Schizophrenia

• The term schizophrenia was coined in 1908 by the Swiss psychiatrist Eugen Bleuler.
• Derived from the Greek skhizo (split) and phren (mind).
• Various definitions of the disorder have evolved, and numerous treatment strategies have been proposed, but none have proved to be uniformly effective or sufficient.
• Of all the mental illnesses, schizophrenia probably is responsible for:
1. Lengthier hospitalizations,
2. Greater chaos in family life,
3. More exorbitant costs to individuals and governments, and
4. More fears than any other.

History

• Emil Kraepelin: This illness develops relatively early in life, and its course is likely deteriorating and chronic. Deterioration reminded dementia ("Dementia praecox"), but was not followed by any organic changes of the brain, detectable at that time.
• Eugen Bleuler (1911): He renamed Kraepelin’s dementia praecox as schizophrenia; he recognized the cognitive impairment in this illness, which he named as a "splitting" of the mind.
• Kurt Schneider (1959): He emphasized the role of psychotic symptoms, such as hallucinations and delusions, and gave them the privilege of "the first-rank symptoms" even in the concept of the diagnosis of schizophrenia.

Definition

• Schizophrenia is defined by:
• A group of characteristic positive and negative symptoms
• Deterioration in social, occupational, or interpersonal relationships
• Continuous signs of the disturbance for at least 6 months
• Schizophrenia is a psychotic condition characterized by a disturbance in thinking, emotions, volitions, and faculties in the presence of clear consciousness, which usually leads to social withdrawal.
• The schizophrenic disorders are characterized in general by fundamental and characteristic distortions of thinking and perception, and affects that are inappropriate or blunted.
• Clear consciousness and intellectual capacity are usually maintained although certain cognitive deficits may evolve in the course of time.

• The most important psychopathological phenomena include:
• Thought echo
• Thought insertion or withdrawal
• Thought broadcasting
• Delusional perception and delusions of control
• Influence or passivity
• Hallucinatory voices commenting or discussing the patient in the third person
• Thought disorders and negative symptoms

4 As of Bleuler

• Bleuler maintained that, for the diagnosis of schizophrenia, the following four fundamental symptoms are most important:
1. Affective blunting
2. Loosening of association (fragmented thinking)
3. Autism
4. Ambivalence (fragmented emotional response)
• These groups of symptoms are called the "four A's," and Bleuler thought that they are "primary" for this diagnosis.

Schneider’s First-Rank Symptoms

• The presence of one or more of these is considered to be strongly suggestive of schizophrenia:
1. Hearing one’s thoughts spoken aloud (thought echo).
2. Hallucinatory voices in the form of statement and reply (the patient hears voices discussing him in the third person).
3. Hallucinatory voices in the form of a running commentary (voices commenting on one’s action).
4. Thought withdrawal (thoughts cease, and the subject experiences them as removed by an external force).
5. Thought insertion.
6. Thought broadcasting.
7. Delusional perception.
8. Somatic passivity.
9. Made volition or acts.
10. Made impulses.
11. Made feelings or affect.

2nd Rank Symptoms

• Perplexity (bewilder, puzzle, or disconcert)
• Emotional blunting
• Other hallucinations and delusions

• Characteristically, disturbances in thought processes, perception, and affect invariably result in severe deterioration of social and occupational functioning.
• Symptoms generally appear in late adolescence or early adulthood.
• The pattern of development can be viewed in four phases:
1. The pre-morbid phase,
2. The prodromal phase,
3. The active psychotic phase (schizophrenia), and
4. The residual phase.

The Pre-morbid Phase

• The pre-morbid personality often indicates social maladjustment, social withdrawal, irritability, and antagonistic thoughts and behavior.
• Very shy and withdrawn, poor peer relationships, doing poorly in school, and demonstrating antisocial behavior.

