Schizophrenia

Schizophrenia is characterized by the presence of delusions and/or hallucinations, as well as disorganized speech and behavior. It is also marked by the loss of executive functions (e.g., planning, organization, concentration), emotional expression, productivity of thought and speech, and goal-directed behavior.[1] Although it is discussed here as a single entity, schizophrenia is likely composed of a group of disorders that are heterogeneous in origin despite similar symptomatology.[2] Disruptions of function involving several neurotransmitters (dopamine, glutamate, gamma-Aminobutyric acid, and acetylcholine) have been proposed as contributing to schizophrenia, but its etiology is likely multifactorial and remains an area of ongoing research.[3],[4] The neurotransmitter dopamine has received the most attention, and all medications that are approved for the treatment of schizophrenia have dopamine-blocking properties.

The disorder affects about 1% of people worldwide. It occurs across all socioeconomic groups and cultures, although patients are often socially and economically marginalized as a result of the disease and its accompanying stigma, resulting in lowered socioeconomic status. Additionally, schizophrenia appears to have a better prognosis in developing countries, where patients are more fully integrated into their communities and family units.

Risk Factors

Age. The onset of schizophrenia is typically before age 25, and the illness persists throughout life. Although the lifetime risk for men and women is similar, onset is often later in women than in men, with a second peak onset around menopause, suggesting a protective role for estrogen.[5] Peak onset for men is age 10-25, and for women it is age 25-35. A later age of onset is associated with a more favorable prognosis.[6]

Genetic factors. Approximately half of monozygotic twins are affected when the other twin has schizophrenia.[7] Monozygotic twins reared by adoptive parents have similar rates of schizophrenia as their twin siblings raised by their biological parents, suggesting the primary importance of genetic factors. First-degree relatives of affected individuals have a 10-fold increased risk for developing schizophrenia compared with the general population. However, no specific gene has been isolated, and it is likely that multiple genes play a role.

Complications during gestation, delivery, and early life. Analgesic use during the second trimester or hypertension and diuretic use during the third trimester of pregnancy may be associated with increased risk of schizophrenia for the newborn.[8],[9] Fetal malnutrition, paternal age over 50 years, and winter and spring births (presumably related to viral infections) are also associated with increased risk.[10]

Complications during delivery (e.g., preterm labor, hemorrhage, fetal hypoxia, maternal infections) have been associated with an increased risk of developing schizophrenia later in life.[11]

Persons who were not breastfed for at least 2 weeks have been shown to have increased prevalence of schizophrenia, and a child with a genetic predisposition to schizophrenia may have a further increased risk if a childhood head injury occurs.[12]

Maternal Toxoplasma gondii. Some interesting but inconclusive evidence indicates that maternal exposure to T gondii is a risk factor for schizophrenia in offspring.[13],[14] Humans can become infected with T gondii in a variety of ways, including ingestion of animal tissues and exposure to soiled cat litter. Mothers with higher T gondii immunoglobulin G (IgG) antibody levels may themselves be at a higher risk for later development of schizophrenia.[15],[16]

Other infections (e.g., influenza, measles) and increases in circulating inflammatory cytokines have also been suggested as potential risks factors for developing the disease.[17]

Tobacco and cannabis use. Limited evidence suggests an association between prenatal nicotine exposure and risk of schizophrenia.[18]

The Finnish Prenatal Study of Schizophrenia found that elevated maternal C-reactive protein (CRP) levels are significantly associated with schizophrenia in offspring.[19] An inflammatory marker, CRP levels are increased by tobacco use and poor diet.

Cannabis use is associated with the development of psychosis.[20] Evidence suggests that the risk of cannabis leading to a psychotic break (presumably in individuals with a preexisting vulnerability) has increased in recent years as the potency of marijuana has increased. Selective breeding has produced varieties that have substantially higher levels of tetrahydrocannabinol (THC), which can be psychotomimetic, and lower levels of cannabidiol (CBD), which counteracts the psychosis-inducing effects of THC.[21]

Diagnosis

The history will clarify acute symptoms, and physical examination may help rule out other causes of psychosis. The diagnostic criteria of the American Psychiatric Association call for 2 or more symptoms in criterion A and the presence of B-D:[1]

  1. Delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms (affective flattening, reduced productivity of thought or speech, or reduced goal-directed behavior), each present for a significant portion of time during a 1-month period
  2. Marked social or occupational dysfunction (e.g., work, self-care, and/or relationships), after the onset of symptoms
  3. Signs of illness for at least 6 months, and at least 1 month of clear symptomatology is present
  4. Condition not attributable to any medical condition, mental health problems, or substance abuse

Schizophrenia cannot be diagnosed through laboratory tests or imaging studies. However, some brain-imaging studies reveal increased ventricular and decreased frontal lobe volume.[22]

Treatment

Treatment for schizophrenia is lifelong and multidisciplinary, aiming to reduce symptoms, maximize functioning, and prevent relapse. This is often challenging because affected individuals may not recognize their illness or seek treatment, or may stop treatment because of undesirable side effects, limited financial resources, or lack of access to mental health services.

