Schizophrenia

Primer

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

Epidemiology
  • The prevalence is the same between men and women, but differs in the course and onset of illness.
  • The incidence of first episode psychosis is highest for men between the ages of 18 and 24, and the incidence subsequently declines rapidly
  • In women, there is a bimodal distribution, and they experience a secondary peak at ages 50 to 54 (women are more likely to have late-onset schizophrenia than men).[1]
    • Generally speaking, women tend to have more positive symptoms and less negative symptoms, in particular with late-onset schizophrenia.[2][3]
  • Though conventional clinical wisdom suggests that the incidence of psychosis is the same across the world, this is not actually the case. The incidence of psychosis can vary up to eightfold between different cities across the world.[4]
Prognosis
  • Suicide is a major cause of mortality in patients with schizophrenia, with some studies estimating between 5 to 13% of patients dying by suicide.[5][6][7]
    • Individuals at higher risk for suicide include being male, high socioeconomic background, high intelligence, high expectations, being single, lack of social supports, having awareness of symptoms, and recent discharge from the hospital.[8]
  • Over the course of the illness, symptoms of psychosis can wax and wane.[9]
  • Cognitive deficits (attention, processing speed, executive function) in schizophrenia are similar to that of bipolar disorder, but more severe.[10][11]
  • Good prognostic factors include: late or acute onset (versus insidious), obvious precipitating factors (e.g. - substance use), good pre-morbid social functioning, a family history of mood disorders, married, good support systems, and positive symptoms (i.e. - predominantly delusions/hallucinations).[12]
    • Treatment with antipsychotic medications can significantly decrease the risk for violence and crime in schizophrenia.[13]
  • Poor prognostic factors include: young or insidious age of onset, lack of obvious precipitating factors, poor pre-morbid social functioning, withdrawn behaviors, isolation, family history, negative symptoms, neurological signs and symptoms, history of perinatal trauma, lack of remission, recurrent relapses, and history of violence/assault.[14]
  • Despite new treatment options proposed for schizophrenia, only about 13% of individuals with schizophrenia meet the criteria for recovery.[15]
  • Individuals with schizophrenia in developing countries may have paradoxically better outcomes than individuals in developed countries.[16][17]
Comorbidity
  • Close to 50% of individuals with psychosis experience insomnia, and this is predictive of the onset of psychotic experiences.[18]
  • Individuals with schizophrenia are at higher risk for developing medical illnesses including type II diabetes (secondary to antipsychotic medication use), and HIV.[19]
Risk Factors
  • Schizophrenia is a highly heritable disorder, accounting for about 80% of the liability of the illness
  • The baseline general population risk for schizophrenia is 1%. A second-degree relative doubles the risk to 2%. Non-twin siblings have a 9% risk.[20] 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.[21] In concordance studies of twins. The concordance rates of schizophrenia for monozygotic (identical) twins have been found to be about 40 to 50%.[22]
  • Advanced paternal age is a risk factor for schizophrenia in the offspring[23][24]

Relative Risk Factors in Schizophrenia

Adapted from: Tandon, R. et al. Schizophrenia, 'Just the facts' What we know in 2008. 2. Epidemiology and etiology. Schizophr Res. 2008 Jul;102(1-3):1-18
Risk Factor (affected) Average Relative Risk (%)
Monozygotic twin 50-70%
Both parents 40-60%
Dizygotic twin or 1st degree relative 9-18%
2nd degree relative (e.g. - grandparent) 3-6%
3rd degree relative (e.g. - 1st cousin) 2-3%
Urbanicity 2-3%
Migration 2-3%
1st or 2nd trimester maternal infection 2-3%
Winter birth 1.1%
Obstetric and Perinatal Complications 2-3%
Paternal Age >35 1.5-3%
Male Gender 1.4%

DSM-5 Diagnostic Criteria

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 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).

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

Catatonia Specifier

Specify if:

Severity Specifier

Specify current severity:

  • Severity is rated by a quantitative assessment of the primary symptoms of psychosis, including delusions, hallucinations, disorganized speech, abnormal psychomotor behaviour, 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 the DSM-5's Clinician-Rated Dimensions of Psychosis Symptom Severity in the chapter “Assessment Measures.”

Older Adults and Late Onset (Paraphrenia)

  • The term paraphrenia was previously used to describe psychotic syndromes in the elderly.
    • Currently the terms late-onset schizophrenia or late-life psychosis are used, which includes symptoms of delusions and hallucinations arising in late life.
  • Though not as common as early-onset schizophrenia, late-onset schizophrenia after age 60 can occur.
    • Individuals with late-onset schizophrenia tend to have better premorbid functioning, fewer negative symptoms, and less severe neurocognitive impairments.[25]
  • 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.[26]
  • 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.
  • However, it is important to recognize that this group is at higher risk for subsequent development of dementia, as psychosis may present as prodromal symptoms.[27]

Screening and Rating Scales

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. Link
Brief Psychiatric Rating Scale (BPRS) Clinician The BPRS is has 24 symptom constructs, each rated on a 7-point scale of severity ranging from “not present” to “extremely severe.” Download
Calgary Depression Scale for Schizophrenia (CDSS) Clinician The CDSS is a 9 item scale that measures the level of depression in individuals with schizophrenia. Link

Pathophysiology

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 not a single disease entity with a single cause. Rather it a heterogenous condition with a variety of causes (most of which are unknown or still being researched). Each patient with a diagnosis of schizophrenia will present with a different set or cluster of symptoms. Even the DSM-5 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. Medications and substance use may also cause psychosis.

