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Table of Contents

Revised November 15, 2004

Jayant
Choure, MD

Departments of
Psychiatry and
Psychology

David J.
Muzina, MD

Departments of
Psychiatry and
Psychology

Print Chapter

Definition

Prevalence

Pathophysiology

Diagnosis

Signs and
Symptoms

Differential Diagnosis

Treatment

Outcomes

References

Schizophrenia, the most severe and debilitating mental illness, has long been the focus of medical, scientific, and societal attention. It is a disease of the brain whose manifestations, although varied among individuals, exacts severe and usually lifelong distress on those who suffer with it.

Emil Kraepelin (1856 to 1926) was a German psychiatrist who devoted his life's work to the task of describing and characterizing the symptoms his patients manifested. From these observations, he concluded that not all mental patients suffered from the same disease. Kraepelin used the Latin of Morel's term to label this chronic illness dementia praecox. Eugene Bleuler (1857 to 1939) was a Swiss psychiatrist generally credited for coining the term schizophrenia, of which he described primary symptoms of abnormal associations, abnormal affect, autistic behavior, and ambivalence.¹

In 1972, Robbins & colleagues presented a list of symptoms and signs that provided a reliable system for differentiating diagnostic groups.² They emphasized the pattern and duration of symptoms (requiring 6 months of persistent symptoms to reach a diagnosis of schizophrenia) without regard to the etiology of the illness being observed. This descriptive approach to psychiatric diagnostic process laid the foundation for our current symptom-based understanding of this brain disorder.

The 1% to 1.5% prevalence rate for schizophrenia has been fairly constant across time, various cultures and continents; however, the associated social disability and cost are enormous.³ The chronicity of the disease and the often profound impairment experienced by schizophrenic patients have made it the most serious and disabling mental illness.⁴ In the United States, about 2.5% of total annual health care expenditures are spent on schizophrenia management.⁵

Schizophrenia is equally prevalent in men and women.⁴ The median age of onset for the first psychotic episode of schizophrenia is in the early to mid-20s for men and in the late 20s for women. The onset may be abrupt or insidious, but most individuals display a prodromal phase manifested by the slow and gradual development of a variety of signs and symptoms of the illness.

Schizophrenia is best conceptualized as a syndrome expressed by a heterogeneous group of disorders rather than as a single disease entity. Although the National Alliance for the Mentally Ill promotes the idea that schizophrenia and other severe mental illnesses are brain disorders, it is difficult to distinguish between causes that have a clear material or biologic basis and those that might be due to environmental or psychological factors. Over the past century, studies have consistently shown that both genetic and non-genetic factors play a significant role in the etiology of schizophrenia. Thus, several observations and theories regarding the etiology and pathophysiology of this disorder have been made.

Genetic Susceptibility
An increasing amount of evidence shows that genetic and neurodevelopmental factors substantially contribute to the pathogenesis of schizophrenia.⁶ According to twin and adoption studies, up to 50% of identical (monozygotic) twins will share a diagnosis of schizophrenia, compared with about 12% of non-identical (dizygotic) twins.⁷ The strength of genetic factors varies across families, but some 10% of a patient's first-degree relatives (parents, siblings, and children) will also be schizophrenic, as will 50% of the children of two schizophrenic parents. Reports indicate suggestive linkage on chromosomes 1, 3, 5, 11 and on the X chromosome.

Winter Birth
The birthrate of patients with schizophrenia during the winter and spring months is 5% to 8% higher worldwide than the birthrate of the general population in the winter and spring months. No proven explanation exists for this phenomenon. It is theorized that early viral infections may play a causative role in the development of schizophrenia; both an increase in birth during influenza epidemics of individuals who subsequently develop schizophrenia and an increase in winter births among patients with schizophrenia because of the higher rate of viral infections in winter months have been observed. The 1957 influenza A2 epidemic in Helsinki resulted in an increase in schizophrenia in the offspring of women who developed this flu during their second trimester.⁸

Early Developmental Insults
Hypoxia in the infant during difficult labor and delivery is associated with increased structural brain abnormalities among schizophrenic patients and their non-schizophrenic siblings, but not among controls at low genetic risk for the disorder.⁹ Schizophrenics who have suffered perinatal complications are especially likely to show lateral ventricular enlargement and decreased hippocampus volume.¹⁰

Other Factors
Population density, industrialization, emigration, and low socioeconomic status at birth¹¹ have been proposed as possible influences on the development of schizophrenia.

