Schizophrenia

Neurodevelopmental vulnerability

Although schizophrenia rarely manifests in early childhood, childhood factors influence disease onset in adulthood. These factors include

• Genetic predisposition

• Intrauterine, birth, or postnatal complications

• Viral central nervous system infections

• Childhood trauma and neglect

Although many people with schizophrenia do not have a family history of the disorder, genetic factors are strongly implicated. People who have a first-degree relative with schizophrenia have 5- to 11-fold increased odds of developing the disorder compared with the general population (3). Monozygotic twins with schizophrenia have a concordance (the risk of the other twin having the illness) of 41 to 79% (4). Genome-wide association studies demonstrate associations in multiple excitatory and inhibitory genes expressed primarily in neurons (2).

Multiple familial, prenatal, and perinatal factors have been associated with increased risk of schizophrenia; protective factors have been noted as well (5).

Strong risk factors (odds ratio ≥ 2) include:

• Any maternal or paternal psychopathology (maternal psychosis is the strongest factor with an odds ratio > 7)

• Maternal stress

• Premature rupture of membranes

• Polyhydramnios

• Congenital malformations

Weaker but still significant risk factors (odds ratio > 1 but < 2) include:

• Maternal age < 20 or 30 to 34 years

• Paternal age < 20 or > 35 years

• Maternal multiparity (≥ 3 pregnancies)

• Maternal hypertension

• Maternal infections, including herpes simplex 2

• Suboptimal prenatal care

• Famine or malnutrition during pregnancy

• Birth in winter or early spring (in the northern hemisphere)

• Perinatal hypoxia, and other obstetric complications

• Birthweight < 3 kg, birth length < 49 cm, or small for gestational age

Protective factors (odds ratio < 1) include:

• Maternal age 20 to 24 or 25 to 29 years

• Maternal nulliparity

• Birthweight ≥ 3.5 kg

Neurobiologic and neuropsychiatric tests suggest that aberrant smooth-pursuit eye tracking, impaired cognition and attention, and deficient sensory gating occur more commonly among patients with schizophrenia than among the general population (6). These findings also can occur among first-degree relatives of people with schizophrenia, and indeed in patients with many other psychotic disorders, and may represent an inherited component of vulnerability. The commonality of these findings across psychotic disorders suggests that our conventional diagnostic categories do not reflect underlying biologic distinctions among psychoses.

Environmental stressors

Environmental stressors can trigger the emergence or recurrence of psychotic symptoms in vulnerable people. Stressors may be primarily drug-related (eg, substance use, especially cannabis) (7) or social (eg, becoming unemployed or impoverished, leaving home for college, breaking off a romantic relationship, joining the Armed Forces). There is emerging evidence that environmental events can initiate epigenetic changes that could influence gene transcription and disease onset (8).

Protective factors that may mitigate the effect of stress on symptom formation or exacerbation include strong psychosocial support, well-developed coping skills, and antipsychotic medications.

Etiology references

1. 1. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 511(7510):421-427, 2014. doi: 10.1038/nature13595

2. 2. Trubetskoy V, Pardiñas AF, Qi T, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604(7906):502-508. doi:10.1038/s41586-022-04434-5

3. 3. Huang J, Perlis RH, Lee PH, et al. Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression. Am J Psychiatry. 2010;167(10):1254-1263. doi:10.1176/appi.ajp.2010.09091335

4. 4. Stern S, Zhang L, Wang M, et al. Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission. Mol Psychiatry. 2024;29(10):3208-3222. doi:10.1038/s41380-024-02561-1

5. 5. Davies C, Segre G, Estradé A, et al. Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis. Lancet Psychiatry. 2020 May;7(5):399-410. doi: 10.1016/S2215-0366(20)30057-2

6. 6. Keshavan MS, Tandon R, Boutros NN, Nasrallah HA. Schizophrenia, "just the facts": what we know in 2008 Part 3: neurobiology. Schizophr Res. 2008;106(2-3):89-107. doi:10.1016/j.schres.2008.07.020

7. 7. D'Souza DC, DiForti M, Ganesh S, et al. Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis. World J Biol Psychiatry. 2022;23(10):719-742. doi:10.1080/15622975.2022.2038797

8. 8. Smigielski L, Jagannath V, Rössler W, et al. Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings. Mol Psychiatry. 2020;25(8):1718-1748. doi:10.1038/s41380-019-0601-3

Phases of schizophrenia

In the premorbid phase, individuals may show no symptoms or may have impaired social competence, mild cognitive disorganization or perceptual distortion, a diminished capacity to experience pleasure (anhedonia), and other general coping deficiencies. Such traits may be mild and recognized only in retrospect or may be more noticeable, with impairment of social, academic, and vocational functioning.