The Prodromal Phase

• The prodromal phase of schizophrenia begins with a change from pre-morbid functioning and extends until the onset of frank psychotic symptoms.
• It has an average length of 2 and 5 years.
• The person experiences substantial functional impairment and nonspecific symptoms such as:
• Sleep disturbance
• Anxiety
• Irritability
• Depressed mood
• Poor concentration
• Fatigue
• Behavioral deficits such as deterioration in role functioning and social withdrawal.

The Active Phase

• In the active phase of the disorder, psychotic symptoms are prominent with characteristics such as:
• Delusions
• Hallucinations
• Disorganized speech
• Catatonic behavior
• Negative symptoms
• Social/occupational dysfunction:
• Persists for a period not less than 6 months
• Schizoaffective and mood disorder exclusion has been ruled out
• Substance/general medical condition has been excluded

The Residual Phase

• During the residual phase, symptoms of the acute stage are either absent or no longer prominent.
• Negative symptoms may remain, and flat affect and impairment in role functioning are common.

• The symptoms of schizophrenia fall into three broad categories.
1. Positive Symptoms: Unusual thoughts or perceptions, including hallucinations, delusions, thought disorder, and disorder of movement.
2. Negative Symptoms: Reductions in normal emotional and behavioral states such as:
• Anhedonia: Inability to feel pleasure; lack of interest or enjoyment in activities or relationships
• Alogia: Lack of meaningful speech, which may take several forms, including poverty of speech (reduced amount of speech) or poverty of content of speech (little information is conveyed; vague, repetitive)
• Asociality: Impairments in social relationships; few friends, poor social skills, little interest in being with other people
• Flat Affect: No stimulus can elicit an emotional response.
• Avolition: Inability or lack of energy to engage in routine activities.
3. Cognitive Symptoms: Subtle and often detected only when neuropsychological tests are performed.
• Poor executive functioning
• Inability to sustain attention
• Problems with working memory
• Others: Ambivalence, association looseness, flight of ideas, echopraxia, echolalia, perseveration, catatonia, verbigeration, neologism, mannerism, etc.

While positive symptoms reflect an excess or distortion of normal function, negative symptoms refer to a diminution or absence of normal behaviors related to motivation and interest.

• Paranoid Schizophrenia
• Hebephrenic Schizophrenia
• Catatonic Schizophrenia
• Simple Schizophrenia
• Undifferentiated Schizophrenia
• Residual Schizophrenia
• Post-schizophrenic Disorder
• Other Schizophrenia
• Unspecified Schizophrenia

Paranoid Schizophrenia

• Commonest
• Characterized by persecutory delusion and auditory hallucination
• Negative symptoms are not prominent
• Good prognosis

Hebephrenic (Disorganized)

• Fleeting delusions and hallucinations
• Mannerisms are common
• Silly and unpredictable behavior
• Negative symptoms appear early
• Poor prognosis
• Commoner in adolescents but not exclusive to them

Catatonic Schizophrenia

• Motor symptoms are most prominent
• Excitement, stupor, waxy flexibility, stereotypies, mannerisms, grimacing, etc.
• Rare
• Good prognosis

Simple Schizophrenia

• Insidious onset
• Odd behavior
• Social withdrawal
• Declined work performance
• There may be wandering tendencies
• Delusions and hallucinations are not evident
• Poor prognosis

Residual Schizophrenia

Persistent negative symptoms for at least one year without positive symptoms. The patient may, however, have had positive symptoms in the past.

Undifferentiated Schizophrenia

Term for cases which do not fit into any of the other types or where there are equally prominent features of more than one of them.

