Schizophrenia Disorders



Title: Schizophrenia
Author: Rawan Osama Abu Nsair
Editor: Rama Qatarneh
Keywords: schizophrenia, psychosis, antipsychotics, positive symptoms



Schizophrenia is as old as the Vedas of ancient Hindus, in which the earliest known record of psychoses was recorded (ca 1400 B.C) (2). It described affected people to be nude, filthy, confused, and lacking self-control. It was thought to be brought on by devils (3).

However, the description and terminology of these cases had evolved throughout the years. The term ‘démence’ was first used by Phillippe Pinel in 1801 to describe the deterioration of mental health abilities in chronically ill, hospitalized patients (4). Later, in 1871, Hecker introduced the term ‘hebephrenia’, which is derived from ‘Hebe’; the Greek Goddess of youth. Hebephrenia was used to describe youthful insanity in a young age group with a deteriorating course (2).

A few years later, in 1893, the term ‘dementia praecox’ appeared for the first time in the fourth edition of  Kraepelin’s concepts of mental illness (5). He believed that ‘dementia praecox’ is a central nervous system disease involving very serious lesions of the cerebral cortex (5).

The term that is used nowadays, ‘schizophrenia’, was introduced by Bleuler, in 1908 (6). He defined it as a disorder in which emotionally charged ideas or drives attain a certain degree of autonomy so that the personality falls into pieces. These fragments can then exist side by side and alternately dominate the main part of the personality and the conscious part of the patient (7). However, the definition underwent many changes with time.

As our understanding of schizophrenia continues to evolve, so too does the exploration of its psychological underpinnings. Offering invaluable insights into the underlying dynamics of this disorder, psychoanalytic explorations delve deep into the complexities of the human psyche. Platforms like serve as guides, providing individuals with a framework to uncover the mysteries of their own minds. Through these explorations, individuals can gain a deeper understanding of themselves and their experiences, paving the way for a more holistic approach to mental health and well-being.

Schizophrenia is a common (8) chronic (9) mental health disorder that involves disturbances in thinking (cognition), emotional responsiveness, and behavior (10). It falls under the DSM category for Schizophrenia Spectrum and Other Psychotic Disorders Class (10). It is multifactorial as both genetic and environmental factors have a proven role in its development (8).

Schizophrenia symptoms can be categorized into three groups: positive, negative, and cognitive symptoms. Positive symptoms represent symptoms that are not normally present like hallucinations and delusions (8). Negative symptoms are characterized by loss or deficits, like social withdrawal and amotivation (8). Cognitive symptoms include deficits in working memory, executive functioning, and processing speed (8).

In contrast to what many people may think, schizophrenia doesn’t involve a split personality (11). It is better described simply as a disruption of the patient’s thoughts and affect (11).



Schizophrenia has a relatively low prevalence (12). Its pooled mean point prevalence is estimated to be 0.28% (12). A systematic review that was done in 2016 estimated that 21 million people worldwide are living with schizophrenia (12).

 No gender differences were identified in prevalence rates (12). Yet, it was noted that men generally have an earlier onset (13).

Although age-specific prevalence remains largely consistent over time and across countries, few countries like China and Netherlands showed higher prevalence estimates (12).  Moreover, prevalence rates are less in most of the developing world countries (12).


Clinical features

 Typically, schizophrenia appears in early adulthood (8). There is a prodromal phase that precedes the first psychotic episode by more than 10 years (14). This phase involves a decline in cognitive and social functioning since early adolescent life (15). Males generally experience their first psychotic episode earlier than females (10). Moreover, they usually have a more serious illness, more negative symptoms, and a poorer outcome (16).

As mentioned before, schizophrenia has positive, negative, and cognitive symptoms. Psychosis, which is a positive symptom, is an important feature in schizophrenia, although it is not unique for this disorder (17). It is manifested mainly by hallucinations and delusions. Hallucinations can be defined as sensory perceptions in the absence of external stimuli (17). They can be auditory, visual, or tactile, but the auditory type is the predominant one (18). Delusions are false beliefs that are held with certainty which cannot be corrected (19). These positive symptoms could be exacerbated by stress and decrease with age (17).