Neuroimaging Findings

  • Many neuroimaging findings have been replicated in schizophrenia, including:
    • Ventricular enlargement (3rd and lateral ventricles)[28]
    • Reduced hippocampus,[29] parahippocampal gyrus,[30] and amygdala volume[31]
    • Reduced grey matter volume[32]
    • Neuronal loss in the medial thalamus[33]
    • Functional neuroimaging shows hypoactivity of dorsolateral prefrontal cortex (DLPFC).[34]

22q Deletion

  • 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.[35] 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.[36]
  • 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.[37]
  • 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.[38]

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).[39]
  • 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).[40][41]

Degenerative Disease Model

  • Traditionally, schizophrenia has been seen as a mental disorder with progressive deterioration.[42]
  • 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.
  • One of the driving factors behind early intervention in psychosis programs 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 may confound the association between untreated psychosis and illness course.[43] A more recent meta-analysis also showed there is minimal evidence that untreated psychosis damages brain structures.[44]
  • Increasing research suggests that schizophrenia is in fact not progressive and that neuropsychological function can remain stable over time.[45][46][47]
  • It is important to recognize that individuals with schizophrenia can achieve a stable remission of symptoms and also achieve satisfaction and happiness.[48]
Future Research
  • There is some research suggests that synaptic pruning (i.e. - global neuronal dysfunction is responsible for the development of schizophrenia).[49]
  • 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.[50]
  • Other theories include the HPA axis and endocrine disruption.[51]

Differential Diagnosis

A wide variety of mental disorders and medical conditions can manifest with psychotic symptoms, and must be considered in the differential diagnosis of a schizophreniform disorder or schizophrenia diagnosis, or any diagnosis of a primary psychotic disorder.[52]

  • Delirium
    • Delirium (“the great imitator”), can often present with psychotic symptoms even in the absence of inattention or clear LOC change. If delirium is suspected, then a thorough work up should be considered in a systematic way.
  • Major neurocognitive disorder (dementia)
  • Substance/medication-induced psychotic disorder
    • Individuals with substance/medication-induced psychotic disorder may have symptoms characteristic of Criterion A for schizophrenia. However, the substance/medication-induced psychotic disorder can usually be distinguished by the temporal relationship between the substance use and onset or remission of the psychosis in the absence of substance use.
  • Psychotic disorder due to another medical condition or its treatment
    • Autoimmune Encephalitis
      • Autoimmune psychosis is increasingly recognized as an important differential diagnosis in first-episode psychosis. Subtle neurological signs, along with focal neurological findings may be suggestive of an autoimmune disorder causing the psychotic symptoms. Extensive neurological investigations including neuroimaging, EEG, CSF, and/or serum investigations are an important part of the diagnostic work up.
    • Neurosyphilis
    • Systemic Lupus Erythematosus (SLE)
    • Temporal lobe epilepsy
    • Hashimoto's Encephalitis (Steroid Responsive Encephalopathy Associated with Autoimmune Thyroiditis [SREAT])
    • Wilson's Disease
      • Psychiatric symptoms due to Wilson's disease are present in about 15% of patients, and symptoms usually begin between the ages of 5 and 35 years (average age of 17).
    • Porphyria
      • The porphyrias are a group of inherited disorders characterized by an enzyme deficiency in the heme biosynthetic pathway. Porphyrias can present with neuropsychiatric symptoms, and can be misdiagnosed as a primary psychiatric disorder. Specialized blood work (e.g., porphobilinogen) is required for diagnostic clarification)
    • In-born errors of metabolism
  • Major depressive disorder or bipolar disorder with psychotic features
    • Distinguishing between schizophrenia and major depressive or bipolar disorder with psychotic features or with catatonia depends on the temporal relationship between the mood disturbance and psychotic symptoms. The severity of the depressive or manic symptoms should also be taken into account, relative to the psychotic symptoms. If delusions or hallucinations occur exclusively during a depressive or manic episode, the diagnosis would be depressive or bipolar disorder with psychotic features.
  • Schizoaffective disorder
    • Schizoaffective disorder requires a major depressive or manic episode occur concurrently with the active-phase symptoms and the mood symptoms are present for the majority of the total duration of the illness.
  • Schizophreniform disorder and brief psychotic disorder.
    • These disorders are of shorter duration than schizophrenia (Criterion C). In schizophreniform disorder, the duration is less than 6 months, and in brief psychotic disorder, symptoms are present between 1 day to 1 month.
  • Major depressive or bipolar disorder with catatonic features
    • Catatonia can present with psychotic-like features, and a thorough history along with physical examination for catatonia is important.
  • Delusional disorder
    • Delusional disorder lacks the symptoms characteristic of schizophrenia (e.g., prominent auditory or visual hallucinations, disorganized speech, grossly disorganized or catatonic behaviour, and negative symptoms).
  • Personality disorders
  • Neurodevelopmental disorders
  • Obsessive-compulsive disorder and body dysmorphia
    • Individuals OCD and body dysmorphic disorder may have with poor or even absent insight, and the preoccupations can even reach delusional intensity. However, these disorders are different from schizophrenia by the presence of prominent obsessions, compulsions, and/or preoccupations with body appearance or body odours, hoarding, or body-focused repetitive behaviors.
  • Posttraumatic stress disorder
    • PTSD may include flashbacks that have a hallucination-like quality. Hypervigilance from previous trauma may also reach paranoid proportions. However, a traumatic event and symptoms relating to reliving or reacting to the event are required to make the diagnosis of PTSD.
  • Traumatic brain injury
    • Individuals with TBIs may experience psychotic symptoms in the context of an underlying brain injury, and psychotic syndromes do occur more frequently in individuals with TBI compared to the general population.