Types I and II Schizophrenia

• Described by Crow (1985)
• Based on clinical and neurobiological factors

Type I

• Acute onset
• Mainly positive symptoms
• Dopamine overactivity
• Preserved social functioning
• Good response to antipsychotics

Type II

• Insidious onset
• Negative symptoms
• Structural brain changes
• No evidence of dopamine overactivity
• Poor response to antipsychotics
• Poor prognosis

• Onset of schizophrenia between 15 and 45 years
• Gender: Equally prevalent in men and women
• Bimodal peak in women
• Mean age of onset is about five years earlier in men.
• Social Class: Low socioeconomic class
• Prevalence is 1% in the general population
• Lifetime risk ranges from 0.7% to 1.3%

Etiology (Cooper, 1978)

• Predisposing Factors: Genetic, season of birth, pregnancy and birth complications, rheumatic disease, substance abuse
• Precipitating Factors: Environmental conditions, stress
• Perpetuating Factors: Poor compliance with medications, substance use, general medical conditions

ETIOLOGICAL THEORIES

Genetic Basis

• Concordance rates of about 50% in monozygotic twins and lifetime risk of about 40% in children of two schizophrenic parents. 12% risk in dizygotic twins and children with only one parent with schizophrenia



Schizophrenia Liability Based on Affected Relatives
Family member(s) affected	Risk (approximate) (%)
Identical twin	46
One sibling/fraternal twin	12–15
Both parents	40
One parent	12–15
One grandparent	6
No relatives affected	0.5–1



• Chromosomal Markers: Current approaches using RFLP have identified the long arm of chromosome 5, 11, 18, 19, and X as being associated with schizophrenia.

Biochemical Basis

• Dopamine Hypothesis: Schizophrenia is due to heightened activity of dopamine at one or more sites in the brain.
• The Fact that All Known Effective Antipsychotics Are DA Antagonists
• Positive correlation between the antipsychotic efficacy of a drug and its potency as a DA receptor antagonist.
• Induction of psychotic symptoms by dopaminergic agents (e.g., amphetamine, cocaine, phencyclidine [PCP], levodopa, bromocriptine).
• Serotonergic overactivity
• The primary mode of action of LSD is through partial 5-HT agonism, associated with sensory distortions and hallucinations.
• The efficacy of clozapine in treatment-resistant schizophrenia is thought to be due to its combined dopaminergic and serotonergic antagonism.
• Gamma-Aminobutyric Acid (GABA) Hypoactivity
• Loss of GABA inhibition has been shown to lead to overactivity in other neurotransmitter systems (e.g., DA, 5-HT, NA).
• There is some evidence to support the loss of GABAergic neurons in the hippocampus of patients with schizophrenia.
• Use of BZDs may augment the therapeutic effects of antipsychotics by their GABA facilitation.
• Glutaminergic hypoactivity
• NMDA receptor antagonists (e.g., ketamine, PCP) have been shown to induce both positive and negative symptoms of schizophrenia in healthy volunteers (possibly via modulation of the DA system) and exacerbate symptoms of patients with schizophrenia.
• The effects of ketamine (in both animals and humans) are attenuated by antipsychotic medication (notably clozapine).
• Neuropathological model with structural abnormalities in the brain
• Enlarged Ventricles
• Increased Loss of Gray Matter in Adolescence
• Shrinkage of Cerebellar Vermis
• Thicker Corpus Callosum

Environmental Factors

• The following have been associated with an increased risk of schizophrenia:
• Complications of pregnancy, delivery, and the neonatal period.
• Delayed walking and neurodevelopmental difficulties.
• Disturbed childhood behavior.
• Severe maternal malnutrition.
• Maternal influenza in pregnancy and winter births.
• Degree of urbanization at birth.
• Use of cannabis, especially during adolescence.

Problems Associated with Schizophrenia

• Comorbidity: Substance use, depression, suicide, general medical conditions
• Stigma
• Mortality
• Homelessness
• Impact on Caregivers

The diagnosis of schizophrenia is made on the basis of the patient’s symptoms, and currently no confirmatory test is available. Subtypes of schizophrenia are no longer retained by DSM-5 or ICD-11.