In the prodromal phase, subclinical symptoms may emerge; they include withdrawal or isolation, irritability, suspiciousness, unusual thoughts, perceptual distortions, and disorganization (1). Onset of overt schizophrenia (delusions and hallucinations) may be sudden (over days or weeks) or slow and insidious (over years). But, even in an advanced prodromal phase, only a fraction of those with subclinical symptoms (20 to 40%) tend to convert to full schizophrenia (2, 3).

In the early psychosis phase, symptoms are active and often at their worst.

In the middle phase, symptomatic periods may be episodic (with identifiable exacerbations and remissions) or continuous; functional deficits tend to worsen.

In the late illness phase, the illness pattern may become established but there is considerable variability; disability may stabilize, worsen, or even diminish.

Symptom categories in schizophrenia

Generally, symptoms are categorized as follows:

• Delusions

• Hallucinations

• Disorganized thoughts and speech

• Disorganized motor behavior (including catatonia)

• Negative symptoms: Diminution or loss of normal functions and affect

• Cognitive impairments: Deficits in memory, information processing, and problem solving

Delusions are erroneous beliefs that are maintained despite clear contradictory evidence. There are several types of delusions:

• Persecutory delusions: Patients believe they are being tormented, followed, tricked, or spied on.

• Delusions of reference: Patients believe that passages from books, newspapers, song lyrics, or other environmental cues are directed at them.

• Delusions of thought withdrawal or thought insertion: Patients believe that others can read their mind, that their thoughts are being transmitted to others, or that thoughts and impulses are being imposed on them by outside forces

Delusions in schizophrenia tend to be bizarre—ie, clearly implausible and not derived from ordinary life experiences (eg, believing that someone removed their internal organs without leaving a scar).

Hallucinations are sensory perceptions that are not perceived by anyone else. They may be auditory, visual, olfactory, gustatory, or tactile, but auditory hallucinations are the most common. Patients may hear voices commenting on their behavior, conversing with one another, or making critical and abusive comments. Delusions and hallucinations may be extremely vexing to patients.

Disorganized thinking involves rambling, non–goal-directed speech that shifts from one topic to another. Speech can range from mildly disorganized to incoherent and incomprehensible.

Disorganized behavior may include childlike silliness, agitation, and inappropriate appearance, hygiene, or conduct. Catatonia is an extreme example of bizarre behavior, which can include maintaining a rigid posture and resisting efforts to be moved or engaging in purposeless and unstimulated motor activity.

Negative (deficit) symptoms include

• Affective blunting: The patient’s face appears immobile, with poor eye contact and lack of expressiveness.

• Alogia (poverty of speech): The patient speaks little and gives terse replies to questions, creating the impression of inner emptiness

• Anhedonia: There is a lack of interest in activities and increased purposeless activity.

• Asociality: There is a lack of interest in relationships.

• Avolition: There is lack of motivation and a reduced desire for goal-directed activities.

Negative symptoms often lead to poor motivation and a diminished sense of purpose and goals.

Cognitive deficits include impairment in the following:

• Attention

• Processing speed

• Working and declarative memory

• Abstract thinking

• Problem solving

• Understanding of social interactions

The patient’s thinking may be inflexible, and the ability to problem solve, understand the viewpoints of other people, and learn from experience may be diminished. Severity of cognitive impairment is a major determinant of overall disability.

Subtypes of schizophrenia

Some experts classify schizophrenia into deficit and nondeficit subtypes based on the presence and severity of negative symptoms, such as blunted affect, lack of motivation, and diminished sense of purpose (4).

Patients with the deficit subtype have prominent negative symptoms unaccounted for by other factors (eg, depression, anxiety, an understimulating environment, medication adverse effects).

Those with the nondeficit subtype may have delusions, hallucinations, and thought disorders but are relatively free of negative symptoms.

The previously recognized subtypes of schizophrenia (paranoid, disorganized, catatonic, residual, undifferentiated) have not proved valid or reliable and are no longer used.