Neuroanatomical Theories
The higher structural resolutions of computed tomography (CT) and magnetic resonance imaging (MRI) scans have shown that a subgroup of schizophrenic individuals had enlarged lateral and third ventricles (which imply changes in the periventricular limbic-striatal area) and decreased size of the frontal and temporal lobes.

Neurochemical Theories
Dopamine hypothesis. Several transmitter systems have been implicated, but the primary focus has been on the dopamine (dopamine= "DA") system¹¹,¹² because evidence indicates that most drugs that ameliorate psychotic symptoms in patients with schizophrenia are DA receptor blockers. In addition, dopamine agonists, such as amphetamine and methylphenidate, exacerbate psychotic symptoms in schizophrenia.

Five subtypes of DA receptors (D₁ through D₅) have been characterized biochemically. The clinical effectiveness of D₂-receptor antagonism on the psychotic symptoms of schizophrenia has been widely demonstrated. This D₂ receptor-blocking effect explains many of the typical actions and side effects of neuroleptics: D₂-receptor blockade of the nigrostriatal tract results in extrapyramidal symptoms, the suppression of positive symptoms seems to be related to blocking excess DA in the mesolimbic tract, and inhibition of the tuberoinfundibular leads to hyperprolactinemia because DA is the prolactin-inhibiting factor.

Although the DA hypothesis is the leading neurochemical hypothesis, it poses two major problems. First, DA antagonists are effective in treating psychosis and agitation due to disorders other than schizophrenia (e.g. delirium). Second, some electrophysiologic data suggest that DA neurons increase their firing rate in response to long-term exposure to antipsychotic drugs.

Serotonin factor. Serotonin(5-HT), often thought to be the primary neurotransmitter associated with mood disorders, also plays a role in schizophrenia symptom emergence and treatment. The hallucinogen lysergic acid diethylamide (LSD) has primary effects on 5-HT neurotransmission. LSD produces symptoms that can mimic schizophrenia, including a profound psychotic state, distractibility, social withdrawal, referential thinking, and delusions. Newer atypical antipsychotic agents have a greater ratio of 5-HT to dopamine D₂-binding affinity that has not only enhanced efficacy but also diminished neurologic side effects from antipsychotic medications. An enhanced neuroendocrine response to 5-HT₂-receptor stimulation by D-fenfluramine in drug-naive schizophrenic patients has been demonstrated,¹³ and this response is blocked by the atypical antipsychotic clozapine.¹⁴

Glutamate and N-methyl- D-aspartate receptor. An association between glutamatergic hypofunction and schizophrenia was found in pharmacologic studies showing that NMDA receptor antagonists such as phencyclidine (PCP) and ketamine hydrochloride can induce many of the psychotic signs and symptoms of schizophrenia in normal subjects as well as exacerbate these signs and symptoms in subjects with schizophrenia.¹⁵,¹⁶,¹⁷

Gamma-amino butyric acid (GABA). Clinical trials have demonstrated that benzodiazepines, which inhibit GABA, administered both in conjunction with antipsychotic drugs and as the sole treatment, are effective at reducing symptoms in subgroups of schizophrenic patients.¹⁸

Peptides. Schizophrenic patients were found to have lower cerebrospinal fluid neurotensin levels than healthy control subjects. In preclinical studies, neurotensin was found to have effects that resembled those of antipsychotic drugs.¹⁹

Norepinephrine. One study found a significant relationship between increases in plasma norepinephrine and improvement in positive symptoms of schizophrenia.²⁰

According to the Diagnostic and Statistical Manual for Psychiatric Disorders - Fourth Edition (DSM-IV), the diagnosis of schizophrenia is based on a constellation of signs and symptoms that are present for a sufficient length of time, are not caused by a another medical disorder or substance, and cause significant impairment in role functioning (Table 1).

All of the following criteria must be present to diagnose schizophrenia:

Criterion A includes delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and negative symptoms (See Signs and Symptoms section). Two or more of these symptoms are required during a 1-month period in the active phase of the illness. However, if the patient describes bizarre delusions or auditory hallucinations consisting of voices conversing or a voice commenting on the patient's behavior only one of these symptoms is needed.