Outcomes vary widely. Some individuals with schizophrenia are symptom free when adequately treated; others remain psychotic, disorganized, and unable to function independently. Emotional and physical support is an important component of treatment, and patients often have better outcomes when family or community support is part of their overall treatment plan.

A baseline physical and neurological examination should be performed prior to initiating medications.

Pharmacologic Therapy

Medications are the most effective treatment. Antipsychotics act as dopamine receptor antagonists and are first-line treatments. Discontinuation of antipsychotics typically results in symptom recurrence. However, relapse is common even with continuous treatment. The disease is characterized by a waxing and waning of symptoms, necessitating close follow-up and continued support.

Typical antipsychotics (or neuroleptics), such as haloperidol or chlorpromazine, can be very effective, but they carry greater risk of tardive dyskinesia and other serious extrapyramidal adverse effects, compared with newer drugs.

Second-generation (atypical) antipsychotics, such as olanzapine, risperidone, ziprasidone, aripiprazole, and quetiapine, generally carry less risk of tardive dyskinesia, neuroleptic malignant syndrome, and other extrapyramidal symptoms. However, they have a higher risk of causing metabolic syndrome, characterized by weight gain, dyslipidemia, and abnormal glucose metabolism. Aripiprazole, lurasidone, brexpiprazole, and cariprazine have lower rates of metabolic syndrome, but they carry a risk of akathisia (motor restlessness), and, with the exception of aripiprazole, are not yet available in generic form. They can cost thousands of dollars per month, which currently limits their use. All antipsychotics carry a black box warning for increased risk of cerebrovascular events when given to elderly patients with dementia. Antipsychotics are associated with increased risk of all-cause mortality in older patients.

Clozapine may be used for refractory cases. It also helps treat suicidal ideation, an important consideration given that as many as 40% of persons with schizophrenia will attempt suicide.[23] Physicians need special authorization to use clozapine. Clozapine has several serious potential adverse effects, including life-threatening agranulocytosis, making weekly blood draws mandatory. Additional adverse effects include weight gain, anticholinergic effects, and increased risk of seizures.

Long-acting injectable formulations. Adherence to treatment is a challenge for patients with schizophrenia. Causes of nonadherence include lack of insight into their illness, intolerable side effects, an unstable living environment or homelessness, and cognitive impairment that can occur with schizophrenia. Long-acting injectable (LAI) antipsychotic medications obviate the need to remember to take a pill each day. Instead, patients receive a monthly injection at their doctors’ offices. The use of LAI medication for the treatment of schizophrenia has been associated with better functioning, quality of life, and patient satisfaction.[24] LAI formulations are available for a variety of first- and second-generation antipsychotics. Examples include haloperidol-LAI and aripiprazole-LAI.

Nonpharmacologic Therapy

Antipsychotic medication is generally considered to be an essential part of any treatment plan for schizophrenia; however, the addition of nonpharmacologic interventions can substantially improve outcomes. Cognitive-behavioral therapy and family therapy are intended to help the patient and family identify warning signs of relapse and its consequences and improve treatment adherence. Family therapy has been shown to reduce relapse and rehospitalization.[25]

Group therapy, job training, and social skills training may improve quality of life and social functioning.[26],[27]

Nutritional Considerations

Researchers have speculated that aspects of Western culture, including diet, may play a role in schizophrenia, citing a higher prevalence in industrialized cultures, compared with unindustrialized (especially Asian) populations. During the Industrial Revolution, intakes of saturated fat, meat, dairy products, and refined sugars paralleled an increase in schizophrenia.[28] However, these geographic differences may have been influenced by differences in reporting, and social changes have occurred simultaneously with nutritional changes. The role of nutrition, therefore, remains speculative.