Risk of suicide

Approximately 4 to 10% of patients with schizophrenia die by suicide (5), and approximately 35% attempt it; many more have significant suicidal ideation (6). Suicide is the major cause of premature death among people with schizophrenia and explains, in part, why on average the disorder reduces lifespan by about 15 years (7).

Risk may be especially high for young men with schizophrenia and a substance use disorder. Risk is also increased in patients who have depressive symptoms or feelings of hopelessness, who are unemployed, or who have just had a psychotic episode or been discharged from the hospital.

Patients who have late onset and good premorbid functioning—the very patients with the best prognosis for recovery—are also at the greatest risk of suicide. Because these patients retain the capacity for grief and anguish, they may be more prone to act in despair based on a realistic recognition of the effects of their disorder.

Risk of violence

Schizophrenia is a surprisingly modest risk factor for violent behavior. Threats of violence and aggressive outbursts are more common than seriously dangerous behavior. Indeed, people with schizophrenia are overall less violent than people without schizophrenia.

Patients more likely to engage in significant violence include those with substance use disorders, persecutory delusions or command hallucinations, and those who do not take their prescribed medications. A very few severely depressed, isolated, paranoid patients attack or murder someone whom they perceive as the single source of their difficulties (eg, an authority, a celebrity, their spouse).

Symptoms references

1. 1. Tsuang MT, Van Os J, Tandon R, et al: Attenuated psychosis syndrome in DSM-5. Schizophr Res.150(1):31–35, 2013. doi: 10.1016/j.schres.2013.05.004

2. 2. Brucato G, Masucci MD, Arndt LY, et al. Baseline demographics, clinical features and predictors of conversion among 200 individuals in a longitudinal prospective psychosis-risk cohort. Psychol Med. 2017;47(11):1923-1935. doi:10.1017/S0033291717000319

3. 3. Raballo A, Poletti M, Preti A, et al. Clinical high risk for psychosis in children and adolescents: A meta-analysis of transition prevalences. Schizophr Res. 2022;243:254-261. doi:10.1016/j.schres.2020.03.063

4. 4. Carpenter WT Jr, Heinrichs DW, Wagman AM. Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry. 1988;145(5):578-583. doi:10.1176/ajp.145.5.578

5. 5. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. Am J Psychiatry. 2020 Sep 1;177(9):868-872. doi: 10.1176/appi.ajp.2020.177901

6. 6. Lieberman JA, First MB. Psychotic Disorders. N Engl J Med. 2018 Jul 19;379(3):270-280. doi: 10.1056/NEJMra1801490

7. 7. Hjorthøj C, Stürup AE, McGrath JJ, et al. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 2017 Apr;4(4):295-301. doi: 10.1016/S2215-0366(17)30078-0. Epub 2017 Feb 22. Erratum in: Lancet Psychiatry. 2017 Sep;4(9):e19. doi: 10.1016/S2215-0366(17)30326-7

Differential diagnosis

Psychosis due to other medical disorders or to substance use disorders must be ruled out by history and examination that includes laboratory tests and neuroimaging (Medical Assessment of the Patient With Mental Symptoms). Although some patients with schizophrenia have structural brain abnormalities present on imaging, these abnormalities are insufficiently specific to have diagnostic value.

Other mental disorders with similar symptoms include several that are related to schizophrenia, varying in their extent, time course, and associated symptoms:

• Delusional disorder

• Brief psychotic disorder

• Schizophreniform disorder

• Schizoaffective disorder

• Schizotypal personality disorder

In addition, mood disorders (ie, major depression, bipolar disorder) and autism spectrum disorders can be associated with psychosis in some people.

Neuropsychologic tests, brain imaging, electroencephalogram, and other tests of brain function (eg, eye-tracking) do not help to distinguish among major psychotic disorders. However, early research (3) suggests that results of such tests can be used to group psychosis patients into 3 distinct biotypes that do not correspond to current clinical diagnostic categories.

Certain personality disorders (especially schizotypal) cause symptoms similar to those of schizophrenia, although they are usually milder and do not involve psychosis.

Diagnosis references

1. 1. Diagnostic and Statistical Manual of Mental Disorders, 5th edition, Text Revision (DSM-5-TR). American Psychiatric Association Publishing, Washington, DC, 2022, pp pp 114-122.