Negative symptoms include a decrease in spontaneous speech, poverty of thought, anhedonia (inability to derive pleasure from usual activities), and social withdrawal (17). Mostly, these symptoms remain stable throughout the disorder’s course (20).

Cognitive impairments affect the patient’s memory, transitive inference, and executive functioning and these are manifested mainly by disorganized speech and behavior (17).


Etiology and risk factors

Schizophrenia has a multifactorial cause (8). This includes interaction between genetic and environmental risk factors that affect early-life brain development (9).

Heritability is estimated to be around 80% (21). It is a polygenic disorder (8). Genome-Wide Association Studies (GWAS) have identified multiple gene loci that are involved in schizophrenia development (22). Moreover, some genetic variants that involve deletion or duplication of DNA sections have been identified to significantly increase the risk of the disorder, but these are only found in 2-3% of cases of schizophrenia (8). One of the most known examples is deletion at chromosome 22q11.2, which carries a 30-40% lifetime risk of schizophrenia development (23). Nonetheless, the concordance rate in monozygotic twins is only about 33%, and this suggests that the disorder’s vulnerability is not attributed only to genetic factors (24).

Various modifiable and non-modifiable environmental risk factors have been identified. Many prenatal and perinatal events increase the risk of developing schizophrenia, e.g. maternal infections, malnutrition during pregnancy, and obstetric complications like preterm birth and pre-eclampsia (25). Being born in late winter and spring is also a risk factor, and that could be due to the higher probability of being exposed to maternal respiratory infections at this time of year (9). In addition, low maternal hemoglobin increases the risk by four times (26).

Advanced paternal age when parenting (27), urban environment (28), migration (29), exposure to discrimination (30), physical and sexual abuse (28), persistent abuse of cannabis, amphetamines, and cocaine (31) are all associated with increased risk of developing schizophrenia.



Amphetamine-induced psychosis and ketamine-induced psychosis gave rise to the dopamine hypothesis and glutamate hypothesis, respectively, in the neurobiology of schizophrenia (31). Now, evidence is established on the role of the neurotransmitters: dopamine, glutamate, and gamma-aminobutyric acid (GABA) in the development of schizophrenia (32).  

The most-known theory emphasizes the role of excess presynaptic synthesis of dopamine in the striatum in the onset of the positive symptoms (33). Drugs that block dopamine receptors, especially D2 receptors have good anti-psychotic properties (34). Also, dopamine interacts with glutamate and GABA in modulating the functioning of excitatory and inhibitory interneurons in cortical circuits (35).

Hypofunction of N-methyl-D-aspartate receptors (NMDAr) (glutamate receptors located between primary and secondary glutamatergic interneurons (36)) are also strongly associated with schizophrenia symptoms (37). In addition, some reports suggest that glutamatergic hypofunction could be the cause of dopamine dysregulation in some cases (38). This hypofunction makes the GABAergic interneurons less effective, which means that there will be insufficient inhibition on the secondary glutamatergic neurons (36). As a result, these neurons will have a higher frequency in firing, and less synchronization (36). This will cause excessive firing of the dopamine neurons in the mesolimbic system (36). Also, the decreased synchronization of the neuronal activity will lead to impaired cognitive processing (39).

Moreover, glutamatergic neurotransmission has been shown to mediate the effects of acute and chronic stress (40), that epidemiological studies have reported that it has a role in the onset of psychosis (41).

Studies have also implicated neuroinflammation as an underlying mechanism in schizophrenia (42). It is noted that people exposed to childhood trauma have significantly elevated peripheral inflammatory markers in adulthood (43). Some peripheral inflammatory markers showed to increase in acute episodes and decline with effective treatment. These include interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFa), soluble interleukin-2 receptor (sIL-2R), and interleukin-1 receptor antagonist (IL-1RA) (44). Moreover, 3.6% of auto-immune diseases are reported to occur in schizophrenic people (45). It is suggested that this theory could mediate the effect of some environmental factors (46).