ICD-10 schizophrenia:

1. At least one of the following:
• Thought echo, insertion, withdrawal, or broadcasting.
• Delusions of control, influence, or passivity; clearly referred to body or limb movements or specific thoughts, actions, or sensations; and delusional perception.
• Hallucinatory voices giving a running commentary on the patient’s behaviour or discussing him/her between themselves, or other types of hallucinatory voices coming from some part of the body.
• Culturally inappropriate or implausible persistent delusions (e.g., religious/political identity, superhuman powers, and ability).
2. Or, at least two of the following:
• Persistent hallucinations in any modality, when accompanied by fleeting or half-formed delusions without clear affective content, persistent over-valued ideas, or occurring every day for weeks or months on end.
• Breaks of interpolations in the train of thought, resulting in incoherence or irrelevant speech or neologisms.
• Catatonic behavior such as excitement, posturing, or waxy flexibility, negativism, mutism, and stupor.
• Negative symptoms such as marked apathy, paucity of speech, and blunting or incongruity of emotional responses.
• A significant and consistent change in the overall quality of some aspects of personal behavior, manifest as loss of interest, aimlessness, idleness, a self-absorbed attitude, and social withdrawal.
3. Duration of ≥1 month.

DSM-5 Schizophrenia Criteria:

A. Characteristics of Symptoms: Two or more of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated). At least one of these must be (1), (2), or (3):

1. Delusions.
2. Hallucinations.
3. Disorganized speech (e.g., frequent derailment or incoherence).
4. Grossly disorganized or catatonic behavior.
5. Negative symptoms (i.e., diminished emotional expression/avolition).

B. Social/Occupational Dysfunction: For a significant portion of the time since onset of the disturbance, the level of functioning in one or more major areas, such as work, interpersonal relations, or self-care, is markedly below the level achieved prior to onset (or when the onset is in childhood or adolescence, there is failure to achieve the expected level of interpersonal, academic, or occupational functioning).

C. Duration: Continuous signs of the disturbance persist for at least 6 months that must include at least 1 month of symptoms meeting criterion A.

D–F. Exclusions:

• Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out.
• Presentation is not attributable to the physiological effects of a substance (e.g., drug of abuse, medication) or other medical condition.
• If there is a history of ASD 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).

ICD-11 Diagnostic Requirements

Schizophrenia or Other Primary Psychotic Disorders is a grouping of disorders characterized by significant impairments in reality testing and alterations in behavior. Manifested by symptoms such as delusions, hallucinations, formal thought disorder (disorganized speech), and disorganized behavior. May be accompanied by psychomotor disturbances and negative symptoms like blunted or flat affect.

Exclusion Criteria:

Symptoms should not occur primarily due to substance use (e.g., Hallucinogen Intoxication) or another medical condition not classified under Mental, Behavioral, or Neurodevelopmental Disorders (e.g., Huntington Disease).

Primary Psychotic Disorders:

The disorders in this grouping are referred to as primary psychotic disorders because psychotic symptoms are their defining feature. Psychotic symptoms may also occur in the context of other mental disorders (e.g., Mood Disorders or Dementia). In these cases, symptoms occur alongside other characteristic features of those disorders. Experiences of reality loss/distortion occur on a continuum throughout the population. Disorders in this group represent patterns of symptoms and behaviors occurring with sufficient frequency and intensity to deviate from expected cultural or subcultural expectations.

Schizophrenia or Other Primary Psychotic Disorders include the following:

• 6A20 Schizophrenia
• 6A21 Schizoaffective Disorder
• 6A22 Schizotypal Disorder
• 6A23 Acute and Transient Psychotic Disorder
• 6A24 Delusional Disorder
• 6A2Y Other Specified Schizophrenia or Primary Psychotic Disorders

Schizophrenia with childhood onset is conceptually the same as schizophrenia in adolescence or adulthood. Although rare, schizophrenia in prepubertal children includes the presence of at least two of the following: hallucinations, delusions, grossly disorganized speech or behavior, social withdrawal for at least 1 month. Social or academic dysfunction must be present, and continuous signs of disturbance must persist for at least 6 months.

