Contents
Introduction
Chronic psychiatric disorder with a heterogeneous genetic and neurobiological background that influences early brain development, and is expressed as a combination of psychotic symptoms — such as hallucinations, delusions and disorganization — and motivational and cognitive dysfunctions.
- M/C functional psychotic disorder
Historical perspective
Bleuler’s four ‘A’s’:
Bleuler’s four putative fundamental disturbances characteristic of schizophrenia.
- Blunted Affect: Diminished emotional response to stimuli)
- Loosening of Associations: Disordered pattern of thought, inferring a cognitive deficit
- Ambivalence: Apparent inability to make decisions, suggesting a deficit of integration and processing of incident and retrieved information
- Autism: Loss of awareness of external events, and a preoccupation with the self and one’s own thoughts
Schneider’s First Rank Symptoms (FRS):
These are the so‐called positive symptoms, i.e. they are symptoms not usually experienced by people without schizophrenia, and are usually given priority among other positive symptoms.
- Auditory hallucinations: Auditory perceptions with no cause
- Thought withdrawal, insertion and interruption: Person’s thoughts are under control of an outside agency and can be removed, inserted (and felt to be alien to him/her) or interrupted by others
- Thought broadcasting: Person thinks everyone is thinking in unison with him/her
- Somatic hallucinations: Hallucination involving the perception of a physical experience with the body
- Delusional perception: A true perception, to which a person attributes a false meaning.
- Feelings/actions as made/influenced by external agents: Where there is certainty that an action of the person or a feeling is caused not by themselves but by some others or other force.
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5):
DSM-5 marks a shift from the presentation of schizophrenia as the archetypal psychotic disorder to its consideration as one of several psychotic disorders existing on a spectrum of psychopathology. Symptoms of schizophrenia spectrum disorders include hallucinations, delusions, disorganized thinking (formal thought disorder, usually inferred from an individual’s speech), grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms.
- Schizotypal (personality) disorder: Characterized by social and interpersonal deficits that reduce the capacity for, and produce marked discomfort with, close relationships
- Delusional disorder: Presence of ≥ 1 delusions lasting at least 1 month in the absence of prominent hallucinations.
- Brief psychotic disorder: Presence of delusions, hallucinations, formal thought disorder (ie, disorganized speech), or abnormal psychomotor behavior (grossly disorganized or catatonic behavior), not better explained by another mental disorder, substance use disorder, or medical condition, lasting 1 day – 1 month, with eventual full return to premorbid function.
- Schizophreniform disorder (represents a point on the spectrum between brief psychotic disorder and schizophrenia): Defined by presence of ≥ 2 psychotic and related symptoms (delusions, hallucinations, disorganized speech reflecting formal thought disorder, abnormal psychomotor behavior such as grossly disorganized or catatonic behavior, negative symptoms)—at least one of which must be delusions, hallucinations, or disorganized speech—lasting 1-6 months.
- Schizophrenia: Presence of ≥ 2 psychotic and related symptoms (delusions, hallucinations, disorganized speech reflecting formal thought disorder, abnormal psychomotor behavior such as grossly disorganized or catatonic behavior, negative symptoms)—at least one of which must be delusions, hallucinations, or disorganized speech—that have been present for at least 6 months (including 1 month, or less if treated successfully, of active psychotic and related symptoms)
Aetiology
Schizophrenia typically presents in early adulthood or late adolescence. Men have an earlier age of onset than women, and also tend to experience a more serious form of the illness with more negative symptoms, less chance of a full recovery, and a generally worse outcome.
Risk factors:
- Family history (biggest risk factor)
- Early risk factors: Birthing complications, the season of birth, severe maternal malnutrition, maternal influenza in pregnancy
- Late risk factors: Childhood trauma, social isolation, cannabis use, minority ethnicity, and urbanization

Abnormal family dynamics:
Schizophrenia is caused by continuous stress and adjustment difficulties
- Schizophrenogenic mother
- Marital schism: Open discord between marital partners that puts a strain on the marriage and may lead to separation or divorce.
- Marital skew: Unhealthy pattern in which the pathological behavior of the dominant partner in a couple is accepted by the other partner
- Expressed emotion (EE): Adverse family environment, which includes the quality of interaction patterns and nature of family relationships among the family caregivers and patients of schizophrenia and other psychiatric disorders
- Double bind: Dilemma in communication in which an individual (or group) receives two or more conflicting messages, with one negating the other.
- Pseudomutality: Shared dread and avoidance of intrafamilial conflict/separation generating a façade of harmony of
- Pseudohostility: Fear of intimacy and closeness generates the persistent bickering (without genuine separation)
Associated conditions:
When psychotic symptoms develop in association with cognitive impairments due to these conditions, the DSM-5 suggests qualifying the neurocognitive disorder diagnosis with the specifier “with behavioral disturbance (psychosis)” rather than offering a concurrent schizophrenia spectrum disorder diagnosis.