2. 2. Larsen TK, Melle I, Auestad B, Haahr U, Joa I, Johannessen JO, Opjordsmoen S, Rund BR, Rossberg JI, Simonsen E, Vaglum P, Friis S, McGlashan T. Early detection of psychosis: positive effects on 5-year outcome. Psychol Med. 2011 Jul;41(7):1461-9. doi: 10.1017/S0033291710002023

3. 3. Clementz BA, Sweeney JA, Hamm JP, et al: Identification of distinct psychosis biotypes using brain-based biomarkers. Am J Psychiatry.173(4):373-384, 2016. doi: 10.1176/appi.ajp.2015.14091200

Rehabilitation and community support services

Psychosocial skill training and vocational rehabilitation programs help many patients work, shop, and care for themselves; manage a household; get along with others; and work with mental health care practitioners.

Supported employment, in which patients are placed in a competitive work setting and provided with an on-site job coach to promote adaptation to work, may be particularly valuable. In time, the job coach acts only as a backup for problem solving or for communication with employers.

Support services enable many patients with schizophrenia to reside in the community. Although most can live independently, some require supervised apartments where a staff member is present to ensure treatment adherence. Programs provide a graded level of supervision in different residential settings, ranging from 24-hour support to periodic home visits. These programs help promote patient autonomy while providing sufficient care to minimize the likelihood of relapse and need for inpatient hospitalization. Assertive community treatment programs provide services in the patient’s home or other residence and are based on high staff-to-patient ratios; treatment teams directly provide all or nearly all required treatment services.

Hospitalization or crisis care in a hospital alternative may be required during severe relapses, and involuntary hospitalization may be necessary if patients pose a danger to themselves or others. Despite the best rehabilitation and community support services, a small percentage of patients, particularly those with severe cognitive deficits and those poorly responsive to medication therapy, require long-term institutional or other supportive care (6).

Cognitive remediation therapy helps some patients. This therapy is designed to improve neurocognitive function (eg, attention, working memory, executive functioning, social cognition) and to help patients learn or relearn how to do tasks. This therapy may enable patients to function better.

Substance use is a significant problem in many people with schizophrenia. There is evidence that use of cannabis or hallucinogens is highly disruptive for patients with schizophrenia and should be strongly discouraged and treated aggressively if present. Comorbid substance use is a significant predictor of poor outcome and may lead to medication nonadherence, repeated relapse, frequent rehospitalization, declining function, and loss of social support, including homelessness (7).

Psychotherapy

The goal of psychotherapy in schizophrenia is to develop a collaborative relationship between the patients, family members, and clinician so that patients can learn to manage their illness, take medications as prescribed, and handle stress more effectively.

Although individual psychotherapy plus medication therapy is a common approach, few empirical guidelines are available. Psychotherapy that begins by addressing the patient’s basic social service needs, provides support and education regarding the nature of the illness, promotes adaptive activities, and is based on empathy and a sound dynamic understanding of schizophrenia is likely to be most effective. Many patients need empathic psychological support to adapt to what is often a lifelong illness that can substantially limit functioning.

Among the approaches to individual psychotherapy, there has been significant development of cognitive behavioral therapy for schizophrenia. This therapy, done in an individual or a group setting, can focus on ways to diminish delusional thoughts, hallucinations, and negative symptoms.

For patients who live with their families, psychoeducational family interventions can reduce the rate of relapse. Support and advocacy groups, such as the National Alliance on Mental Illness, are often helpful to families.

Disease course

For the first year after diagnosis, prognosis is closely related to adherence to prescribed psychoactive medications and avoiding illicit drug use.

During the first 5 years after onset of symptoms, functioning may deteriorate and social and work skills may decline, with progressive neglect of self-care. Negative symptoms may increase in severity, and cognitive functioning may decline. Thereafter, the level of disability tends to plateau. Severity of illness may lessen in later life, particularly among women (8). Spontaneous movement disorders may develop in patients who have severe negative symptoms and cognitive dysfunction, even when antipsychotics are not used.