Comparison of Psychotic Disorders

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.

DSM-IV to DSM 5 Psychotic Disorder Criteria Changes

Substance Abuse and Mental Health Services Administration. Table 3.20, DSM-IV to DSM-5 Psychotic Disorders

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

Investigations

Bloodwork

  • Routine bloodwork may include some or all of the following depending on the patient's clinical presentation to rule out other etiologies that could be contributing to a psychotic syndrome:[53]

Inflammatory Markers

Imaging

  • Depending on the specifics of the history, neurological exam, or neuropsychological testing results, neuroimaging may be warranted.
    • For example, imaging would be warranted if there are signs and symptoms of intracranial pathology such as headaches, nausea, vomiting, seizure-like activity, and/or a late age of onset of psychotic symptoms.[54]
    • A rapid progression of cognitive and memory deficits in conjunction with psychotic symptoms would also be an indication for neuroimaging.
    • Some patients may have clinical features that are suggestive of an autoimmune encephalitis, in which case magnetic resonance imaging (MRI), and a comprehensive neurologic evaluation would be warranted.
  • Multiple systematic studies now advise against routine neuroimaging in first-episode psychosis due to risks of radiation exposure (from computed tomography).[55]
  • If there is a clear gynecological history (e.g., concerning for an ovarian mass), an abdominal ultrasound may be warranted.

Genetic Testing

  • A clinical microarray (CMA) is clinically recommended and a first-line test for any individual with intellectual disability, developmental delay and/or multiple congenital anomalies.[56] For example, adults with 22q11 deletion have a 25% chance of developing schizophrenia.

Cognitive Testing

  • Neuropsychological testing is recommended in patients with first episode psychosis or poor treatment response.[57]
    • For example, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery can be used.[58]

Treatment

  • Regardless of the type of treatment employed for schizophrenia, clinicians should always involve the patient with shared decision making.[59] This means building consensus with the patient about preferred treatments, and having an integrative approach. A good therapeutic alliance can help patients go a long way![60]

First Episode Psychosis (FEP) Programs

  • Many developed countries now have first episode psychosis or early intervention in psychosis (EIP) programs for youth and young adults with a first episode of psychosis.
  • These programs have a comprehensive approach to treatment, and medication is only one part of the treatment.
  • Comprehensive care for first episode psychosis can improve functional and clinical outcomes, and the effects are more pronounced for those with shorter duration of untreated psychosis.[61]
  • The positive and negative symptoms of schizophrenia should be reassessed at least every three months in individual who is stable.[62]

Pharmacotherapy

In Canada, aripiprazole and lurasidone are the only antipsychotics indicated for children and adolescents with schizophrenia or bipolar disorder.
  • Antipsychotics are considered the gold-standard of medication treatment.
  • In first episode psychosis or schizophrenia, there is no difference in efficacy between typical (first generation) and atypical second generation antipsychotics.[63]
    • Clozapine is the only exception to this, for treatment-resistant schizophrenia.[64]
  • 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.[65]
    • However, before labelling patients as treatment resistant, it is important to recognize that many patients may be on sub-therapeutic levels of antipsychotics or may have poor adherence to medications.[66]

Acute Pharmacotherapy

  • When starting an antipsychotic medication for a first episode of psychosis, the antipsychotic should be continued for at least 2 weeks unless there are significant tolerability issues.[67]
    • If after 4 weeks of optimizing the dose, there is absolutely no response to this initial antipsychotic, a change in antipsychotic should be considered.[68]
    • If there is partial response at 4 weeks, then the original antipsychotic should be optimized or continued for another 4 weeks (i.e. - total 8 weeks before declaring a failed trial of the medication) before making any medication switches.[69]
    • Remember that starting and staying with the lowest possible therapeutic dose is important to minimize the risk for side effects and adverse reactions. There is no evidence that higher doses improve outcomes.[70]
    • It has been recommended that long-acting injectable antipsychotics be offered to patients as a treatment choice, even in a first-episode of psychosis.[71][72]
  • 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.[73][74]

