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Although many clinical and experimental vulnerability markers have been proposed, none is ubiquitous. Psychophysiologically, deficits in information processing, attention, and sensory inhibition may be markers for vulnerability. Psychologically and behaviorally, vulnerability may be reflected by impaired social competence, cognitive disorganization or perceptual distortion, a diminished capacity to experience pleasure, and other general coping deficiencies. Such traits, particularly when severe, may impair social, academic, and vocational functioning among vulnerable persons before onset of schizophrenia symptoms. These premorbid disabilities often limit functional recovery once the disorder is established.

Although most persons with schizophrenia do not have a family history of it, genetic factors have been implicated. Persons who have a first-degree relative with schizophrenia have about a 15% risk of developing the disorder, compared with a 1% risk among the general population. A monozygotic twin whose co-twin has schizophrenia has a > 50% probability of developing it. Sensitive neurologic and neuropsychiatric tests often indicate that aberrant smooth-pursuit eye tracking, impaired performance on tests of cognition and attention, and deficient sensory gating occur more commonly among patients with schizophrenia than among the general population. These psychophysiologic markers also occur among first-degree relatives of persons with schizophrenia and may indicate vulnerability before overt onset of illness.

Various environmental stressors can trigger the emergence or recurrence of symptoms in vulnerable persons. Examples are stressful life events such as ending a relationship or leaving home for the armed forces, work, or college and biologic stressors such as substance abuse. Stressful family relations can cause or result from frequent illness exacerbation. Protective factors that may mitigate the effect of stress on symptom formation or exacerbation are discussed under Treatment, below.

What Causes Schizophrenia?

As with other psychological disorders, it's believed that schizophrenia is a complex interplay of genetics, biology (brain chemistry and structure) and environment.

Genetics: Schizophrenia typically runs in families, so it's likely the disorder is inherited. If an identical twin has schizophrenia, the other twin is 50 percent more likely to have the disorder. That also points out the likelihood of other causes: If schizophrenia were purely genetic, both identical twins always would have the disorder.

Brain chemistry and structure: Neurotransmitters - chemicals in the brain, including dopamine and glutamate, that communicate between neurons - are believed to play a role. There also is evidence to suggest that the brains of individuals with schizophrenia are different from those of healthy individuals (for details, see Keshavan, Tandon, Boutros & Nasrallah, 2008).

Environment: Some research points to child abuse, early traumatic events, severe stress, negative life events and living in an urban environment as contributing factors. Additional causes include physical and psychological complications during pregnancy, such as viral infection, malnutrition and the mother's stress.

Symptoms and Signs

Symptoms of schizophrenia vary in type and severity. Generally they are categorized as positive or negative (deficit) symptoms. Positive symptoms are characterized by an excess or distortion of normal functions; negative symptoms, by diminution or loss of normal functions. Individual patients may have symptoms from one or both categories.

Positive symptoms can be further categorized as (1) delusions and hallucinations or (2) thought disorder and bizarre behavior. Delusions and hallucinations are sometimes referred to as the psychotic dimension of schizophrenia. Delusions are erroneous beliefs that usually involve misinterpreting experience. In persecutory delusions, the patient believes he is being tormented, followed, tricked, or spied on. In delusions of reference, the patient believes that passages from books, newspapers, song lyrics, or other environmental cues are directed at him. In delusions of thought withdrawal or thought insertion, the patient believes that others can read his mind, that his thoughts are being transmitted to others, or that thoughts and impulses are being imposed on him by outside forces. Hallucinations may occur in any sensory modality (auditory, visual, olfactory, gustatory, or tactile), but auditory hallucinations are by far the most common and characteristic of schizophrenia. The patient may hear voices commenting on his behavior, conversing with one another, or making critical and abusive comments.

Thought disorder and bizarre behavior are termed the disorganized symptom cluster. Thought disorder involves disorganized thinking, evidenced primarily by speech that is rambling, shifts from one topic to another, and is non-goal-directed. Speech can range from mildly disorganized to incoherent and incomprehensible. Bizarre behavior may include childlike silliness, agitation, and inappropriate appearance, hygiene, or conduct. Catatonic motor behavior is an extreme form of bizarre behavior that can include maintaining a rigid posture and resisting efforts to be moved or engaging in purposeless and unstimulated motor activity.

Negative (deficit) symptoms include blunted affect, poverty of speech, anhedonia, and asociality. With blunted affect (flattening of emotions), the patient's face may appear immobile, with poor eye contact and lack of expressiveness. Poverty of speech refers to a diminution of thought reflected in decreased speech and terse replies to questions, creating the impression of inner emptiness. Anhedonia (diminished capacity to experience pleasure) may be reflected by a lack of interest in activities with substantial time spent in purposeless activity. Asociality refers to a lack of interest in relationships. Negative symptoms are often associated with a general loss of motivation and diminished sense of purpose and goals.

