Which of the following forms of treatment helps in treating negative symptoms of schizophrenia?

Am Fam Physician. 2014;90(11):775-782

Patient information: See related handout on schizophrenia, written by the authors of this article.

Author disclosure: No relevant financial affiliations.

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Schizophrenia is the most common psychotic disease, with a global prevalence of less than 1%. It affects all ethnicities and is slightly more common in men. Patients with schizophrenia commonly experience debilitating social and occupational impairments, but some are able to function well with proper treatment. Symptom onset is generally between late adolescence and the mid-30s. There are two categories of symptoms: positive and negative. Hallucinations, delusions, and disorganized speech are examples of positive symptoms, whereas decreased emotional expression and lack of motivation are negative symptoms. Antipsychotic medications can treat some symptoms of schizophrenia but are associated with multiple adverse effects, including extrapyramidal symptoms and metabolic changes. Patients receiving antipsychotic medications, especially second-generation (or atypical) antipsychotics, should be monitored regularly for metabolic changes and cardiovascular risk factors. Persons with schizophrenia who undergo psychosocial therapy in addition to medical therapy have better outcomes. Patients diagnosed with schizophrenia have a higher overall mortality rate than the general public, partly because of the increased suicide risk associated with schizophrenia.

Schizophrenia is a pervasive, chronic mental disorder with a global prevalence of 0.3% to 0.7%.1 Although there is no significant difference between sexes, a slight predominance is noted in men.1,2 Schizophrenia affects persons in all ethnicities. However, a recent study confirmed that in the United States, blacks are diagnosed with schizophrenia at a disproportionately higher rate compared with non-Hispanic whites.3 This finding could point to a racial or ethnic bias in the diagnosis of schizophrenia in black persons who present with psychosis.3

Schizophrenia is the most common psychotic disease.4 Therefore, family physicians should have an overall knowledge of the disease, including the initial presentation, treatment and its challenges, and how to address comorbidities. Whenever possible, family physicians should educate patients and their families about medication reactions and the importance of compliance with treatment. Referral to a psychiatrist is appropriate for patients presenting with psychosis.

Etiology and Risk Factors

Genetics have an important role in the etiology of schizophrenia, even though most patients diagnosed with the disease have no family history of psychosis. The genetic variation responsible for the disease has not been identified. Relatives of persons with schizophrenia are also at risk of schizoaffective disorder, schizotypal personality disorder, bipolar disorder, depression, and autism spectrum disorder.1,5

Environmental factors may have a role.1 Possible environmental factors include being born and raised in an urban area, cannabis use, infection with Toxoplasma gondii,2,6,7 obstetric complications, central nervous system infection in early childhood, and advanced paternal age (older than 55 years).1

Clinical Presentation

The symptoms of schizophrenia usually begin between late adolescence and the mid-30s. Cases involving children as young as five years have been reported, but these are rare. In men, the symptoms tend to present between 18 and 25 years of age. In women, the onset of symptoms has two peaks, the first between 25 years of age and the mid-30s, and the second after 40 years of age.1

Patients may have symptoms during a prodromal phase before they become psychotic. These symptoms include social withdrawal, loss of interest in work or school, deterioration of hygiene, angry outbursts, and behavior that is out of character.1 This phase may be mistaken for depression or other mood disorders. The patient will eventually exhibit active-phase symptoms of the disorder.1

Diagnosis

Criteria for schizophrenia include signs and symptoms of at least six months' duration, including at least one month of active-phase positive and negative symptoms (Table 1).1 Delusions, hallucinations, disorganized speech, and disorganized behavior are examples of positive symptoms. Negative symptoms include a decrease in the range and intensity of expressed emotions (i.e., affective flattening) and a diminished initiation of goal-directed activities (i.e., avolition).