Maintenance Pharmacotherapy

  • After the resolution of the positive symptoms (i.e. - hallucinations, delusions) of a first episode of psychosis, it is recommended that individuals remain on an antipsychotic for at least another 18 months.[75]
    • Between 1 to 20% of individuals will only have a single episode of psychosis, and thus the length of treatment on antipsychotics is an important clinical discussion between the patient and clinician.[76]
  • For individuals with a diagnosis of schizophrenia who have an acute episode (not first episode psychosis), following resolution of psychosis, individuals should remain on maintenance antipsychotics for another 2 to 5 years.[77]
    • On the other hand, it is also important to recognize that relapse rates are very high, and up to 80% of individuals will relapse within 5 years.[78]

Length of Medication 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.”[79][80][81]
  • A recent 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 still did receive medication.[82]
    • 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.[83]
  • Yet other retrospective studies have shown that more breaks in antipsychotic treatments may result in greater risk of relapse and longer time to remission.[84]
  • 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.
    • The 2023 RADAR Trial found that slow, supported dose reduction of antipsychotics was associated with a higher risk for relapse and did not result in improved social outcomes.[85]
    • Further meta-analyses have suggested a higher risk for relapse with antipsychotic discontinuation.[86]
    • More studies are needed to investigate these very important clinical questions.[87][88] 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.[89]
  • Relapse involves hospitalization, recurrent psychosis, and significant psychosocial impact, and this needs to be weighed carefully against discontinuation of medication.
    • Thus, long-term antipsychotic use for treating first-episode schizophrenia for the majority of patients remains the most evidence-based practice, as the relapse rates are greater than 80% with medication-discontinuation after several years.

Medication Monitoring

  • It is important to note that there is no evidence for antipsychotic polypharmacy in schizophrenia (i.e. - using more than one antipsychotic)
    • Yet, sadly, it has been estimated that the average prevalence of antipsychotic polypharmacy is 20%, and more than 80% of these individuals were able to be successfully discontinued off their second antipsychotic.[90]
  • Individuals with schizophrenia die up to 20 years earlier than individuals without schizophrenia, and there are multiple reasons, including lifestyle risk factors, metabolic side effects from antipsychotics, and decreased access to care.
    • Cardiovascular disease represent the major cause for excess mortality.

All patients who are on long-term antipsychotics must be medically monitored routinely.

Antipsychotic Monitoring

Adapted from: Pringsheim, T. et al. (2017) Physical health and drug safety in individuals with schizophrenia. The Canadian Journal of Psychiatry, 62(9), 673-683.
Initiation 1 month after initiation 3 months after initiation Then annually
Electrolytes, Cr, LFTs, TSH ✓ As clinically indicated As clinically indicated As clinically indicated
Fasting plasma glucose ✓ As clinically indicated ✓ ✓
HbA1c ✓ - ✓ ✓
Lipid panel (total cholesterol, LDL, HDL, triglycerides) ✓ As clinically indicated ✓ ✓
Body mass (BMI) ✓ ✓ ✓ ✓
Blood pressure (BP) ✓ As clinically indicated ✓ ✓
Extrapyramidal symptom (EPS) exam ✓ ✓ ✓ ✓
Endocrine function history (gynecomastia, galactorrhea, libido) ✓ - ✓ ✓
Prolactin If clinically indicated If clinically indicated If clinically indicated If clinically indicated
ECG (QT monitoring) If clinically indicated (some clinicians will order this routinely as a baseline) - If on multiple QTc-prolonging medications
(or if clinically indicated) 		As clinically indicated, or yearly
Smoking history ✓ - ✓ ✓

Treatment-Resistant Schizophrenia

  • Between 25 to 30% of individuals with schizophrenia meet criteria for treatment resistant schizophrenia (TRS).[91]
    • The official criteria is defined as persistence of 2 or more positive symptoms with at least moderate severity, or a single positive symptom with severe severity, that still remain after 2 or more adequate trials of different (non-clozapine) antipsychotics.
    • For oral antipsychotics, this means you must be certain the patient has had reasonable adherence to the other antipsychotic for at least 6 weeks at the midpoint of the therapeutic dose range.[92]
    • For long-acting injectables (LAI), this means at least 6 weeks of treatment after reaching steady state (this would mean for medications such as aripiprazole LAI, the first 2 weeks do not count!).[93]
  • Clozapine should thus be considered in patients with schizophrenia who have not responded to 2 antipsychotics of an adequate trial.
    • An adequate trial of clozapine is considered as 8 to 12 weeks at ≥400mg per day.[94]
    • For these individuals, clozapine has been shown to be the most effective and only recommended medication treatment, with response rates between 30 to 60%.[95]
    • If after an adequate trial of clozapine, the treatment-resistant criteria above continue to be met, the term clozapine-resistant schizophrenia is used.
      • This should make the clinician think about why treatment response is not occurring, including not just medication adherence, but also revisiting the diagnosis and considering a broader differential diagnosis (e.g. - doing a neurological exam, considering autoimmune causes, or other medical conditions).