Pathophysiology
Neurochemical abnormality hypothesis:
Imbalance of dopamine, serotonin, glutamate, and GABA result in the psychiatric manifestations of the disease. It postulates that four main dopaminergic pathways are involved in the development of schizophrenia. This dopamine hypothesis attributes the positive symptoms of the illness to excessive activation of D2 receptors via the mesolimbic pathway, while low levels of dopamine in the nigrostriatal pathway are theorized to cause motor symptoms through their effect on the extrapyramidal system.
- Nigrostriatal pathway (substantia nigra → caudate nucleus): Low dopamine levels in the pathway affect extrapyramidal system, leading to motor symptoms
- Mesolimbic pathway: (Ventral tegmental area (VTA) → limbic areas): Role in positive symptoms of schizophrenia in the presence of excess dopamine
- Mesocortical pathway: (VTA → cortex): Negative symptoms and cognitive deficits in schizophrenia are thought to be caused by low mesocortical dopamine levels
- Tuberoinfundibular pathway: (Hypothalamus → pituitary gland): Decrease/blockade of tuberoinfundibular dopamine results in elevated prolactin levels and, as a result, galactorrhea, amenorrhea, and reduced libido.

Neurodevelopmental hypothesis:
Based on abnormalities present in the cerebral structure, an absence of gliosis suggesting in utero changes and the observation that motor and cognitive impairments in patients precede the illness onset.

Disconnect hypothesis:
Focuses on the neuroanatomical changes seen in PET and fMRI scans. There is a reduction in grey matter volume in schizophrenia, present not only in the temporal lobe but in the parietal lobes as well. Differences in frontal lobes and hippocampus are also seen, potentially contributing to a range of cognitive and memory impairments associated with the disease.



Clinical features
Psychosis:
“Gross impairment in reality testing” or “loss of ego boundaries” that interferes with the capacity to meet the ordinary demands of life
Hallucinations:
Sensory perception in the absence of a corresponding external or somatic stimulus and described according to the sensory domain in which it occurs. Hallucinations may occur with or without insight into their hallucinatory nature.

Positive symptoms:
- Lack of insight: Failure to appreciate that symptoms are not real or caused by illness
- Hallucination: Perception without a stimulus (touch, smell, taste, or vision)
- Auditory hallucinations: M/C (usually “hearing voices”)
- Delusions: Fixedly held false belief that is not shared by others from the patient’s community. Delusions often develop along personal themes like:
- Thought disorder: Manifests as distorted/illogical speech—a failure to use language in a logical and coherent way. Typified by “knight’s move” thinking or tangentiality—thoughts proceed in one direction but suddenly go off at right angles, like the knight in chess, with no logical chain of thought
ICD classification:
ICD-10 further subcategories schizophrenia based on the key presenting symptoms
- Paranoid schizophrenia
- Hebephrenic schizophrenia
- Catatonic schizophrenia
- Undifferentiated schizophrenia
- Post-schizophrenic depression
- Residual schizophrenia
- Simple schizophrenia
Cognitive symptoms:
- Attention deficit
- Deficit in executing functions

Negative symptom:
Negative symptoms have been reported as among the most common first symptom of schizophrenia, although they generally do not represent the reason that clinical care is initially sought for patients. Negative symptoms commonly appear during the prodromal phase of schizophrenia and before the first acute psychotic episode
- Diminished expression:
- Blunted affect: Decreased expression of emotion
- Alogia: Reduction in quantity of words spoken
- Avolition/apathy:
- Avolition: Reduced initiation and persistence of goal-directed activity due to decreased motivation
- Asociality: Reduced social interactions and initiative due to decreased interest in relationships with others
- Anhedonia: Reduced experience of pleasure during an activity or in anticipation of an activity

Secondary negative symptoms:
Secondary symptoms, which can respond to treatment, occur in association with or result from positive symptoms, affective symptoms, medication side effects, environmental deprivation, or other treatment- or illness-related factors. For example, negative symptoms could be a secondary effect of primary positive symptoms in a patient who becomes socially withdrawn after experiencing delusions of persecution or paranoia; or diminished expression could be a coping strategy in a patient who is unable to process overwhelming external stimuli associated with psychotic episodes in schizophrenia.

Diagnosis
The diagnosis of schizophrenia is clinical; made exclusively after obtaining a full psychiatric history and excluding other causes of psychosis.

Putative disease biomarkers:
- Oculomotor abnormalities:
- Smooth pursuit eye movement alterations
- Saccadic eye movement disinhibition
- Prepulse inhibition (PPI) of startle response paradigms
- P50 auditory evoked potential: Standard auditory ‘paired stimuli’ paradigm measured with EEG-based event-related potential (ERP)
DSM-5 criteria:

Differential diagnosis:
- Substance-induced psychotic disorder
- Mood disorders with psychotic features
- Sleep-related disorders
- Delusional disorder
- Paranoid personality disorder
- Schizotypal personality disorder
- Pervasive developmental disorder
- Psychosis secondary to organic causes


Management
Although pharmacological treatments for schizophrenia can relieve psychotic symptoms, such drugs generally do not lead to substantial improvements in social, cognitive and occupational functioning. Psychosocial interventions such as cognitive–behavioural therapy, cognitive remediation and supported education and employment have added treatment value, but are inconsistently applied.

Pharmacotherapy: Somatic treatment
Pharmacotherapy is the mainstay of schizophrenia management, but residual symptoms may persist
- Oral second-generation antipsychotic (SGA): Aripiprazole, olanzapine, risperidone, quetiapine, asenapine, lurasidone, sertindole, ziprasidone, brexpiprazole, molindone, iloperidone, etc
- Benzodiazepine (BZD) (if needed to control behavioral disturbances and non-acute anxiety): Diazepam, clonazepam or lorazepam
- Clozapine (for resistant cases)

Nonpharmacological Therapy
Psychotherapeutic approaches may be divided into three categories: individual, group, and cognitive behavioral. Nonpharmacological treatments should be used as an addition to medications, not as a substitute for them.

Summary