Criterion B addresses deterioration of social and occupational function for a significant portion of the time since the onset of the disturbance.

Criterion C eliminates patients with less than 6 months of continued disturbance.

Criterion D excludes patients whose illness has a compelling mood aspect and, therefore, might meet the criteria for schizoaffective disorder or a mood disorder.

Criterion E clarifies the fact that patients with schizophrenia are not suffering from other medical illnesses or the physiologic effects of substances that might mimic the symptoms of schizophrenia.

Criterion F acknowledges that schizophrenia can be diagnosed in patients with autistic disorder or developmental disorder as long as there have been prominent delusions or hallucinations that have lasted at least 1 month.

The first episode of schizophrenia typically occurs in the late teenage years or the early 20s. Early recognition is hindered by the often-insidious prodrome of schizophrenia, which includes subtle, non-specific problems in language, cognitive ability, and behavior.²¹ Frequently, neurotic features (social anxiety, panic attacks, and obsessional ideas), antisocial behavior, or substance misuse dominate the clinical picture and obscure the underlying psychosis.²² Functional deficits such as emotional flattening, social withdrawal, and a lack of motivation and pleasure are usually prominent.²² The most commonly reported psychotic features are auditory hallucinations and delusions.

It is well established that symptomatology in psychotic disorders can be ascribed by factor analysis to three main psychotic symptom dimensions:

1. Positive symptoms include actively expressed and easily observed symptoms such as hallucinations, thought disorder, delusions, and bizarre behavior.Negative symptoms include decrease in emotional range, poverty of speech, loss of interests, and loss of drive.
2. Cognitive symptoms include deficits in attention, memory, and executive functions, such as abstract reasoning and the ability to organize.

Symptoms usually wax and wane. A patient's pattern of symptoms may change over the years. Positive symptoms respond fairly well to antipsychotic medication, but negative and cognitive symptoms can be quite persistent. Full recovery is uncommon, especially if the illness has been present for some years. The course is usually worse if there is comorbid substance abuse.

No specific clinical presentation of a patient, laboratory test, or neuroimaging study yields a definitive diagnosis of schizophrenia. Schizophrenia can present with a wide variety of symptoms. Other disorders to consider are:

Schizoaffective Disorder
This chronic mental illness comprises a mixture of mood, thought, and functional disturbances that is often difficult to differentiate from schizophrenia. To diagnose schizoaffective disorder, criterion A for schizophrenia must be met concurrent with a major mood disturbance (major depressive or manic episode). Although mood symptoms and episodes must be present for a substantial portion of the total course of illness, a diagnosis of schizoaffective disorder also requires that psychotic symptoms, such as delusions or hallucinations, have been present for a minimum of 2 weeks in the absence of an active mood disturbance.

Brief Psychotic Disorder and Schizophreniform Disorder
The distinctions among brief psychotic disorder, schizophreniform disorder, and schizophrenia are based on duration of active symptoms. Brief psychotic disorder lasts for at least 1 day and up to 1 month. Schizophreniform disorder falls in between and requires symptoms for at least 1 month but not exceeding 6 months.

Delusional Disorder
In delusional disorder, the delusions that a patient describes are not bizarre and, apart from having the delusions, the patient's functioning is not markedly impaired.

Affective Disorder with Psychotic Features
If psychotic symptoms occur solely during times when affective symptoms are present, the diagnosis is more likely to be mood disorder with psychotic features — for example, major depression with psychotic features.

Substance Abuse and Related Conditions
Psychotic disorders that are caused by substance use are distinguished from schizophrenia by clear-cut evidence of substance use leading to symptoms.

Medical Disorders
Medical disorders ranging from vitamin B₁₂ deficiency to Cushing's syndrome have been associated with a clinical presentation resembling that of schizophrenia. The medical workup includes a physical examination; laboratory analyses, including thyroid function tests, syphilis screening, and measurement of folate and vitamin B₁₂ levels; a CT or MRI scan; and a lumbar puncture when indicated in new-onset cases (Table 2).

The psychiatrist-patient relationship is the foundation for treating patients with schizophrenia. Relationship qualities should include consistency, acceptance, and appropriate levels of warmth.

