Schizophrenia: Causes, Diagnosis, Treatment by NJE


Schizophrenia is a disorder that causes significant distortions in thinking, perception, speech, and behavior. Characteristics include psychosis, apathy, social withdrawal, and cognitive impairment, which result in significant social impairment.


INCIDENCE: 0.2 per 1000.

PREVALENCE: 0.5%; lifetime prevalence risk, 0.4%.

PREDOMINANT SEX: Males have a more severe illness with earlier onset. Prevalence in males is approximately 1.4 times higher.


• Age of onset of psychotic symptoms is the early 20s for males and the late 20s for females.

• Age of onset of negative symptoms is usually earlier (i.e., the mid-teenage years).

PEAK INCIDENCE: Between ages of 16 and 30 yr.


• Genetics accounts for 70% of risk; the remaining 30% is associated with other factors such as urban environments, migration, or cannabis use.

• First-degree relatives have a 10 times great￾er chance of becoming schizophrenic.

• Discordant rates among identical twins are higher than expected with the simple inheritance pattern.

• Associations with several chromosomes have been described, but none has been replicated.

• Evidence exists that triple nucleotide repeat expansion (e.g., such as that seen with Huntington’s disease) may play a role in the inheritance of the disease.



• Schizophrenia is best defined as a dementing illness that begins early in life and progresses slowly throughout the lifetime.

• Frequent structural brain imaging findings include the enlargement of the ventricular system, a loss of brain volume and cortical gray matter, and an alteration of the white matter tracts.

• The initial “negative” symptoms of adolescence (prodromal phase)—cognitive decline, social withdrawal and awkwardness, loss of motivation and pleasure, and loss of emotional expressiveness—begin after a period of normal development.

• During early adulthood, positive symptoms of psychosis and thought disturbance occur; psychotic symptoms then wax and wane throughout life. Treatment ameliorates positive symptoms but generally does little for negative ones.

• The condition is also accompanied by cognitive impairment, including problems with attention and concentration, psychomotor speed, learning, memory, and executive functions (e.g., abstract thinking, problem-solving, planning).

• Social and occupational dysfunction can be profound. 

Causes of Schizophrenia

• The basic determination of whether this is a degenerative or developmental condition has not been made.

• The major hypothesis is that abnormality of the mesocortical pathways produces hypofrontality and the negative symptoms. This occurs along with a compensatory hyperactivation of the mesolimbic pathways, which produces the positive symptoms of psychosis. 



• Schizophrenia is diagnosed when an individual has experienced at least 6 mo (1 mo if using ICD-10 criteria) of hallucinations, delusions, thought disorders, catatonia, or negative symptoms (e.g., avolition, anhedonia, social isolation, affective flattening).

• Any medical condition, medicine, or substance that can affect brain homeostasis can cause psychosis; this is distinguished from schizophrenia by a relatively brief course and an alteration in mental status that suggests an underlying delirium.

• Other neurologic conditions that have psychosis as the initial presentation (e.g., Huntington’s disease) need to be ruled out.

• Mood disorders with psychosis: these are indistinguishable from schizophrenia cross-sectionally but have a longitudinal course that includes full recovery.

• Delusional disorder involves nonbizarre delusions and lacks the thought disturbance, hallucinations, and negative symptoms of schizophrenia.

• Autism in the adult has an early age of onset and lacks significant hallucinations or delusions.


• History and physical examination to help determine whether the psychosis is primary or secondary.

• Neurologic examination to uncover the soft neurologic signs (e.g., clumsiness, cortical thumb, loss of fine motor movements) that are common with schizophrenia. 


• No laboratory tests are specific.

• Laboratory examinations (e.g., chemistry profile, blood count, sedimentation rate, toxicology screen, and urinalysis) are geared toward excluding a primary medical condition or toxic state. Note that new common drugs of abuse may not be detectable with regular screening tests.


• CT or MRI of the brain during the initial workup; repeated if the course of the illness varies from what is expected.

• ECG may reveal slowing when psychosis is the result of an encephalopathy. Findings can be similar as a result of common medication use for the treatment of psychosis.



• Significant social support is required by most schizophrenic patients, but available support services are grossly inadequate. Schizophrenic patients constitute nearly one-third of all homeless individuals and approximately 5% of the incarcerated population. They usually require help with basic social, occupational, and interaction skills.

• Family stress can precipitate relapse and re-hospitalization. Family interventions can reduce morbidity.

• Cognitive behavioral therapy can reduce the severity of both psychotic and negative symptoms.

