Schizophrenia

Schizophrenia is a mental disorder characterized by the presence of positive symptoms (delusions, hallucinations), disorganization, and negative symptoms (poverty of thought, amotivation).

Epidemiology

The incidence of first episode psychosis is highest for men between the ages of 18 and 24. The incidence subsequently declines more rapidly in men but decreases more slowly in women, who experience a secondary peak at ages 50 to 54 (women are more likely to have late-onset schizophrenia than men).[1] Though conventional clinical wisdom suggests that the incidence of psychosis is the same across the world, this is not the case. The incidence of first episode psychosis can vary up to eightfold between different cities across the world.[2]

Prognosis

Suicide is a major cause of mortality in patients with schizophrenia, with some studies estimating 5–13% of patients dying by suicide.[3][4] Individuals with late-onset schizophrenia tend to have better premorbid functioning, fewer negative symptoms, and less severe neurocognitive impairments.[5]

Comorbidity

Close to 50% of individuals with psychosis experience insomnia, and this is predictive of the onset of psychotic experiences.[6]

Risk Factors

Schizophrenia is a heritable disorder. The baseline general population risk for schizophrenia is 1%. A second-degree relative is doubled to 2%. Non-twin siblings have a 9% risk.[7] If one parent has schizophrenia the risk is about 13%. If both parents have schizophrenia, the offspring has a 30 to 50% chance of developing schizophrenia.[8] In concordance studies of twins. The concordance rates of schizophrenia for monozygotic (identical) twins have been found to be about 40 to 50%.[9]

Criterion A

At least 2 of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated). At least 1 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 behaviour
  5. Negative symptoms (i.e. - diminished emotional expression or avolition)
Criterion B

For a significant portion of the time since the onset of the disturbance, level of functioning in at least 1 major area, 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).

Criterion C

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 2 or more symptoms listed in Criterion A present in an attenuated form (e.g. - odd beliefs, unusual perceptual experiences).

Criterion D

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.
Criterion E

The disturbance is not attributable to the physiological effects of a substance (e.g. - a drug of abuse, a medication) or another medical condition.

Criterion F

If there is a history of autism spectrum disorder or a communication disorder of child hood 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).

Specifiers

Episode Specifier

Specify if:

  • First episode, currently in acute episode: First manifestation of the disorder meeting the defining diagnostic symptom and time criteria. An acute episode is a time 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 deter mined after a minimum of two episodes (i.e., after a first episode, a 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 be ing very brief relative to the overall course.
  • Unspecified

Severity Specifier

Specify if:

Though not as common as early-onset schizophrenia, late-onset schizophrenia after age 60 can occur. Partition delusions, the belief that people or objects can transgress impermeable barriers and access their homes with malign intent, is more common in late-onset than in early-onset schizophrenia.[10] Hallucinations in very late-onset schizophrenia can also be more prominent and may occur in multiple modalities, including auditory, visual, and olfactory. Generally, late-onset schizophrenia responds well to antipsychotic treatment and requires only about 50% the dosage required for younger patients.

Various scales can be used to measure schizophrenia symptoms in an individual. Below are the most common ones, with an indication for each.

Psychometric Scales for Schizophrenia

Name Rater Description Download
Positive and Negative Syndrome Scale (PANSS) Clinician The patient is rated from 1 to 7 on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers. It is a 45-minute clinical interview. PANSS Download
Dopamine Hypothesis

One theory in the pathophysiology of schizophrenia is that an increase dopamine activity causes the positive symptoms of schizophrenia. This is similar to how methamphetamines and cocaine increases dopamine activity, which can also cause psychosis. Therefore, antipsychotics target the mesolimbic pathway to decrease the incidence of positive symptoms. Antipsychotics work by binding to dopaminergic neuroreceptors. It is important to keep in mind that this is a theoretical model, and that the pathophysiology of schizophrenia remains poorly understood.

What Exactly is 'Schizophrenia'?