Psychosocial

  • Family interventions, which includes communication skills, problem-solving, and psychoeducation should be offered to all individuals with schizophrenia. A minimum of 10 sessions over a 3-month period is considered to be the bare minimum.[96]
    • How family members respond to an individual's illness can have a significant effect on their clinical outcomes. Randomized controlled trials have shown that family interventions can both reduce the severity of patient's symptoms and the chance of hospitalization.[97]
    • For example, individuals with schizophrenia who live in households with high expressed emotion (EE) have a significantly greater chance of relapse than those living in lower EE households.[98][99]
  • Supported employment that includes job development, job support, and integration of vocational and mental health services can help for both symptoms and psychological well-being.[100]
  • Various psychotherapies have been shown to be effective in schizophrenia:[101]
    • Cognitive behavioural therapy (CBT) for psychosis should be offered to all patients who have not adequately responded to antipsychotics or have residual symptoms, or other symptoms such as depression and anxiety. CBT is effective for reducing symptoms, hospitalization, and risk of relapse. The minimum recommended number of sessions is 16.[102]
    • 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 outcomes.[103]
    • Social skills training (similar to what is offered in ADHD) is recommended for individuals who have difficulty and/or are experiencing stress and anxiety from social interactions.[104]

ECT

Assertive Community Treatment (ACT)

  • For individuals with chronic psychosis, Assertive Community Treatment (ACT) Teams can help reduce rehospitalization rates, improve occupational functioning, and improve quality life. Disappointingly, however, these programs do not improve the overall clinical state and do not change the overall costs of care.[105]

Guidelines

Schizophrenia Guidelines

Guideline Location Year PDF Website
Canadian Schizophrenia Guidelines Canada 2017 - Link
National Institute for Health and Care Excellence (NICE) UK 2014 - Link
Scottish Intercollegiate Guidelines Network (SIGN) UK 2013 - Link
American Psychiatric Association (APA) USA 2021 - Link
Royal Australian and New Zealand College of Psychiatrists (RANZCP) AUS, NZ 2016 - Link