Treatment references

1. 1. Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019 Oct 31;381(18):1753-1761. doi: 10.1056/NEJMra1808803

2. 2. Zipursky RB, Menezes NM, Streiner DL. Risk of symptom recurrence with medication discontinuation in first-episode psychosis: a systematic review. Schizophr Res. 2014 Feb;152(2-3):408-14. doi: 10.1016/j.schres.2013.08.001

3. 3. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. Am J Psychiatry. 2020 Sep 1;177(9):868-872. doi: 10.1176/appi.ajp.2020.177901

4. 4. Correll CU, Rubio JM, Inczedy-Farkas G, et al. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: Systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 74(7):675-684, 2017. doi: 10.1001/jamapsychiatry.2017.0624

5. 5. Wang SM, Han C, Lee SJ. Investigational dopamine antagonists for the treatment of schizophrenia. . Investigational dopamine antagonists for the treatment of schizophrenia.Expert Opin Investig Drugs 26(6):687-698, 2017.  doi: 10.1080/13543784.2017.1323870

6. 6. Uggerby P, Nielsen RE, Correll CU, et al. Characteristics and predictors of long-term institutionalization in patients with schizophrenia. Schizophr Res. 2011 Sep;131(1-3):120-6. doi: 10.1016/j.schres.2011.03.001

7. 7. Patel R, Chan KMY, Palmer EOC, et al. Associations of comorbid substance use disorders with clinical outcomes in schizophrenia using electronic health record data. Schizophr Res. 2023 Oct;260:191-197. doi: 10.1016/j.schres.2023.08.023

8. 8. Grossman LS, Harrow M, Rosen C, Faull R, Strauss GP. Sex differences in schizophrenia and other psychotic disorders: a 20-year longitudinal study of psychosis and recovery. Compr Psychiatry. 2008;49(6):523-529. doi:10.1016/j.comppsych.2008.03.004

Prognosis references

1. 1. Molstrom IM, Nordgaard J, Urfer-Parnas A, Handest R, Berge J, Henriksen MG. The prognosis of schizophrenia: A systematic review and meta-analysis with meta-regression of 20-year follow-up studies. Schizophr Res. 2022 Dec;250:152-163. doi: 10.1016/j.schres.2022.11.010

2. 2. Jääskeläinen E, Juola P, Hirvonen N, McGrath JJ, Saha S, Isohanni M, Veijola J, Miettunen J. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013 Nov;39(6):1296-306. doi: 10.1093/schbul/sbs130

3. 3. Hjorthøj C, Stürup AE, McGrath JJ, Nordentoft M. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 2017 Apr;4(4):295-301. doi: 10.1016/S2215-0366(17)30078-0. Epub 2017 Feb 22. Erratum in: Lancet Psychiatry 2017 Sep;4(9):e19. doi: 10.1016/S2215-0366(17)30326-7

4. 4. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. Am J Psychiatry. 2020;177(9):868-872. doi:10.1176/appi.ajp.2020.177901

5. 5. van Dee V, Schnack HG, Cahn W. Systematic review and meta-analysis on predictors of prognosis in patients with schizophrenia spectrum disorders: An overview of current evidence and a call for prospective research and open access to datasets. Schizophr Res. 2023;254:133-142. doi:10.1016/j.schres.2023.02.024

6. 6. Kane JM, Robinson DG, Schooler NR, et al. Comprehensive Versus Usual Community Care for First-Episode Psychosis: 2-Year Outcomes From the NIMH RAISE Early Treatment Program. Am J Psychiatry. 2016;173(4):362-372. doi:10.1176/appi.ajp.2015.15050632

7. 7. Ochoa S, Usall J, Cobo J, Labad X, Kulkarni J. Gender differences in schizophrenia and first-episode psychosis: a comprehensive literature review. Schizophr Res Treatment. 2012;2012:916198. doi:10.1155/2012/916198

8. 8. Storosum BWC, Mattila T, Wohlfarth TD, Gispen-de Wied CC, Roes KCB, den Brink WV, de Haan L, Denys DAJP, Zantvoord JB. Gender differences in the response to antipsychotic medication in patients with schizophrenia: An individual patient data meta-analysis of placebo-controlled studies. Psychiatry Res. 2023 Feb;320:114997. doi: 10.1016/j.psychres.2022.114997

9. 9. Giordano GM, Bucci P, Mucci A, Pezzella P, Galderisi S. Gender Differences in Clinical and Psychosocial Features Among Persons With Schizophrenia: A Mini Review. Front Psychiatry. 2021 Dec 22;12:789179. doi: 10.3389/fpsyt.2021.789179

10. 10. Etchecopar-Etchart D, Korchia T, Loundou A, Llorca PM, Auquier P, Lançon C, Boyer L, Fond G. Comorbid Major Depressive Disorder in Schizophrenia: A Systematic Review and Meta-Analysis. Schizophr Bull. 2021 Mar 16;47(2):298-308. doi: 10.1093/schbul/sbaa153