DIFFERENTIAL DIAGNOSIS

Other organic and psychiatric diagnoses can present with symptoms of psychosis (Table 2).1 Initially, patients should be evaluated for any intrinsic cause of psychosis (e.g., delirium, mood disorder with psychosis, Cushing syndrome, drug use [illicit and prescribed]). Ideally, patients should be observed in a controlled setting for an extended time. This allows for differentiation between psychiatric disorders; however, this is not always feasible. In most situations, physicians must rely on a history provided by family members.1 The physical examination will also help determine organic causes of psychosis.

Treatment

Patients diagnosed with psychosis, schizophrenia, or both should be urgently referred for psychiatric evaluation.8 Not all patients with acute psychosis require hospitalization, but it should be considered for those who may pose a danger to themselves or others.4 The most effective treatment for schizophrenia is a multidisciplinary approach including medication, psychological treatment, and social support.5,9–11 The goal of treatment is remission, which is defined as a period of six months with no symptoms or mild symptoms that do not interfere with a person's behaviors.12

ANTIPSYCHOTICS

Antipsychotic agents are the first-line treatment for patients with schizophrenia. There are two general types of antipsychotic drugs: first-generation (typical) and second-generation (atypical) agents. Table 3 lists commonly used antipsychotic drugs, their adverse effects, typical dosages, and price.11,13–21 Multiple guidelines recommend starting antipsychotic medications as soon as possible after psychotic symptoms are recognized and/or the patient is diagnosed with schizophrenia.8,10,11,13,21,22 The National Institute for Health and Care Excellence suggests urgent referral to mental health services when a person presents with psychotic symptoms, and recommends that primary care physicians initiate antipsychotic medications only in consultation with a psychiatrist (Table 4).8 Initial medication choice should be individualized, taking into account financial considerations, adverse effect profiles, dosing regimens, and patient preferences.

Antipsychotic medications are more effective than placebo in reducing overall symptoms of schizophrenia and preventing relapse.13–15 Patients with schizophrenia who are receiving antipsychotic drugs report a better quality of life, but have a higher incidence of weight gain, sedation, and movement disorders.15 As such, all patients who report symptom relief while receiving medication should be offered maintenance therapy with antipsychotics.11 A patient's response to treatment during the first two to four weeks is highly predictive of long-term response, although it may take several months to achieve maximal effect.17 Patients should be given an adequate trial of therapy (at least four weeks at a therapeutic dose) before discontinuing the drug or transitioning to a different medication.22

Studies have shown that there is no difference in effectiveness between first- and second-generation antipsychotics.23,24 Quality of life is also similar at one year between groups of patients treated with each drug class.23 The main difference between these medications is their adverse effect profiles; first-generation antipsychotics most commonly cause extrapyramidal symptoms, whereas second-generation agents most commonly cause weight gain and metabolic changes.22,25–27 Adverse reactions and previous response to antipsychotic medications should be taken into account when deciding which class of medication to initiate.

ADVERSE EFFECTS AND MONITORING

Extrapyramidal symptoms such as pseudoparkinsonism, akathisia (a sensation of inner restlessness and inability to be still), and dystonia are associated with first-generation antipsychotics. Patients receiving these medications should be routinely monitored for adverse effects and maintained on the lowest effective dose that controls their symptoms. Medications such as propranolol, lorazepam (Ativan), amantadine, benztropine, and diphenhydramine (Benadryl) are used to treat extrapyramidal symptoms.25 Tardive dyskinesia involving facial muscles generally occurs after the patient has been taking antipsychotic medications for a prolonged time. Symptoms include puffing of the cheeks, protrusion of the tongue, chewing motions, and pursing of the lips. The condition is typically irreversible, but symptoms may lessen after the medication is discontinued. Laboratory monitoring is not necessary for patients receiving first-generation antipsychotics. Patients receiving the second-generation antipsychotic clozapine (Clozaril) are at high risk of agranulocytosis, and the package insert recommends a complete blood count weekly for six months, then every two weeks for an additional six months, then monthly. Clozapine is reserved for patients with severe refractory symptoms because of its increased risk of adverse effects; it should be prescribed only by a psychiatrist.11