Resources

For Patients
For Providers
Articles
Research

References

1) Folsom, D. P., Lebowitz, B. D., Lindamer, L. A., Palmer, B. W., Patterson, T. L., & Jeste, D. V. (2006). Schizophrenia in late life: emerging issues. Dialogues in Clinical Neuroscience, 8(1), 45.
2) Lindamer, L. A., Lohr, J. B., Harris, M. J., & Jeste, D. V. (1999). Gender-related clinical differences in older patients with schizophrenia. The Journal of clinical psychiatry, 60(1), 61-67.
3) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
4) Jongsma, H. E., Gayer-Anderson, C., Lasalvia, A., Quattrone, D., Mulè, A., Szöke, A., ... & Berardi, D. (2018). Treated incidence of psychotic disorders in the multinational EU-GEI study. JAMA psychiatry, 75(1), 36-46.
5) Pompili, M., Amador, X. F., Girardi, P., Harkavy-Friedman, J., Harrow, M., Kaplan, K., ... & Montross, L. P. (2007). Suicide risk in schizophrenia: learning from the past to change the future. Annals of general psychiatry, 6(1), 10.
6) Addington, D., Abidi, S., Garcia-Ortega, I., Honer, W. G., & Ismail, Z. (2017). Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. The Canadian Journal of Psychiatry, 62(9), 594-603.
7) Zaheer, J., Olfson, M., Mallia, E., Lam, J. S., de Oliveira, C., Rudoler, D., ... & Kurdyak, P. (2020). Predictors of suicide at time of diagnosis in schizophrenia spectrum disorder: A 20-year total population study in Ontario, Canada. Schizophrenia Research.
8) Caldwell, C. B., & Gottesman, I. I. (1990). Schizophrenics kill themselves too: a review of risk factors for suicide. Schizophrenia bulletin, 16(4), 571-589.
9) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
10) Chen, C. K., Lee, C. Y., Lee, Y., Hung, C. F., Huang, Y. C., Lee, S. Y., ... & Wang, L. J. (2018). Could schizoaffective disorder, schizophrenia and bipolar I disorder be distinguishable using cognitive profiles?. Psychiatry research, 266, 79-84.
11) Huang, Y. C., Lee, Y., Lee, C. Y., Lin, P. Y., Hung, C. F., Lee, S. Y., & Wang, L. J. (2020). Defining cognitive and functional profiles in schizophrenia and affective disorders. BMC psychiatry, 20(1), 39.
12) Sadock, B. J., Sadock, V. A., & Ruiz, P. (2015). Kaplan & Sadock's synopsis of psychiatry: Behavioral sciences/clinical psychiatry (Eleventh edition.). Philadelphia: Wolters Kluwer.
13) Addington, D., Abidi, S., Garcia-Ortega, I., Honer, W. G., & Ismail, Z. (2017). Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. The Canadian Journal of Psychiatry, 62(9), 594-603.
14) Sadock, B. J., Sadock, V. A., & Ruiz, P. (2015). Kaplan & Sadock's synopsis of psychiatry: Behavioral sciences/clinical psychiatry (Eleventh edition.). Philadelphia: Wolters Kluwer.
15) Jääskeläinen, E., Juola, P., Hirvonen, N., McGrath, J. J., Saha, S., Isohanni, M., ... & Miettunen, J. (2013). A systematic review and meta-analysis of recovery in schizophrenia. Schizophrenia bulletin, 39(6), 1296-1306.
16) Padma, T. V. (2014). Developing countries: The outcomes paradox. Nature, 508(7494), S14-S15.
17) Cohen, A., Patel, V., Thara, R., & Gureje, O. (2008). Questioning an axiom: better prognosis for schizophrenia in the developing world?. Schizophrenia Bulletin, 34(2), 229-244.
18) Waite, F., Sheaves, B., Isham, L., Reeve, S., & Freeman, D. (2020). Sleep and schizophrenia: From epiphenomenon to treatable causal target. Schizophrenia research, 221, 44-56.
19) Gottesman, I. I., & Groome, C. S. (1997). HIV/AIDS risks as a consequence of schizophrenia. Schizophrenia bulletin, 23(4), 675-684.
20) Tsuang, M. (2000). Schizophrenia: genes and environment. Biological psychiatry, 47(3), 210-220.
21) Tsuang, M. (2000). Schizophrenia: genes and environment. Biological psychiatry, 47(3), 210-220.
22) Gejman, P. V., Sanders, A. R., & Duan, J. (2010). The role of genetics in the etiology of schizophrenia. Psychiatric Clinics, 33(1), 35-66.
23) Wu, Y., Liu, X., Luo, H., Deng, W., Zhao, G., Wang, Q., ... & Li, T. (2012). Advanced paternal age increases the risk of schizophrenia and obsessive–compulsive disorder in a Chinese Han population. Psychiatry research, 198(3), 353-359.
24) Malaspina, D., Harlap, S., Fennig, S., Heiman, D., Nahon, D., Feldman, D., & Susser, E. S. (2001). Advancing paternal age and the risk of schizophrenia. Archives of general psychiatry, 58(4), 361-367.
25) Folsom, D. P., Lebowitz, B. D., Lindamer, L. A., Palmer, B. W., Patterson, T. L., & Jeste, D. V. (2006). Schizophrenia in late life: emerging issues. Dialogues in Clinical Neuroscience, 8(1), 45.
26) Howard, R., Castle, D., O'Brien, J., Almeida, O., & Levy, R. (1992). Permeable walls, floors, ceilings and doors. Partition delusions in late paraphrenia. International Journal of Geriatric Psychiatry, 7(10), 719-724.
27) Stafford, J., Dykxhoorn, J., Sommerlad, A., Dalman, C., Kirkbride, J., & Howard, R. (2020). Association between risk of dementia and very late-onset schizophrenia-like psychosis: a Swedish population-based cohort study.
28) Schwarzkopf, S. B., Olson, S. C., Coffman, J. A., & Nasrallah, H. A. (1990). Third and lateral ventricular volumes in schizophrenia: support for progressive enlargement of both structures. Psychopharmacology bulletin.
29) Heckers, S. (2001). Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus, 11(5), 520-528.
30) Sim, K., DeWitt, I., Ditman, T., Zalesak, M., Greenhouse, I., Goff, D., ... & Heckers, S. (2006). Hippocampal and parahippocampal volumes in schizophrenia: a structural MRI study. Schizophrenia bulletin, 32(2), 332-340.
31) Rich, A. M., Cho, Y. T., Tang, Y., Savic, A., Krystal, J. H., Wang, F., ... & Anticevic, A. (2016). Amygdala volume is reduced in early course schizophrenia. Psychiatry Research: Neuroimaging, 250, 50-60.