In some patients with schizophrenia, cognitive functioning declines, with impaired attention, abstract thinking, and problem solving. Severity of cognitive impairment is a major determinant of overall disability in these patients.

Symptoms of schizophrenia typically impair the ability to function and are often severe enough to markedly interfere with work, social relations, and self-care. Unemployment, social isolation, deteriorated familial relationships, and diminished quality of life are common outcomes.

Types of Schizophrenia

Some investigators believe schizophrenia is a single disorder; others believe it is a syndrome that comprises numerous underlying disease entities. Classical subtypes used to classify patients into more uniform groups include paranoid, disorganized (hebephrenic), catatonic, and undifferentiated. Paranoid schizophrenia is characterized by preoccupation with delusions or auditory hallucinations, without prominent disorganized speech or inappropriate affect. Disorganized schizophrenia is characterized by disorganized speech, disorganized behavior, and flat or inappropriate affect. In catatonic schizophrenia, physical symptoms, including either immobility or excessive motor activity and the assumption of bizarre postures, predominate. In undifferentiated schizophrenia, symptoms are mixed. Patients with paranoid schizophrenia tend to be less severely disabled and more responsive to available treatments.

Schizophrenia can also be classified based on the presence and severity of negative symptoms, such as blunted affect, lack of motivation, and diminished sense of purpose. Patients with deficit subtype have prominent negative symptoms unaccounted for by other factors (eg, depression, anxiety, an understimulating environment, drug side effects). These patients are typically more disabled, have a poorer prognosis, and are more resistant to treatment than those with nondeficit subtype, who may have delusions, hallucinations, and thought disorders but are relatively free of negative symptoms.

Among individual patients, subtype may change over time, generally from paranoid to disorganized or undifferentiated or from nondeficit to deficit.

Diagnosis

No definitive test for schizophrenia exists. Diagnosis is based on a comprehensive assessment of clinical history, symptoms, and signs. Information from ancillary sources, such as family, friends, and teachers, is often important in establishing chronology of illness onset. According to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), two or more characteristic symptoms (delusions, hallucinations, disorganized speech, disorganized behavior, negative symptoms) for a significant portion of a 1-mo period are required for the diagnosis, and prodromal or attenuated signs of illness with social, occupational, or self-care impairments must be evident for a 6-mo period that includes 1 mo of active symptoms.

Psychotic disorders due to physical disorders or associated with substance abuse and primary mood disorders with psychotic features must be ruled out by clinical examination and history. Additionally, laboratory tests can rule out underlying medical, neurologic, and endocrine disorders that can present as psychosis (eg, vitamin deficiencies, uremia, thyrotoxicosis, electrolyte imbalance).

Structural brain abnormalities that can be seen on MRI or CT scans are consistently found in patients with schizophrenia as a group but are insufficiently specific to have diagnostic value for individual patients. In general, medial and superior temporal lobe abnormalities are associated with positive symptoms; frontal cortical and ventricular system abnormalities, with negative symptoms. In functional studies of regional brain glucose or oxygen utilization, diminished activation in the prefrontal cortex and mesolimbic regions is associated with negative symptoms and cognitive dysfunction in patients with schizophrenia.

Natural History

Vulnerability to schizophrenia may be manifest before the onset of illness as poor premorbid functioning, poor social skills, odd and eccentric behavior, and isolation or withdrawal. Onset of schizophrenia may be sudden (over days or weeks) or slow and insidious (over years).

The natural history of schizophrenia can be described in sequential phases. In the premorbid phase, the influence of risk factors and developmental vulnerabilities may be detectable. In the prodromal phase, subclinical signs and symptoms--such as withdrawal, irritability, suspiciousness, and disorganization--develop before manifest illness, signaling impending decompensation. In the early illness phase, onset of positive symptoms, deficit symptoms, and functional disabilities leads to the diagnosis of schizophrenia. In the middle phase, symptomatic periods may be episodic (with identifiable exacerbations and remissions) or continuous (without identifiable remissions); functional deficits worsen. In the late illness phase, the illness pattern may be established, disability levels stabilized, or late improvements manifested.

Of patients who have one episode of schizophrenia, 60 to 70% ultimately have subsequent episodes. The course may be continuous or intermittent. During the first 5 yr of illness, functioning may deteriorate and social and work skills may decline, with progressive neglect of self-care; negative symptoms may increase in severity and cognitive functioning may decline, particularly for patients with deficit forms. Thereafter, the level of disability tends to plateau. Some evidence suggests that severity of illness may lessen in later life, particularly among women. Spontaneous movement disorders may develop in patients who have severe negative symptoms and cognitive dysfunction, even when antipsychotic drugs are not used.