• Illness management training for patients can increase medication adherence and reduce symptom distress.

• Integrated treatment that includes assertive community treatment, family involvement programs, and social skills training reduces the severity of both psychotic and negative symptoms, reduces comorbid substance misuse reduces hospital days, increases adherence to treatment, and increases satisfaction with treatment. 


• Acute psychosis is usually adequately controlled with antipsychotic agents.

• Few differences in effectiveness exist between first-generation antipsychotics (e.g., haloperidol, perphenazine, fluphenazine, chlorpromazine) and second-generation antipsychotics (e.g., risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, clozapine, lurasidone) for non-refractory patients. First-generation antipsychotics are slightly more likely than second-generation antipsychotics to cause a parkinsonian state and eventual tardive dyskinesia (rate of tardive dyskinesia, 15%-30%). Antiparkinsonian drugs (e.g., benztropine, amantadine) are used to ameliorate parkinsonism. Risperidone has been shown to be superior to haloperidol for the prevention of acute psychotic relapse.

• Sedatives (i.e., benzodiazepines and, to a lesser degree, barbiturates) can be used transiently if a patient is in an agitated state.


• Relapse prevention is a major goal of treatment. Noncompliance is common and leads to high relapse rates. Antipsychotic agents usually must be continued at the same doses that controlled psychosis. For non-compliant patients, long-acting injectable preparations given biweekly, monthly, or every three months can be used.

• Most patients frequently switch among antipsychotics; there is considerable individual variability with regard to antipsychotic response and vulnerability to specific adverse effects.

• Clozapine is more effective than other agents for treatment-refractory patients. However, it requires monitoring to prevent life-threatening adverse effects. Olanzapine may also be more effective than less expensive first-generation drugs but has substantial adverse metabolic effects. Lurasidone is a newer second-generation antipsychotic that appears to be better tolerated, but longer-term studies are needed.

• Neurocognitive improvement associated with antipsychotic treatment among patients with schizophrenia is small and does not differ between first-generation and second-generation antipsychotics.

• Antiparkinsonian agents may also need to be continued for the long term.

• Tardive dyskinesia (i.e., choreoathetoid movements of the muscles of tongue and face and occasionally of other muscle groups) can occur in as many as 30% of patients with the long-term use of neuroleptics.

• The negative symptoms of schizophrenia can resemble depression. In addition, depressive disorders may occur in schizophrenic patients. Antidepressant treatment of the negative symptoms is usually not effective. However, antidepressants can improve the symptoms of a comorbid depressive episode.

• Mood stabilizers (e.g., lithium, valproate, carbamazepine) are of little use unless the patient has a comorbid impulse control disorder.

• Substance abuse is a major problem for more than a third of schizophrenic patients. More than half of these patients smoke cigarettes. Unfortunately, these individuals do poorly in traditional substance abuse treatment programs. Specialized “dual-diagnosis” programs with highly structured aftercare are required.

• Specific antipsychotic medications have been associated with weight gain (i.e., olanzapine and clozapine) and QT prolongation. Hyperlipidemia and diabetes mellitus are associated with second-generation antipsychotics, and hyperprolactinemia is associated with first-generation antipsychotics. (Risperidone, a second-generation antipsychotic, can also produce hyperprolactinemia.) Clozapine is associated with agranulocytosis and a decrease in intestinal motility. Metabolic status and weight should be screened before the start of treatment and at regular intervals.

• Patients with schizophrenia have a higher lifetime incidence of suicide, with 20% attempting on one or more occasions and 5% to 6% completing suicide. Comorbid use of substances and hopelessness are associated risk factors. Clozapine has shown the ability to decrease the incidence of suicidal attempts in schizophrenia patients.

• Several 1st and 2nd generation antipsychotics are available in long-acting injectable preparations that may be helpful in addressing issues of poor compliance or difficulty when treatment needs to be supervised.


• The positive symptoms of as many as 20% to 30% of schizophrenic patients do not respond to available treatments. A much higher fraction of patients experience relapse as a result of poor compliance.

• Negative symptoms are responsible for the 50% to 70% of patients in whom deterioration in occupational and social function continues.

• Approximately 10% of schizophrenic patients will complete suicide.

• The course of the illness is most strongly predicted by the level of social development attained at the onset of psychosis.

• Schizophrenic patients die 12 to 15 years sooner than the average population, mostly as a result of physical causes related to a lack of access to health care or as a result of health risk factors (e.g., smoking, obesity).


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