Hospitalization
Hospitalization is indicated for first-onset psychosis and should include a comprehensive medical, psychiatric, psychological, and family/psychosocial assessment. For patients with chronic schizophrenia, hospitalization is often required to manage periods of illness exacerbation, which are associated with grossly disorganized thoughts and behaviors, depression, suicidal or homicidal thinking, and inability to care for oneself during active phases of the illness. Often, medication noncompliance and/or substance abuse will precipitate acute exacerbations, necessitating hospitalization.

Psychopharmacologic Treatment
The primary goal of acute treatment is the amelioration of any behavioral disturbances or symptoms that would put the patient or others at risk of being harmed. The antipsychotic drugs include two major classes: DA-receptor antagonists (called typical antipsychotics) and serotonin-dopamine antagonists (called atypical antipsychotics). Studies in medicated schizophrenic patients have shown that treatments with traditional antipsychotic compounds such as haloperidol consistently induce 70% to 80% occupancy of the striatal D2 receptors.²³,²⁴ Furthermore, high levels of D2-receptor occupancy in the striatum are associated with a higher risk of extrapyramidal side effects.²⁵ Atypical antipsychotics such as clozapine have a lower tendency to induce extrapyramidal side effects. This may be consistent with the lower in vivo D2 striatal blockade reported with standard doses of clozapine.²⁶ In a multicenter, randomized, international study (InterSePT ) comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine, clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder. The results of this study suggest that serious suicide attempts and hospitalizations to prevent suicide can be reduced by about one fourth with clozapine treatment vs olanzapine treatment. The analysis of this study led to the US Food and Drug Administration (FDA) approval of clozapine specifically to reduce suicide risk in this patient population.²⁷

More recent theories regarding the speed with which atypical antipsychotics attach and then dissociate from DA-receptors have been put forth to explain pharmacologic efficacy and side effects. Side effects and risks of antipsychotic agents. The extrapyramidal side effects of typical antipsychotic medications include dystonias, pseudoparkinsonism, akinesia, and akathisia. Treatment of acute extrapyramidal symptoms usually involves administration of anticholinergic medications. Non-extrapyramidal side effects of typical antipsychotic agents include sedation, tachycardia, and anticholinergic side effects. Other non-extrapyramidal side effects include cardiac conduction disturbances, retinal changes, sexual dysfunction, weight gain, lowered seizure threshold, and agranulocytosis. Neuroleptic malignant syndrome is a relatively rare but serious phenomenon characterized by fever, rigidity, confusion, and instability of pulse and blood pressure; it is seen in approximately 1% of patients taking neuroleptics.²⁸ One of the major risks of neuroleptic treatment with traditional antipsychotic agents is tardive dyskinesia, a potentially irreversible syndrome of involuntary choreoathetoid movements and chronic dystonias associated with long-term neuroleptic exposure.

Atypical antipsychotic medications are associated with fewer extrapyramidal adverse effects and are preferred over the older, typical antipsychotics. Atypical antipsychotic agents also are probably more effective in treating the negative symptoms and cognitive impairment of schizophrenia than are the typical (conventional) agents. Five serotonin-dopamine antagonists have been approved for use in the United States (Table 3). These medications generally have a better side-effect profile than older medications, although other problems, such as sedation and weight gain, can be seen.

Until now, haloperidol and fluphenazine were the only antipsychotics available in depot preparation. Both of these medications are first generation antipsychotics (typical). The two main disadvantages of these medications were limited efficacy on negative symptoms and EPS side effects. Now long acting risperidone, the first second generation (atypical) long acting intramuscular preparation is available. Starting dose is 25 mg IM once every two weeks. Patient should be on short acting antipsychotic supplementation for the first three weeks of treatment. Maximum dose should not exceed 50 mg every two weeks.²⁹

Now one of the newer agents available on the market is Aripiprazole, a third-generation antipsychotic. Aripiprazole differs from second generation agents by its unique action as an agonist or antagonist depending upon dopamine receptors stimulation. In circumstances of low dopamine receptor stimulation it will act as an agonist whereas in case of high dopamine stimulation will act as an antagonist.³⁰ Most common side effects include nausea and vomiting that can be reduced by taking it with food. The efficacy of aripiprazole for the treatment of schizophrenia and schizoaffective disorder has been evaluated in placebo-controlled, randomized, multicenter trial which revealed that it is effective, safe, and well tolerated for the positive and negative symptoms of the disorder.³¹