Schizophrenia is associated with about a 10% risk of suicide. Suicide is the major cause of premature death among persons with schizophrenia, and on average the disorder reduces the life span of those affected by 10 yr. Patients who have paranoid forms with late onset and good premorbid functioning--the very patients with the best prognosis for recovery--are also at the greatest risk for suicide. Because these patients retain the capacity for grief and anguish, they may be more prone to act in despair, based on a realistic recognition of the effect of their disorder.

Schizophrenia is a relatively modest risk factor for violent behavior; the level of risk is much less than that conveyed by substance abuse. Threats of violence and minor aggressive outbursts are far more common than dangerous behavior occurring when a patient obeys hallucinatory voices or attacks an imagined persecutor. Very rarely, a severely depressed, isolated, paranoid person attacks or murders someone who is perceived as the single source of his difficulties (eg, an authority, a celebrity, his spouse). Patients with schizophrenia may present in an emergency setting with threats of violence to obtain food, shelter, or needed medical or psychiatric care. A thorough, ongoing assessment of dangerousness and suicidal risk should be included in the evaluation and treatment of patients with schizophrenia.

Prognosis

Over a 1-yr period, prognosis is closely related to adherence to prescribed psychoactive drugs. Over longer periods, prognosis varies. Overall, 1/3 of patients achieve significant and lasting improvement; 1/3 improve some but have intermittent relapses and residual disability; and 1/3 are severely and permanently incapacitated. Factors associated with a good prognosis include relatively good premorbid functioning, late and/or sudden onset of illness, a family history of mood disorders rather than schizophrenia, minimal cognitive impairment, and paranoid or nondeficit subtype. Factors associated with a poor prognosis include early age of onset, poor premorbid functioning, a family history of schizophrenia, and disorganized or deficit subtype with many negative symptoms. Men have poorer outcomes than women; women respond better to treatment with antipsychotic drugs.

Schizophrenia can occur with other mental disorders. When associated with significant obsessive-compulsive symptoms, it has a particularly poor prognosis; with symptoms of borderline personality disorder, a better prognosis.

Substance abuse is a significant problem in up to 50% of patients with schizophrenia. Comorbid substance abuse is a significant predictor of poor outcome and may lead to drug noncompliance, repeated relapse, frequent rehospitalization, declining function, and loss of social support, including homelessness.

Treatment

Patients with schizophrenia tend to develop psychotic symptoms an average of 12 to 24 mo before presenting for medical care. The time between onset of psychotic symptoms and first treatment, termed duration of untreated psychosis, correlates with the rapidity of initial treatment response, quality of treatment response, and severity of negative symptoms. When treated early, patients tend to respond more quickly and fully. Without prophylactic antipsychotic drugs, 70 to 80% of patients who have had a schizophrenia episode have a subsequent episode during the next 12 mo. Continuous prophylactic antipsychotic drugs can reduce the 1-yr relapse rate to about 30%.

General goals of treatment are to reduce the severity of psychotic symptoms, prevent recurrences of symptomatic episodes and associated deterioration of functioning, and help patients function at the highest level possible. Antipsychotic drugs, rehabilitation with community support services, and psychotherapy are the major components of treatment.

Antipsychotic drugs:

Conventional antipsychotic (neuroleptic) drugs include chlorpromazine, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, perphenazine, pimozide, thioridazine, thiothixene, and trifluoperazine. These drugs are characterized by their affinity for the dopamine 2 receptor and can be classified as high, intermediate, or low potency. Different drugs are available in tablet, liquid, and short- and long-acting IM preparations. A specific drug is selected primarily based on adverse effects, required route of administration, and the patient's previous response to the drug.

Two conventional antipsychotic drugs are available as long-acting depot preparations. These preparations are useful mainly for ruling out covert drug noncompliance as a cause of symptom exacerbation and lack of drug response. They may also help patients who cannot reliably take daily oral drugs.

Conventional antipsychotic drugs are associated with adverse effects, such as sedation, dystonia and muscle stiffness, tremors, elevated prolactin levels, and weight gain (for treatment of adverse effects). Akathisia (motor restlessness) is particularly unpleasant and is often associated with drug refusal and outpatient noncompliance. These drugs may also cause tardive dyskinesia, an involuntary movement disorder most often characterized by puckering of the lips and tongue and/or writhing of the arms or legs. The incidence of tardive dyskinesia is about 5%/yr of drug exposure among patients taking conventional antipsychotic drugs. In about 2%, tardive dyskinesia is severely disfiguring. Because of this risk, patients receiving long-term maintenance therapy should be evaluated at least q 6 mo. Rating instruments, such as the Abnormal Involuntary Movement Scale, may be used. Neuroleptic malignant syndrome, a rare but potentially fatal adverse effect, is characterized by rigidity, fever, autonomic instability, and elevated creatinine phosphokinase.

