chronic stress by itself seems to cause wear and tear on the brain. Cortisol levels increase with age and studies have shown shrinkage of the hippocampus and memory impairment even in healthy older people.

Cushing's disease is an illness that causes the body to make too much cortisol. Patients with Cushing's have memory problems that can actually be reversed when the disease is successfully treated.

Finally, both healthy research subjects who take medications that resemble cortisol, such as prednisone, and patients who take these medications for medical reasons, demonstrate these same reversible memory problems.

New Possibilities for the Treatment of Schizophrenia
Cognitive deficits such as problems with memory are a major component of schizophrenia. If these problems are related to the stress cascade, as they seem to be, then the exciting possibility exists that reducing stress may be an effective way of treating the disease.

Not only may stress management techniques prevent the onset or lessen the severity of schizophrenia, delay relapse in those already ill and reduce overall anxiety, but studies indicate that cells within a damaged hippocampus can regenerate when stress or cortisol is reduced.

There are also several drugs with good safety records that seem to prevent stress-induced damage to the hippocampus. These include tianeptine, 46 an anti-depressant, and phenytoin (sold under the brand name Dilantin®) which is used to treat seizures (epilepsy).

Stress has long been suspected as a player in the onset and course of schizophrenia. And, although the precise details of the relationship between the two remains poorly understood, there is extensive and consistent research linking stress, cortisol regulation, the area of the brain called the hippocampus, as well as memory and other brain functions in schizophrenia.

Because schizophrenia is a group of varied disorders, not one disease, and because there is unquestionably a genetic component to the disease, stress may well be a more important factor in some cases of schizophrenia than in others.

Nevertheless, a better understanding of how stress may affect the onset and course of schizophrenia is likely to lead to the development of newer and better treatments, including more effective drugs, for the devastating and, up to now, relatively untreatable cognitive problems that are one of the chief effects of this terrible disease.