• Between 5-6 years of age.
• Visual hallucination commoner.
• Hallucinations and delusions are less elaborate.

Epidemiology:

Before the 1960s, the term childhood psychosis was applied to a heterogeneous group of pervasive developmental disorders without hallucinations and delusions.

In the 1980s, schizophrenia with childhood onset was formally separated from autistic disorder. A subgroup of autistic children will eventually have schizophrenia.

Schizophrenia in prepubertal children is much more rare than in adolescence and young adulthood.

Boys : Girls Ratio: 1.67 : 1. Boys are often more symptomatic at a younger age than girls. Symptoms are usually insidious, and the prevalence rate in their parents is about 8%.

Schizophrenia usually begins in late adolescence or young adulthood and persists throughout life. Although first episode diagnoses after age 65 are rare, a late-onset type beginning after age 45 has been described. Women are more likely to have a late onset than men. Another difference between late-onset and early-onset is the greater prevalence of paranoid schizophrenia in the late-onset type.

Good Prognostic Factors:

• Sudden onset
• Short episode
• 1st episode
• Female sex
• Prominent affective symptoms
• Paranoid type of illness
• Old age
• Married
• Good premorbid personality
• Good work record
• Good psychosexual adjustment
• Good social support
• Compliance with treatment

Poor Prognostic Factors:

• Insidious onset
• Long episode
• Previous psychiatric history
• Negative symptoms
• Male sex
• Younger age at onset
• Single, separated, widowed, divorced
• Poor psychosexual adjustment
• Poor work record
• Social isolation
• Poor compliance with treatment

High Expressed Emotion (EE):

High expressed emotion (EE) in a patient's family is a known risk factor for relapse in schizophrenia.

Worse prognosis in patients returning home because of:

• Critical comments
• Expressing hostility
• Emotional over-involvement

Risk of relapse is high in patients in contact with relatives for more than 35 hours per week.

• Organic Disorders:
• Drug-Induced States: Psychotic symptoms triggered by the use of drugs.
• Mood Disorders with Psychotic Symptoms:
• Delusional Disorders:
• Personality Disorders:

Others

I. Body Dysmorphic Disorder (BDD)

Overlap with Delusional Disorder: Significant overlap with delusional disorder. Few significant differentiating factors exist.

II. Post-Traumatic Stress Disorder (PTSD)

Evidence of Past Trauma: Diagnosis requires evidence of a past life-threatening trauma.

III. Pervasive Developmental Disorder

Early Evidence of Impairment: Requires evidence of impairment in functioning from the preschool years.

IV. Obsessive-Compulsive Disorder (OCD)

Overlap with Delusional Disorder: Significant overlap with delusional disorder. If reality testing regarding obsessions or compulsions is lost, delusional disorder is often diagnosed.

V. Hypochondriasis

Differentiation from Delusional Disorder: Health concerns are generally more amenable to reality testing. Less fixed than in delusional disorder.

VI. Paranoid Personality Disorder

Distinguishing Features: Absence of clearly circumscribed delusions. Presence of a pervasive, stable pattern of suspiciousness or distrust.

VII. Schizotypal Personality Disorder

Features: Odd or eccentric behavior. Absence of clearly circumscribed delusions.

VIII. Misidentification Syndromes

Confusion with Delusional Disorder: Easily confused with delusional disorder. May be associated with other CNS abnormalities.

IX. Induced/Shared Psychotic Disorder

Evidence of Shared Delusional Beliefs: Requires evidence that relatives or close friends share similar delusional beliefs.

X. Anxiety Disorder

Terminology Clarification: Sometimes patients use 'paranoia' or 'feeling paranoid' to describe over-concern, hypersensitivity, anxiety, agoraphobia, or social phobia. Clarification is required when terminology has acquired common parlance.

XI. Factitious Disorder

Feigning Psychotic Symptoms: Rarely, psychotic symptoms may be feigned. Usually to avoid responsibilities and/or to maintain a sick role.