About 30% of patients with schizophrenia do not respond to conventional antipsychotic drugs (treatment refractory). They may respond to atypical antipsychotic drugs.

Atypical antipsychotic drugs have some or most of the following properties: They alleviate positive symptoms; improve negative symptoms to a greater extent than conventional antipsychotics; may improve neurocognitive deficits; have greater efficacy for refractory schizophrenia; are less likely to cause extrapyramidal (motor) side effects; have a lower risk of tardive dyskinesia; and produce little or no elevation of prolactin.

Atypical antipsychotic drugs may have selective affinity for brain regions involved in schizophrenia symptoms and reduced affinity for areas associated with motor symptoms and prolactin elevation. They affect other neurotransmitter systems, including serotonin, or have selective affinity for specific dopamine receptor subtypes.

Clozapine, the first atypical antipsychotic drug marketed in the USA, is effective in up to 50% of patients who are resistant to conventional antipsychotic drugs. Clozapine reduces negative symptoms, produces few or no motor adverse effects, and has no risk of tardive dyskinesia, but it produces other adverse effects, including sedation, hypotension, tachycardia, weight gain, and increased salivation. It also may cause seizures in a dose-dependent fashion. The most serious adverse effect is agranulocytosis, which can occur in about 1% of patients. Consequently, frequent monitoring of WBCs is required, and clozapine is generally reserved for patients who have responded inadequately to other drugs.

Newer atypical antipsychotic drugs currently or soon to be available are risperidone, olanzapine, quetiapine, sertindole, and ziprasidone. For most patients with schizophrenia, these drugs are more effective and have fewer adverse effects than conventional antipsychotics. They provide many of the benefits of clozapine without the risk of agranulocytosis and are generally preferable to conventional antipsychotics for treatment of an acute episode and for prevention of recurrence. The new antipsychotics have similar efficacy and differ primarily in adverse effects, so drug choice is based on the patient's response and vulnerability to specific adverse effects. A 4- to 8-wk trial is usually required to assess efficacy. Rapid resolution of symptoms is the goal of acute treatment. For maintenance treatment, the lowest dose that prevents symptoms is used.

Rehabilitation and community support services:

Psychosocial skill training and vocational rehabilitation programs help many patients work, shop, care for themselves; manage a household; get along with others; and work with mental health professionals. Supported employment, in which patients are placed in a competitive work setting and provided with an on-site job coach to promote adaptation to work, may be particularly valuable. In time, the job coach acts only as a backup for problem solving or communication with employers.

Support services enable many patients with schizophrenia to reside in the community. Patients may require supervised apartments where a staff member is present to ensure drug compliance. Programs provide a graded level of supervision in different residential settings, ranging from 24-h support to periodic home visits. These programs help promote patient autonomy while providing sufficient care to minimize the likelihood of relapse and reducing the need for inpatient hospitalization. Aggressive community programs provide services in the patient's home or other residence and are based on high staff-to-patient ratios; treatment teams directly provide all or nearly all required treatment services.

Hospitalization or crisis care in a hospital alternative may be required during severe relapses, and involuntary hospitalization may be necessary if the patient poses a danger to himself or others. Despite the best rehabilitation and community support services, a small percentage of patients, particularly those with severe cognitive deficits and those resistant to drug therapy, require long-term institutional or other supportive care.

Psychotherapy:

The goal is to develop a collaborative relationship among the patient, family, and physician so that the patient can learn to understand and manage his illness, to take drugs as prescribed, and to handle stress more effectively.

The quality of the physician-patient relationship is often a major determinant of treatment outcome. Although individual psychotherapy in combination with drug therapy is a common approach, few empirical guidelines are available. Psychotherapy that begins by addressing the patient's basic social service needs, provides support and education regarding the nature of the illness, promotes adaptive activities, and is based on empathy and a sound dynamic understanding of schizophrenia is likely to be most effective. Many patients need empathic psychologic support to adapt to what is often a lifelong illness that can substantially limit functioning. Case management, designed to ensure that patients have access to necessary entitlements, treatment services, and safe and affordable housing, is often a prerequisite to the pursuit of other therapeutic goals.

For patients who live with their families, psychoeducational family interventions can reduce the rate of relapse. Support and advocacy groups, such as the Alliance for the Mentally Ill, provide families with information pertinent to care and with support as well as act as an advocate.