32) Gur, R. E., Turetsky, B. I., Bilker, W. B., & Gur, R. C. (1999). Reduced gray matter volume in schizophrenia. Archives of general psychiatry, 56(10), 905-911.
33) Popken, G. J., Bunney, W. E., Potkin, S. G., & Jones, E. G. (2000). Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. Proceedings of the National Academy of Sciences, 97(16), 9276-9280.
34) Callicott, J. H., Bertolino, A., Mattay, V. S., Langheim, F. J., Duyn, J., Coppola, R., ... & Weinberger, D. R. (2000). Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cerebral cortex, 10(11), 1078-1092.
35) Torrey, E. F., & Yolken, R. H. (2003). Toxoplasma gondii and schizophrenia. Emerging infectious diseases, 9(11), 1375.
36) Kępińska, A. P., Iyegbe, C. O., Vernon, A. C., Yolken, R., Murray, R. M., & Pollak, T. A. (2020). Schizophrenia and influenza at the centenary of the 1918-1919 Spanish influenza pandemic: mechanisms of psychosis risk. Frontiers in Psychiatry, 11, 72.
37) Davies, G., Welham, J., Chant, D., Torrey, E. F., & McGrath, J. (2003). A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophrenia bulletin, 29(3), 587-593.
38) Kępińska, A. P., Iyegbe, C. O., Vernon, A. C., Yolken, R., Murray, R. M., & Pollak, T. A. (2020). Schizophrenia and influenza at the centenary of the 1918-1919 Spanish influenza pandemic: mechanisms of psychosis risk. Frontiers in Psychiatry, 11, 72.
39) Morgan, V. A., Clark, M., Crewe, J., Valuri, G., Mackey, D. A., Badcock, J. C., & Jablensky, A. (2018). Congenital blindness is protective for schizophrenia and other psychotic illness. A whole-population study. Schizophrenia research, 202, 414-416.
40) Pollak, T. A., & Corlett, P. R. (2019). Blindness, psychosis, and the visual construction of the world. Schizophrenia Bulletin.
41) VICE: People Born Blind Are Mysteriously Protected From Schizophrenia
42) Zipursky, R. B., Reilly, T. J., & Murray, R. M. (2012). The myth of schizophrenia as a progressive brain disease. Schizophrenia Bulletin, 39(6), 1363-1372.
43) Jonas, K. G., Fochtmann, L. J., Perlman, G., Tian, Y., Kane, J. M., Bromet, E. J., & Kotov, R. (2020). Lead-time bias confounds association between duration of untreated psychosis and illness course in schizophrenia. American Journal of Psychiatry, 177(4), 327-334.
44) Anderson, K. K., Rodrigues, M., Mann, K., Voineskos, A., Mulsant, B. H., George, T. P., & McKenzie, K. J. (2015). Minimal evidence that untreated psychosis damages brain structures: a systematic review. Schizophrenia research, 162(1-3), 222-233.
45) Heaton, R. K., Gladsjo, J. A., Palmer, B. W., Kuck, J., Marcotte, T. D., & Jeste, D. V. (2001). Stability and course of neuropsychological deficits in schizophrenia. Archives of general psychiatry, 58(1), 24-32.
46) Folsom, D. P., Lebowitz, B. D., Lindamer, L. A., Palmer, B. W., Patterson, T. L., & Jeste, D. V. (2006). Schizophrenia in late life: emerging issues. Dialogues in clinical neuroscience, 8(1), 45.
47) Harvey, P. D., Silverman, J. M., Mohs, R. C., Parrella, M., White, L., Powchik, P., ... & Davis, K. L. (1999). Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients. Biological psychiatry, 45(1), 32-40.
48) Zipursky, R. B., & Agid, O. (2015). Recovery, not progressive deterioration, should be the expectation in schizophrenia. World Psychiatry, 14(1), 94-96.
49) Whalley K. Psychiatric disorders: Linking genetic risk to pruning. Nat Rev Neurosci. 2016 Apr;17(4):199
50) Anne-Laure Lemaitre, Marion Luyat, Gilles Lafargue, Individuals with pronounced schizotypal traits are particularly successful in tickling themselves, Consciousness and Cognition, Volume 41, 2016, Pages 64-71
51) Brown JS. Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia. Schizophrenia Bulletin. 2009;35(1):256-278.
52) McClellan, J., & Stock, S. (2013). Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. Journal of the American Academy of Child & Adolescent Psychiatry, 52(9), 976-990.
53) McClellan, J., & Stock, S. (2013). Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. Journal of the American Academy of Child & Adolescent Psychiatry, 52(9), 976-990.
54) Addington, D., Abidi, S., Garcia-Ortega, I., Honer, W. G., & Ismail, Z. (2017). Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. The Canadian Journal of Psychiatry, 62(9), 594-603.
55) Addington, D., Abidi, S., Garcia-Ortega, I., Honer, W. G., & Ismail, Z. (2017). Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. The Canadian Journal of Psychiatry, 62(9), 594-603.
56) Miller, D. T., Adam, M. P., Aradhya, S., Biesecker, L. G., Brothman, A. R., Carter, N. P., Church, D. M., Crolla, J. A., Eichler, E. E., Epstein, C. J., Faucett, W. A., Feuk, L., Friedman, J. M., Hamosh, A., Jackson, L., Kaminsky, E. B., Kok, K., Krantz, I. D., Kuhn, R. M., Lee, C., … Ledbetter, D. H. (2010). Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American journal of human genetics, 86(5), 749–764.
57) Addington, D., Abidi, S., Garcia-Ortega, I., Honer, W. G., & Ismail, Z. (2017). Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. The Canadian Journal of Psychiatry, 62(9), 594-603.
58) Kaneda, Y., Ohmori, T., Okahisa, Y., Sumiyoshi, T., Pu, S., Ueoka, Y., ... & Sora, I. (2013). Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery: Validation of the Japanese version. Psychiatry and clinical neurosciences, 67(3), 182-188.
59) Addington, D., Abidi, S., Garcia-Ortega, I., Honer, W. G., & Ismail, Z. (2017). Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. The Canadian Journal of Psychiatry, 62(9), 594-603.
60) Addington, D., Abidi, S., Garcia-Ortega, I., Honer, W. G., & Ismail, Z. (2017). Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. The Canadian Journal of Psychiatry, 62(9), 594-603.