It is important to recognize that schizophrenia itself is very likely not a single disease entity with a single cause. Rather it a heterogenous with a variety of etiologies. Each patient with a diagnosis of schizophrenia will present with a different set or cluster of symptoms. Even the DSM and ICD each have different conceptualizations of the disease. Additionally, psychosis is a syndrome and not a diagnosis. For example, in rare cases, patients initially diagnosed with schizophrenia may in fact be misdiagnosed and have anti-NMDA Receptor Encephalitis.

It is often forgotten, even among psychiatrists and other medical professionals, that there is in fact already a molecular subtype of schizophrenia that can be genetically identified. 22q11 Deletion Syndrome (also known as DiGeorge Syndrome) confers a 1 in 4 risk for an individual to develop schizophrenia, and remains under-recognized and under-diagnosed.

Toxoplasma gondii

Since the 1950s, there have been multiple studies showing higher levels of Toxoplasma gondii antibodies in schizophrenia and other severe psychiatric disorders.[11] Exposure to cats (which are commonly infected) in childhood is also a risk factor for the development of schizophrenia.

Influenza

The association between influenza infection and psychosis has been observed since the early eighteenth century.[12] Some population studies on the timing of births show that individuals born in winter/spring are at higher risk for schizophrenia compared to those born in summer/autumn, which coincides with influenza season.[13] The etiology behind influenza infections and psychosis is thought to be linked to processes such as maternal immune activation, disruption of cytokine networks, and microglial activation of pathogenic processes that lead to schizophrenia. More recent theories also focus on neuronal autoimmunity and the NMDA receptor.[14]

Visual Input

Interestingly, individuals with congenital blindness are protected against psychosis and schizophrenia. There has been no documented cases of psychosis or schizophrenia in individuals with congenital blindness (born blind).[15] The hypothesis behind this is that individuals who cannot see at birth rely on the context extracted from other senses. This results in a model of the world that is less susceptible to false inferences (i.e. - delusions, hallucinations).[16][17]

Degenerative Disease Model

Traditionally, schizophrenia has been seen as a mental disorder with progressive deterioration.[18] Indeed, the diagnostic term dementia praecox proposed by Emil Kraepelin came under the assumption that schizophrenia was a form of juvenile dementia caused by a degenerative process. Indeed, one of the driving factors behind early intervention in psychosis clinics is meant to reduce the duration of untreated psychosis (and hence degree of neurodegeneration). However, one recent paper suggests that lead-time biases in research methodology confounds the association between untreated psychosis and illness course.[19] A more recent meta-analysis also showed there is minimal evidence that untreated psychosis damages brain structures.[20] However, increasing research suggests that schizophrenia is in fact not progressive and that neuropsychological function can remain stable over time.[21][22][23] It is important to recognize that individuals with schizophrenia can achieve a stable remission of symptoms and also achieve satisfaction and happiness.[24]

Future Research

There is some research suggests that synaptic pruning (i.e. - global neuronal dysfunction is responsible for the development of schizophrenia.[25] Sensory prediction deficits is also another theory of why psychotic symptoms develop, and why individuals with schizotypal personalities are more likely to be able to tickle themselves, compared to the general population.[26] Other theories include the HPA axis and endocrine disruption.[27]

The term psychosis has been defined in various ways in the medical literature over time. The narrowest and current definition of psychosis is hallucinations and delusions, with the lack of reality testing or insight. A broader definition of psychosis would also include disorganized thought, emotions, and behaviour. This loose definition was more common in the past, and schizophrenia was often overdiagnosed as a result.

Comparison of Psychotic Disorders

Type Onset Length Psychotic Symptoms Mood Symptoms Functional Decline?
Brief psychotic disorder Sudden 1 day to 1 month At least 1 of:
• Delusions
• Hallucinations
• Disorganized speech
• Grossly disorganized or catatonic behaviour
No Full resolution of symptoms
Schizophreniform disorder Can be prodromal 1 month to 6 months At least 2 of:
• Delusions
• Hallucinations
• Disorganized speech
• Grossly disorganized or catatonic behaviour
• Negative symptoms
No Not required
Schizophrenia Can be prodromal > 6 months At least 2 of:
• Delusions
• Hallucinations
• Disorganized speech
• Grossly disorganized or catatonic behaviour
• Negative symptoms
No Required
Schizoaffective disorder Can be prodromal Major mood episode
+ 2 weeks of isolated psychotic symptoms + predominantly mood symptoms over course of illness
• Delusions or hallucinations for 2 or more weeks, which must be in absence of a major mood episode (depressive or manic) during the lifetime duration of the illness Required Not required
Delusional disorder Can be prodromal > 1 month • One or more delusions, with no other psychotic symptoms. No Normal function aside from impact of delusions