The following factors have been studied for their roles in schizophrenia prevention or management:

A heart-healthy diet. Among the sequelae of schizophrenia is an increased risk of cardiovascular disease.[29] Patients’ diets are often poor, smoking and physical inactivity are common, and antipsychotic medications may contribute to weight gain, hyperglycemia, and hypertriglyceridemia.[28],[30],[31],[32] Metabolic syndrome is also significantly more prevalent in people with schizophrenia, even among those who have not yet started taking an antipsychotic medication.[33] A typical Western (i.e., high-fat, high-sugar) diet also reduces hippocampal expression of brain-derived neurotrophic factor (BDNF), an important growth and maintenance factor for dendrites, which is reduced in the prefrontal cortex of patients with schizophrenia. Low concentrations of BDNF have also been implicated in both coronary atherosclerosis and insulin-resistance syndrome.[34] The latter is twice as common in schizophrenia patients as it is in the general US adult population and helps explain the greater incidence of coronary heart disease in these patients.[35] A case report of a patient with schizophrenia documented less-frequent and shorter-duration symptomology and heightened feelings of well-being while following a vegan diet compared with eating a high-protein, meat-based diet.[36]

A healthy body weight. Weight gain in schizophrenia patients is a concern, due to psychotropic drugs, lack of exercise, potential metabolic changes, and poor diet.[37],[38] A small study suggests that schizophrenic patients, especially males, may have 2-5 times more visceral fat than controls, which increases cardiovascular disease risk.[39] Evidence indicates that behavioral interventions can improve weight control in persons with schizophrenia.[30],[40] Clarification of these issues awaits further research.[41]

Adequate polyunsaturated fatty acids levels. Several studies have suggested that individuals with schizophrenia have lower serum levels of some polyunsaturated fatty acids (PUFAs), and supplementation may slow progression in young adults.[42],[43],[44] However, current research has failed to produce evidence for omega-3, docosahexaenoic acid, or eicosapentaenoic acid supplementation as efficacious treatment.[45],[46] Schizophrenia patients likely have excess oxidative stress with increased lipid peroxidation that reduces PUFA levels, and oxidative stress may play a role in the psychopathology and symptomatology.[47],[48],[49] New studies using plant compounds such as as nitric oxide, polyphenols, and sulforaphane to reduce oxidation and improve PUFA levels suggests a potential role for antioxidants, though more research is needed.[50][51],[52],[53]

Vitamin supplementation. The B-vitamin complex, especially riboflavin, plays a key role in brain function, and supplementation in schizophrenia patients, who may be low in B-vitamins, could be beneficial. A small double-blind, placebo-controlled study found significant improvement in psychiatric symptoms with folic acid, vitamin B6, and B12 supplementation in hyperhomocysteinemic patients.[54] A similar study using folic acid and B12 supplementation that controlled for baseline folic acid status found a similar reduction in symptoms.[55] Although data are sparse and somewhat mixed, some evidence supports supplementation with the antioxidant vitamin C as a way to reduce symptoms. Vitamin E has not been studied on its own; however, some evidence has suggested that, when combined with other nutritional supplements, it worsens symptoms at higher doses. It is possible that vitamin E acts as a pro-oxidant at high doses.

Supplementation with vitamin D during the first year of life may reduce the later risk of schizophrenia in males; no effect has been seen in females. Treating schizophrenia with vitamin D has not been shown to have an effect.[56]

For treatment of tardive dyskinesia, small trials suggest that vitamin E may not improve existing symptoms but may protect against worsening of the condition.[57] Vitamin B6 is under investigation for possible effects on the progression of tardive dyskinesia.[58]

Branched-chain amino acid supplementation. One group of investigators has found a reduction in tardive dyskinesia symptoms with the use of branched-chain amino acid formulas.[59],[60],[61] Tardive dyskinesia is associated with deficient clearance of phenylalanine, an excess of which may increase production of catecholamines and indolamines, which may drive the hyperkinetic movements of tardive dyskinesia.[59] Branched-chain amino acids compete with phenylalanine at the blood-brain barrier, reduce the entry of phenylalanine into the central nervous system, and subsequently reduce production of catecholamines and indolamines.

Gut Microbiome and Schizophrenia

The relationship between mental health and the gut microbiome has become an area of interest and research. However, there is no concrete evidence that dysbiosis plays a role in schizophrenia. There have been mixed results in studies using prebiotics and probiotics for the treatment of schizophrenia. Potential areas of research for the nutritional modulation of the microbiome for treatment and prevention of schizophrenia include reducing inflammation in the central nervous system, improving gut barrier function, and preventing constipation and weight gain.[62]

Orders

See Basic Diet Orders and Coronary Heart Disease chapters.

What to Tell the Family

Schizophrenia is a lifelong illness that requires medication and support from both mental health professionals and family members. Persons with schizophrenia are at greater-than-average risk for cardiovascular disease from a combination of medication, sedentary lifestyle, poor diet, and smoking. Family members can support the affected person by providing a healthful diet and a smoke-free environment, and by encouraging participation in regular physical activity. The potential benefit of additional nutritional interventions is a matter of ongoing research.

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