61) Kane JM, Robinson DG, Schooler NR, et al. Comprehensive Versus Usual Community Care For First Episode Psychosis: Two-Year Outcomes From The NIMH RAISE Early Treatment Program. The American journal of psychiatry. 2016;173(4):362-372.
62) Addington, D., Abidi, S., Garcia-Ortega, I., Honer, W. G., & Ismail, Z. (2017). Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. The Canadian Journal of Psychiatry, 62(9), 594-603.
63) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
64) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
65) Remington, G., Agid, O., Foussias, G., Fervaha, G., Takeuchi, H., Lee, J., & Hahn, M. (2015). What does schizophrenia teach us about antipsychotics?. Canadian journal of psychiatry. Revue canadienne de psychiatrie, 60(3 Suppl 2), S14.
66) McCutcheon, R., Beck, K., D'Ambrosio, E., Donocik, J., Gobjila, C., Jauhar, S., ... & Howes, O. D. (2017). Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatrica Scandinavica.
67) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
68) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
69) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
70) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
71) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
72) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
73) Long-term benzodiazepine use is associated with increased mortality in people with schizophrenia
74) Fontanella, C. A., Campo, J. V., Phillips, G. S., Hiance-Steelesmith, D. L., Sweeney, H. A., Tam, K., ... & Hurst, M. (2016). Benzodiazepine use and risk of mortality among patients with schizophrenia: a retrospective longitudinal study. The Journal of clinical psychiatry, 77(5), 661-667.
75) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
76) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
77) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
78) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
79) Harrow, M., & Jobe, T. H. (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. The Journal of nervous and mental disease, 195(5), 406-414.
80) Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment StrategyLong-term Follow-up of a 2-Year Randomized Clinical Trial. JAMA Psychiatry. 2013;70(9):913–920.
81) Insel, T. Post by Former NIMH Director Thomas Insel: Antipsychotics: Taking the Long View (2013).
82) Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment StrategyLong-term Follow-up of a 2-Year Randomized Clinical Trial. JAMA Psychiatry. 2013;70(9):913–920.
83) Murray, R. M., Quattrone, D., Natesan, S., van Os, J., Nordentoft, M., Howes, O., ... & Taylor, D. (2016). Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?. The British Journal of Psychiatry, 209(5), 361-365.
84) Winton-Brown, T. T., Elanjithara, T., Power, P., Coentre, R., Blanco-Polaina, P., & McGuire, P. (2017). Five-fold increased risk of relapse following breaks in antipsychotic treatment of first episode psychosis. Schizophrenia research, 179, 50-56.
85) Moncrieff, J., Crellin, N., Stansfeld, J., Cooper, R., Marston, L., Freemantle, N., ... & Priebe, S. (2023). Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial. The Lancet Psychiatry.
86) McCutcheon, R. A., Taylor, D., Rubio, J., Nour, J., Pillinger, T., Murray, R. M., & Jauhar, S. (2024). Does Slow and Steady Win the Race? Rates of Antipsychotic Discontinuation, Antipsychotic Dose, and Risk of Psychotic Relapse. Schizophrenia Bulletin, 50(3), 513-520.
87) Murray, R. M., & Di Forti, M. (2018). Increasing expectations and knowledge require a more subtle use of prophylactic antipsychotics. World Psychiatry, 17(2), 161.
88) Dr. Joanna Moncrieff - joannamoncrieff.com
89) Tiihonen, J., Tanskanen, A., & Taipale, H. (2018). 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. American Journal of Psychiatry, appi-ajp.
90) Pringsheim, T., Kelly, M., Urness, D., Teehan, M., Ismail, Z., & Gardner, D. (2017). Physical health and drug safety in individuals with schizophrenia. The Canadian Journal of Psychiatry, 62(9), 673-683.
91) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
92) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
93) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
94) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
95) Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.
96) Norman, R., Lecomte, T., Addington, D., & Anderson, E. (2017). Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 617-623.
97) Norman, R., Lecomte, T., Addington, D., & Anderson, E. (2017). Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 617-623.
98) Leff, J., & Vaughn, C. (1981). The role of maintenance therapy and relatives' expressed emotion in relapse of schizophrenia: A two-year follow-up. The British Journal of Psychiatry, 139(2), 102-104.
99) Moline, R. A., Singh, S., Morris, A., & Meltzer, H. Y. (1985). Family expressed emotion and relapse in schizophrenia in 24 urban American patients. The American journal of psychiatry.
100) Norman, R., Lecomte, T., Addington, D., & Anderson, E. (2017). Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 617-623.
101) Norman, R., Lecomte, T., Addington, D., & Anderson, E. (2017). Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 617-623.
102) Norman, R., Lecomte, T., Addington, D., & Anderson, E. (2017). Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 617-623.
103) Norman, R., Lecomte, T., Addington, D., & Anderson, E. (2017). Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 617-623.
104) Norman, R., Lecomte, T., Addington, D., & Anderson, E. (2017). Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 617-623.
105) Addington, D., Anderson, E., Kelly, M., Lesage, A., & Summerville, C. (2017). Canadian practice guidelines for comprehensive community treatment for schizophrenia and schizophrenia spectrum disorders. The Canadian Journal of Psychiatry, 62(9), 662-672.