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Introduction to Schizophrenia

The symptoms of schizophrenia can be generally classified into positive and negative symptoms. Most of the disability of schizophrenia is caused by the negative symptoms of the disorder and the impairment in cognitive ability. The most common forms of impaired cognitive ability include impairments in attention, working memory, and executive functioning.

Pathophysiology of Schizophrenia

Our current understanding of schizophrenia is based on an observation that was made by scientists. Scientists have found that abnormalities in certain neurotransmitters such as dopamine, serotonin, and glutamate are related to the pathophysiology of schizophrenia. Imbalances in these neurotransmitters are believed to be responsible for the different symptoms of the disorder. We will focus on the most common theory of the pathophysiology of schizophrenia, i.e. the dopaminergic theory.

Dopamine receptor sites abnormalities are associated with the symptoms of schizophrenia. The nigrostriatal pathway which originates in the substantia nigra and ends in the caudate nucleus is thought to control the extrapyramidal system. The mesolimbic pathway which is rich in dopamine receptors (D2) is believed to be impaired in patients with schizophrenia. Abnormalities in this pathway might explain the positive symptoms of schizophrenia. The second pathway that is believed to be impaired in schizophrenia is the mesocortical pathway.

Abnormalities in the dopamine receptors of this pathway explain the negative symptoms and cognitive deficits observed in patients with schizophrenia. Patients with schizophrenia typically have an over-activated “excess dopamine” mesolimbic pathway and an under-activated mesocortical pathway.

Dopamine pathway
Mesolimbic (positive symptoms)


“Neurotransmitter Tracts. Mesolimbic” Image created by Lecturio

Mesocortical (negative symptoms)


“Neurotransmitter Tracts. Mesocortical” Image created by Lecturio

Nigrostriatal (extrapyramidal symptoms and tardive dyskinesia)


“Neurotransmitter Tracts. Nigrostriatal” Image created by Lecturio

Tuberoinfundibular (hyperprolactinemia)


“Neurotransmitter Tracts. Tuberoinfundibular Image created by Lecturio

In addition to abnormalities in neurotransmission, patients with schizophrenia also have physical abnormalities of the brain tissue. Volumetric brain magnetic resonance imaging (MRI) studies are used in research-focused approaches to elucidate more light on the pathophysiology of schizophrenia. Volumetric brain MRI showed that patients with schizophrenia have a smaller medial temporal lobe. The medial temporal lobe is related to short-term memory functioning among other cognitive abilities.

Etiology of Schizophrenia

A single etiological factor for schizophrenia is yet to be discovered. The currently accepted hypothesis about the etiology of schizophrenia is that the disorder manifests when a subject with genetic susceptibility is exposed to an environmental risk factor.

Genetic predisposition is supported by the following findings that have been published recently:

 Affected Person Risk
 First-degree relative  10%
 Second-degree relative  48%
 Dizygotic twins in one twin if the other has schizophrenia  14%
 Offspring of both parents have schizophrenia  40%

Environmental stressors are believed to be triggers of schizophrenia rather than true causes of the disorder. The most common stressors are:

  • Childhood trauma
  • Minority ethnicity
  • Residence in an urban area
  • Social isolation

Epidemiology of Schizophrenia

The estimated prevalence of schizophrenia in the United States is around 1.25%. The annual incidence of the disorder in the United States is approximately 5.1 per 1000 lives. The prevalence of the disorder seems to be equal between the two genders.

The age of onset in males appears to be earlier than that of females. Accordingly, the onset of the disorder in males usually happens in their early twenties, whereas women typically experience their first episode in their late twenties or thirties. The incidence of schizophrenia appears to be different in different countries which could be explained by societal differences. For instance, people who live in countries where discrimination against them might be a challenge are more likely to develop schizophrenia than those who live in a more welcoming environment.

Image: “Age-standardised disability-adjusted life year (DALY) rates from Schizophrenia by country (per 100,000 inhabitants).” by Lokal_Profil. License: CC BY-SA 2.5

Clinical Presentation of Schizophrenia

People with schizophrenia, in contrast to popular belief, do not have a split personality. They, however, suffer from a chronic psychotic disorder that affects their thoughts and effect. The impairments are severe enough to affect the patient’s ability to participate in social events or to form a meaningful relationship. The symptoms of schizophrenia can be classified into premorbid, positive, negative, and cognitive symptoms.

Premorbid symptoms appear before the onset of the first episode of schizophrenia and they include social withdrawal and some paranoid thoughts. In some people, the first psychotic episode is preceded by no warning symptoms. In that case, the premorbid period is said to be asymptomatic.