Antipsychotics are considered the gold-standard of treatment. It is increasingly important to realize that schizophrenia is not a homogenous disorder, and that individuals can be subtyped based on their response to antipsychotics. In particular, there are (1) patients who are responsive to antipsychotics, (2) those that fail first-line antipsychotics are require clozapine, and (3) those who are clozapine-resistant.[28] However, before labelling patients as treatment resistant, it is important to recognize that many patients may be on sub-therapeutic levels of antipsychotics.[29] Benzodiazepines can be prescribed for short-term management of acute agitation, but should not be used as long-term pharmacotherapy as it increases all-cause mortality.[30][31] Comprehensive care for first episode psychosis can improve functional and clinical outcomes. Effects are more pronounced for those with shorter duration of untreated psychosis.[32]

In Canada, aripiprazole and lurasidone are the only antipsychotics indicated for children and adolescents with schizophrenia or bipolar disorder.
Length of Antipsychotic Treatment

How long should patients remain on antipsychotics for schizophrenia? The general consensus is that patients with chronic schizophrenia should remain on therapy long-term. However, there is some new evidence for first-episode psychosis patients that “less is more.”[33][34][35] This study observed that compared with a standard maintenance treatment regimen, dose reduction or supervised discontinuation of antipsychotic medication during the early phases of FEP led to a higher relapse rate initially, but improved long-term outcomes. This study has been criticized for its unequal distribution across diagnostic groups, high attrition rate, failure to separate the dose reduction and discontinuation groups, and the fact that most patients in each arm of the study did receive medication. Other studies have suggested that up to 40% of first episode psychosis patients are able to achieve good outcomes with either low or no doses of antipsychotics.[36] Yet other retrospective studies have shown that more breaks in antipsychotic treatments may result in greater risk of relapse and longer time to remission.[37]

Practically speaking, however, clinicians and researchers are still unable to discern which populations will do well with an antipsychotic taper, and those who would worsen symptomatically. More studies are needed to investigate these very important clinical questions.[38][39] Other more recent studies have shown that the risk of relapse after antipsychotic discontinuation does not decrease over time, and that antipsychotic use is associated with increased survival.[40] Long-term antipsychotic use for treating first-episode schizophrenia for the majority of patients remains a the most evidence-based practice, as the relapse rates are greater than 80% with medication-discontinuation after several years. Relapse involves hospitalization, psychosis, and significant psychosocial impact, and this needs to be weighed carefully against discontinuation of medication.

Various psychotherapies have been shown to be effective in schizophrenia:[41]

  • Cognitive behavioural therapy for psychosis should be offered to all patients who have not adequately responded to antipsychotic or have residual symptoms. CBT is effective for reducing symptoms, hospitalization, and risk of relapse
  • Family intervention has strong evidence for decreased symptoms, reduced likelihood of hospitalization. and some evidence on improved functioning
  • Cognitive remediation may improve cognitive domains, and could translate to improved social and functional outcome
  • Supported employment if interested
  • Prevocational training can be provided if patients cannot find employment, and there is some evidence of financial benefit, benefits for symptoms and well-being

Schizophrenia Guidelines

Guideline Location Year PDF Website
Canadian Schizophrenia Guidelines Canada 2017 - Link
National Institute for Health and Care Excellence (NICE) UK 2014 - Link
American Psychiatric Association (APA) USA 2021 - Link
Royal Australian and New Zealand College of Psychiatrists (RANZCP) AUS, NZ 2016 - Link