Neuroimaging showed that schizophrenic patients have lower grey matter volume (46). Loss happens mostly in the pre-frontal and para-hippocampal regions (35). The rate of loss is reported to be associated with elevated levels of immunologic factors like TNFa (47).

However, all of these are still possible mechanisms, and there are interrelationships between all of these pathways.


DSM-5 Diagnostic Criteria (10)

  • Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated). At least one of these must be (1), (2), or (3):
    1. Delusions
    2. Hallucinations
    3. Disorganized speech (e.g., frequent derailment or incoherence).
    4. Grossly disorganized or catatonic behavior.
    5. Negative symptoms (i.e., diminished emotional expression or avolition).
  • For a significant portion of the time since the onset of the disturbance, level of functioning in one or more major areas, such as work, interpersonal relations, or self-care, is markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, there is failure to achieve expected level of interpersonal, academic, or occupational functioning).
  • Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or by two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
  • Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out because either 1) no major depressive or manic episodes have occurred concurrently with the active-phase symptoms, or 2) if mood episodes have occurred during active-phase symptoms, they have been present for a minority of the total duration of the active and residual periods of the illness.
  • The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition.
  • If there is a history of autism spectrum disorder or a communication disorder of childhood-onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms of schizophrenia, are also present for at least 1 month (or less if successfully treated).

Specify if:

The following course specifiers are only to be used after a 1-year duration of the disorder and if they are not in contradiction to the diagnostic course criteria.

  • First episode, currently in acute episode: First manifestation of the disorder meeting the defining diagnostic symptom and time criteria. An acute episode is a period in which the symptom criteria are fulfilled.
  • First episode, currently in partial remission: Partial remission is a period of time during which an improvement after a previous episode is maintained and in which the defining criteria of the disorder are only partially fulfilled.
  • First episode, currently in full remission: Full remission is a period of time after a previous episode during which no disorder-specific symptoms are present.
  • Multiple episodes, currently in acute episode: Multiple episodes may be determined after a minimum of two episodes (i.e., after a first episode, remission, and a minimum of one relapse).
  • Multiple episodes, currently in partial remission
  • Multiple episodes, currently in full remission
  • Continuous: Symptoms fulfilling the diagnostic symptom criteria of the disorder are remaining for the majority of the illness course, with subthreshold symptom periods being very brief relative to the overall course.


Specify if:

With catatonia (refer to the criteria for catatonia associated with another mental disorder, pp. 119-120, for definition).
Coding note: Use additional code 293.89 (F06.1) catatonia associated with schizophrenia to indicate the presence of the comorbid catatonia.

Specify current severity:

Severity is rated by a quantitative assessment of the primary symptoms of psychosis, including delusions, hallucinations, disorganized speech, abnormal psychomotor behavior, and negative symptoms. Each of these symptoms may be rated for its current severity (most severe in the last 7 days) on a 5-point scale ranging from 0 (not present) to 4 (present and severe). (See Clinician-Rated Dimensions of Psychosis Symptom Severity in the chapter “Assessment Measures.”)

Note: Diagnosis of schizophrenia can be made without using this severity specifier.


Differential diagnoses

It is important to distinguish schizophrenia from other disorders with similar clinical features in order to provide appropriate treatment.

  • Some psychotic disorders such as schizophreniform disorder and brief psychotic disorder have symptoms that may overlap with schizophrenia. Yet, the duration of symptoms in schizophrenia is at least 6 months, while in schizophreniform disorder it is less than 6 months, and less than 1 month in brief psychotic disorder (10).
  • Delusional disorder is a main differential as well, but unlike schizophrenia other psychotic features are absent (48).
  • Mood disorders could also mimic symptoms of schizophrenia. However, in major depressive disorder and bipolar disorder, psychotic features occur exclusively during the major depressive or manic episode (10).
  • Other non-psychiatric conditions should be considered as well. These include medical illnesses or conditions like hepatic encephalopathy, hypoglycemia, some electrolyte abnormalities, and sepsis (48). Nevertheless, symptoms resolve by treatment of the underlying cause (48).
  • Substance abuse could also present similarly which is why the diagnosis of schizophrenia should not be made if the patient is actively using illicit drugs (48).