The most worrisome adverse effects associated with second-generation antipsychotics are metabolic changes, such as weight gain, insulin resistance, hyperglycemia, and lipid abnormalities.15,25,27,28 All second-generation antipsychotics confer varying degrees of risk for metabolic changes,28 and these effects are not dose-dependent.29 Weight gain is usually rapid in the first few weeks of treatment, then plateaus; however, this can take a year or more to occur.27 Therefore, patients should be examined frequently after initiating treatment with second-generation antipsychotics, and at least annually if they have normal baseline values. Patients with cardiovascular risk factors require more frequent monitoring.28,30 Table 5 outlines the recommended frequency of monitoring for patients receiving second-generation antipsychotics.28,30 Primary care physicians should regularly assess body mass index, fasting glucose levels, and lipid profiles, and work toward minimizing these and other cardiovascular risk factors.8,30,31

ADJUNCTIVE TREATMENTS

In addition to medication, patients with schizophrenia should be offered adjunctive therapies such as cognitive behavior therapy, family interventions, and social skills training.8–10,13 Cognitive behavior therapy is the most commonly used adjunctive therapy, but a Cochrane review found no clear evidence that it is superior to other talking therapies, although it may be helpful in dealing with emotions and distressing feelings.32 A Chinese study found that psychosocial treatment combined with medication improved treatment adherence, insight, and quality of life, and decreased hospital admissions.9 Patients receiving combined treatment were less likely to discontinue their medication or to relapse (absolute risk reduction = 14% and 8%; number needed to treat = 7 and 12, respectively).

There is a higher incidence of anxiety disorders, panic symptoms, posttraumatic stress disorder, and obsessive compulsive disorder in patients with schizophrenia compared with the general public.33 Medications such as selective serotonin reuptake inhibitors and anxiolytics can be helpful in treating comorbid mood disorders in these patients, but do not treat the symptoms of schizophrenia.34

Clinical Course and Prognosis

Patients with schizophrenia have a varied clinical course that may include remission, exacerbations, or a more persistent chronic illness. Among patients who remain ill despite therapy, some have a stable clinical course, whereas others experience worsening symptoms and functioning. Factors that predict the clinical course and prognosis of these patients are not understood, and there is no reliable way to predict outcomes. Approximately 20% of patients can be expected to have a positive outcome.1

Suicide is a concern when treating patients with schizophrenia. The risk of suicide is 13 times greater in persons diagnosed with schizophrenia compared with the general public, with a lifetime risk of about 5%.1,4,35 Patients with auditory hallucinations, delusions, substance abuse, or a history of suicide attempts are at higher risk. Adequate treatment of schizophrenia and its comorbidities, along with diligent screening for risk factors, reduces the likelihood of suicide.35 The overall mortality rate for patients with schizophrenia is two to three times higher than that of the general public.1,36 Most deaths are related to an increased rate of cardiovascular and respiratory diseases, stroke, cancer, and thromboembolic events.36

In the past, schizophrenia was viewed as a disease with a poor prognosis. Currently, the disease course and response to treatment are marked by heterogeneity; differences in treatment response, disease course, and prognosis are to be expected.5,12 Despite adequate treatment, one-third of patients will remain symptomatic. Although most patients need some form of support, most are able to live independently and actively participate in their lives.5

Data Sources: We were provided a search from Essential Evidence Plus using the search term schizophrenia. We searched the National Institute for Health and Care Excellence, U.S. Preventive Services Task Force, and Agency for Healthcare Research and Quality. A PubMed search was completed using the search subjects schizophrenia, schizophrenia diagnosis, schizophrenia treatment, and schizophrenia prognosis. Search dates: March and September 2012, and August 2014.

The authors thank Monica Kalra, DO; Robert Suter, DO; Khadija Kabani, DO; Brenda Wilson; and Sharon West for their assistance with the preparation of the manuscript.

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