The positive symptoms of schizophrenia are easy to identify by the clinician. They include:

  • Delusions
  • Hallucinations
  • Abnormal motor behavior

Negative symptoms, on the other hand, are more difficult to recognize. Schizophrenia morbidity is related to the negative and cognitive symptoms of the disorder; therefore, it is important to recognize such symptoms and treat them properly. The most common symptoms of schizophrenia include diminished emotional expression and avolition. Alogia and anhedonia are other negative symptoms that might be experienced by a person with schizophrenia.

Cognitive symptoms are usually nonspecific; however, they are related to the disorder’s impact on the quality of life of the person affected. Cognitive symptoms include disorganized speech, thought or attention. These cognitive symptoms eventually result in impaired communication.

Patients with schizophrenia lack awareness about their illness. The different symptoms of schizophrenia may lead to occupational and social dysfunction. Patients might be unable to complete their education or can become unable to hold a stable job. Moreover, patients with schizophrenia find it very difficult to maintain a normal social relationship with a partner. Unfortunately, only 20% of patients with schizophrenia report good outcome after starting treatment with antipsychotics.

Diagnosis of Schizophrenia

The diagnosis of schizophrenia can be established by following the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for schizophrenia:

Criterion A Two or more of the following, each present for a significant portion of time, during a 1-month period and one of them should include symptoms 1 to 3:

  1. Delusions
  2. Hallucinations
  3. Disorganized speech
  4. Grossly disorganized or catatonic behavior
  5. Negative symptoms
Criterion B Social and/or occupational dysfunction for a significant portion of the time since the onset of the disturbance.
Criterion C These disturbances must have a duration of 6 months with at least one month of active-phase symptoms from Criterion A.
Criterion D Schizoaffective and mood disorders must be reliably excluded.
Criterion E Substance abuse must be excluded.
Criterion F If there is a history of autism spectrum disorder or other communication disorder of childhood onset, the diagnosis of schizophrenia can be established only if the patient has prominent new-onset delusions or hallucinations for a one-month period.

Treatment of Schizophrenia

The nonpharmacological approach to schizophrenia focuses on psychotherapy. The following types of psychotherapy were used before in schizophrenia and they showed some success:

  • Cognitive behavioral therapy
  • Compliance therapy
  • Individual psychotherapy
  • Group therapy

The individual psychotherapy includes supportive and counseling therapy sessions, personal therapy, social skills therapy, and vocational sheltered employment rehabilitation therapy while group therapy focuses on interactive and social skills.

The goals of nonpharmacological therapies include that they are known to be at least partially effective in treating the negative and cognitive symptoms of the disorder. They help to ensure that patients remain adherent to their medication and the non-adherence report can be lowered from 74% to 37%.

Almost all patients with schizophrenia need an antipsychotic to be added to their treatment regimen in addition to non-pharmacological therapies.

The American Psychiatric Association recommends that a second-generation atypical antipsychotic therapy is the first-line treatment for schizophrenia. The Texas Medication Algorithm Project (TMAP) has provided a six-step approach for the treatment of schizophrenia which can be summarized in the following points:

 Step 1 First-line monotherapy with a second-generation atypical antipsychotic is initiated.
 Step 2 If the patient shows no or little response, another second-generation antipsychotic can be tried, or a first-generation antipsychotic might be used.
 Step 3  The patient is moved to clozapine monotherapy with white-blood-cell-count monitoring. If the patient develops agranulocytosis, clozapine must be discontinued.
 Step 4 Clozapine is combined with either a second-generation or a first-generation antipsychotic. Clozapine with electroconvulsive therapy is another viable option at this stage.
 Step 5 This is a rescue stage which means if the patient is still unresponsive you are supposed to simply try another first-generation or second-generation antipsychotic as monotherapy.
 Step 6 If all the above failed, then combination therapy with a second-generation antipsychotic, a first-generation antipsychotic, electroconvulsive therapy, and a mood stabilizer is needed.

First-generation antipsychotics are associated with a higher risk of extrapyramidal symptoms. They include:

  • Chlorpromazine
  • Haloperidol
  • Perphenazine
  • Thioridazine
  • Thiothixene

Second-generation antipsychotics are safer than first-generation antipsychotics, however, they are associated with an increased risk of weight gain. They include:

  • Aripiprazole
  • Asenapine
  • Iloperidone
  • Olanzapine
  • Risperidone
  • Clozapine

Clozapine is the only exception to the safety-rule of second-generation antipsychotics. Clozapine is associated with agranulocytosis and is only considered in later stages of treatment per the TMAP recommendations.

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