Another recent development in the use of parenteral anti-psychotics is the introduction of intra-muscular olanzapine preparation. Intra-muscular olanzapine has been proven to be highly efficacious in the treatment of acute agitation in schizophrenia and bipolar mania with a favorable safety profile. Dose range is 2.5 to 10 mg intra-muscular. It is available in 10 mg vial.^32,33

Schizophrenia is a chronic condition that frequently has devastating effects on several aspects of the patient's life. Goals and strategies of treatment vary according to the phase and severity of illness. Although various guidelines for treatment of schizophrenia have been proposed³⁴, it is best for the clinician to individualize treatment plans and medications for each individual patient. The most recently developed expert guidelines were developed by the American Psychiatric Association³⁵, and are summarized below.

Acute Phase
Assessment. Each patient should have a thorough initial workup to rule out conditions that can mimic schizophrenia, to determine the presence of comorbid conditions, and to establish a baseline for the administration of antipsychotic medications.

Choice of treatment setting. Hospitalization is indicated for diagnostic purposes, for stabilization of medication, for patients' safety because of suicidal or homicidal ideation, and for grossly disorganized or inappropriate behavior. Alternative treatment settings such as partial hospitalization, home care, family crisis therapy, crisis residential care, and assertive community treatment should be considered for patients who do not need formal hospitalization.

Psychiatric management. Interventions are aimed at reducing overstimulating or stressful life events in a structured and predictable environment and develop an alliance with the patient and family. Formulation of short-term and long-term treatment plans as well as connecting the patient with appropriate maintenance and follow-up care in the community are critical elements of care.

Antipsychotic medications. In choosing a medication, the psychiatrist should consider past treatment responses, side-effect profiles, patient preference for a particular medication, and intended route of administration. Because of their efficacy and safety, atypical antipsychotic medications are first-line medications for patients in acute phases of schizophrenia. It is important to select a dose that is both effective and not likely to cause serious side effects (Table 3).

Other medications. Lithium, carbamazepine, valproic acid, or a benzodiazepine are commonly added to antipsychotic medication when the patient continues to demonstrate active psychotic symptoms despite an adequate antipsychotic medication trial. However, because none of these adjunctive medications has demonstrated the effectiveness of clozapine, they should be reserved for treatment-resistant patients for whom clozapine is not adequate.

Stabilization Phase
If a patient has improved with a particular medication regimen, he or she should continue taking the same medication at the same dose for the next 6 months before a lower maintenance dose is considered for continued treatment. Premature lowering of the dose or discontinuation of the medication during this phase may lead to relapse.

Psychotherapeutic interventions remain supportive. Patients should be helped with the transition to life in the community and helped to adjust to their lives outside the hospital through realistic goal setting.

Stable Phase
The frequency of psychiatric assessments depends on the specific nature of the treatment and expected fluctuations of the illness. Stable patients who do not have positive symptoms may be candidates for dose reduction. It is prudent to reduce the medication dose gradually, to a level of at least one fifth the usual maintenance dose, as long as the patient remains stable.

The need for maintenance antipsychotic medication and the required dose should be reviewed at least annually. Patients with only one episode of positive symptoms who have had no symptoms during the following year of maintenance therapy may be considered for a trial period without medication. For patients who have experienced multiple episodes, maintenance antipsychotic medication treatment should be continued in most cases for at least 5 years and possibly indefinitely. Continuing antipsychotic medications indefinitely should also be considered for patients with a history of serious suicide attempts or violent, aggressive behavior.

The longer-term course of schizophrenia is generally characterized by frequent remissions and relapses. In three separate long-term studies of schizophrenia ranging in duration of follow-up from 22 to 59 years, rates of recovery or significant improvement were between 49 to 68 percent.³⁰

Although the intensity of this illness tends to fade with age, it is often difficult to overcome years of dysfunction and disability secondary to schizophrenia. Most patients continue to experience and express symptoms of their illness throughout their lives, with only a minority reaching a stable residual phase of illness and even fewer fully recovered, especially in areas of occupational functioning and social proficiency. Multi-modal treatments combining medication and psychosocial rehabilitation are most effective in maximizing potential for favorable long-term outcome.

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