In general, treatment aims to relieve symptoms, prevent relapse, and increase adaptive functioning (49). But, as it is unlikely for schizophrenia patients to return to their baseline level of functioning, therapy is directed to optimize the long-term outcomes (49). There are two available types of schizophrenia treatment: pharmacotherapy and non-pharmacotherapy. Pharmacotherapy should be initiated immediately in the event of an acute psychotic episode (11). It is also vital within the first 5 years following the first episode when disease-related brain changes occur (50). Additionally, it is important to continue maintenance therapy to avoid relapse (11).

Antipsychotics are the cornerstone of schizophrenia treatment  (51). There are two types of antipsychotics: typical (first generation) antipsychotics and atypical (second generation) antipsychotics. Typical antipsychotics (e.g. haloperidol) are dopamine D2 receptors antagonists and to a lesser extent serotonin 5-HT2A receptor antagonists (49). These drugs are associated with extrapyramidal adverse effects like parkinsonism, akathisia, and tardive dyskinesia (9). Atypical antipsychotics (e.g. risperidone, olanzapine, clozapine) have an antidopaminergic effect and relatively high antiserotonergic effect (49). These drugs are preferred as first-line treatment because they have fewer extrapyramidal adverse effects (50). Still, they are associated with metabolic side effects like weight gain, diabetes mellitus type 2, hyperlipidemia, and metabolic syndrome (52). Hence, they do contribute to an increased risk of cardiovascular mortality in schizophrenic patients (53).

Clozapine has a problematic safety profile as it is known to induce agranulocytosis, orthostatic hypotension, and seizures on higher doses (49). Despite this, it remains the most effective antipsychotic in treatment-resistant schizophrenia (49). Furthermore, it has the benefit of decreasing the risk of suicide by nearly tenfold (54).

When no improvement is established, augmentation therapy can be used. Augmentation involves using another class of agents in addition to antipsychotics, such as mood stabilizers which could improve mood and behavior despite not having antipsychotic effects (49). Combination therapy, which involves adding another antipsychotic drug, may be used (49).

Non-pharmacological therapy is used as an adjunct to pharmacotherapy, not as an alternative (49). This includes individual, cognitive, and behavioral psychotherapy (49). It is reported that non-pharmacotherapy could help ensure adherence to medications (55). Stopping medications increases the risk of relapse, and thus, hospitalization (55). Additionally, this type of therapy may be directed to family members, raising their awareness about the importance of support and side effects of medications. It has been shown that this leads to a decline in rehospitalizations and improvement in social functioning (49).



The long-term outcome is heterogeneous; it ranges from complete recovery to chronic need of care (56). 75% of cases of schizophrenia have a course that is characterized by a remission phase alternating with relapses (57). However, two-thirds never recover after the first onset of psychosis (17).

In 2016, schizophrenia was ranked as the 12th most disabling disorder globally despite its relatively low prevalence (58). It accounts for a significant health care burden (8). This could be attributed to the early onset of the disease, the low remission rates, and the high disability associated with the disease (12).

Schizophrenia is linked to high rates of comorbidities (12). These patients are at increased risk of developing coronary heart disease, stroke, and diabetes mellitus type 2 (56). They also have a three- to fourfold higher prevalence of substance abuse (17).

Schizophrenia is also associated with psychosocial impairments, that make these patients more likely to be unemployed, homeless, living in poverty, and having difficulties keeping up with household and self-care tasks (12). All of this makes them more dependent on family carers and the available mental health services (12).

In general, these patients have a lifespan that is shorter than the normal population by about 15 years (59). Mostly, deaths are related to associated physical illnesses previously mentioned (56) yet suicide does play a major role as the lifetime risk of death by suicide is 5-10% (59).



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