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Schizophrenia spectrum disorders

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.

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
Aetiological model of schizophrenia | Picchioni, M. M., & Murray, R. M. (2007). Schizophrenia. BMJ (Clinical research ed.), 335(7610), 91–95. https://doi.org/10.1136/bmj.39227.616447.BE

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.
Examples of neurologic conditions associated with psychosis | Arciniegas D. B. (2015). Psychosis. Continuum (Minneapolis, Minn.), 21(3 Behavioral Neurology and Neuropsychiatry), 715–736. https://doi.org/10.1212/01.CON.0000466662.89908.e7

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.
Schematic representation of cerebral circuits impacted in NS, in particular in relation to deficits in anticipatory reward. As discussed in the text, a perturbation of frontocortico-temporal networks has been consistently related to NS, while a disruption of cortico-striatal loops is strongly implicated in amotivation and anticipatory anhedonia. As depicted, these sub-domains of NS reflect the impaired operation of several, anatomically- and functionally-distinct (yet interdependent and interacting) pathways running from the prefrontal cortex (PFC) to the dorsal or ventral striatum. From the latter regions, pathways project to sub-regions of the pallidum which, via the thalamus and dopaminergic nuclei of the ventrotegmental area (VTA), close the loops in projecting back to the PFC. The nucleus accumbens, itself also under the influence of the amygdala, is a core region for modulation of reward and emotional processing. Several other cerebral regions implicated in NS are not shown for reasons of space (see text), and the thalamus has been anatomically relocated for better visibility. Glutamatergic fibres interconnecting the various territories of the PFC are not shown for reasons of clarity, nor projections from the PFC to the VTA. Many neurotransmitters are implicated in NS, as highlighted for amotivation/anticipatory anhedonia in the inset. | STG; superior temporal gyrus; GP, Globus pallidus; VP, Ventral pallidum; SNpc, Substantia nigra, pars compacta; OT, Oxytocin and Glu, glutamate CB. | Millan, M. J., Fone, K., Steckler, T., & Horan, W. P. (2014). Negative symptoms of schizophrenia: Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. European Neuropsychopharmacology, 24(5), 645–692. https://doi.org/https://doi.org/10.1016/j.euroneuro.2014.03.008

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.
Representative molecular pathway for schizophrenia: fine-tuning of the glutamate synapse: Recent advances in human genetics, from both GWAS and large-scale sequencing, have further supported the significance of fine-tuning of glutamatergic neurotransmission in the pathology of schizophrenia. The genes underscored by these studies include those encoding the glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A); glutamate receptor ionotropic, AMPA 1 (GRIA1); serine racemase (SRR); calcium channel, voltage-dependent (VDCC), L type, alpha 1C subunit; the ARC complex, and a number of proteins located in, or associated with, the postsynaptic density of glutamatergic synapses. The N-methyl D-aspartate (NMDA)-type glutamate receptors are fine-tuned by a co-agonist D-serine, which is synthesized by SRR. The GRIN2A subunit (in dark green) dimerizes with other type of subunit, forming the NMDA receptors, whereas the GRIA1 subunit (in brown) also forms heterodimers for the AMPA receptors. VDCCs (e.g., the protein encoded by the CACNA1C gene) are also likely to be involved in tuning neural excitability and synaptic transmission via intracellular calcium signalling. Proteins associated with postsynaptic scaffold include PSD95, Stargazin, several kinases, Rho/Cdc42/Rac small G-proteins, and ARC complex. In response to activation of glutamate receptors, these proteins convey intracellular signalling that underlies cytoskeletal regulation and receptor trafficking crucial for synaptic plasticity. | Owen, M. J., Sawa, A., & Mortensen, P. B. (2016). Schizophrenia. Lancet (London, England), 388(10039), 86–97. https://doi.org/10.1016/S0140-6736(15)01121-6

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.
Changes in brain volume in schizophrenia: a) Coronal sections of the brains of a patient with schizophrenia with poor outcome, a patient with good outcome and a healthy comparison subject b) Annual whole-brain volume changes from a longitudinal study were modelled as time derivatives of the brain volume–age function by applying a locally weighted running line smoother (degrees of freedom = 3); the integral of this fit yielded brain volume as a function of age for healthy control individuals and patients with schizophrenia. | a: Schnack, H. G. et al. Changes in thickness and surface area of the human cortex and their relationship with intelligence. Cereb. Cortex 25, 1608–1617 (2015). | b: Kahn, R., Sommer, I., Murray, R. et al. Schizophrenia. Nat Rev Dis Primers 1, 15067 (2015). https://doi.org/10.1038/nrdp.2015.67
Schizophrenia involves changes in cortical thickness.: Maps of change in cortical thickness (mm) and F values, comparing patients with schizophrenia and healthy control individuals. Patients with schizophrenia show cortical thinning or excessive thinning (blue), or thickening or excessive thickening (red) compared with healthy controls. Maps with F values show where patients (n = 154) have significantly thinner or thicker cortex relative to controls (n = 156) at baseline or where change in cortical thickness during the 5-year interval is significantly more pronounced in patients with schizophrenia (n = 96) relative to controls (n = 113). | van Haren, N. E. M. et al. Changes in cortical thickness during the course of illness in schizophrenia. Arch. Gen. Psychiatry 68, 871–880 (2011).
yu-y-schizophrenia-pathogenesis-and-clinical-findings-march-26-2016
The Calgary Guide | http://calgaryguide.ucalgary.ca/

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.
Disturbances of perception and experience in the differential diagnosis of hallucinations: Hallucination is distinguished from illusion (misperception of an actual sensory stimulus) and the other disturbances of perception or experience described in the table | Arciniegas D. B. (2015). Psychosis. Continuum (Minneapolis, Minn.), 21(3 Behavioral Neurology and Neuropsychiatry), 715–736. https://doi.org/10.1212/01.CON.0000466662.89908.e7

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
Schematic course of negative symptoms in schizophrenia. Negative symptoms are present throughout the course of schizophrenia. They can occur early, persist over time, increase in severity, and remain between acute episodes of illness. Correll, C. The Prevalence of Negative Symptoms in Schizophrenia and Their Impact on Patient Functioning and Course of Illness. | The Journal of Clinical Psychiatry. 74(2):e04, 2013. Copyright 2019, Physicians Postgraduate Press.

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
The “compass” of schizophrenia: interrelationship between negative symptoms (NS) and other core facets of the disorder. In this particular depiction, all roads lead South – to NS, which are comprised of two sub-domains, diminished expression (blunted affect and alogia) and avolition (amotivation, asociality and anticipatory anhedonia), respectively. Reciprocally, NS themselves may feedback to aggravate other facets of schizophrenia. Impaired social cognition is strongly interrelated with, and may drive, NS. For example, social withdrawal is both a feature of NS and a consequence of faulty social cognition. On the other hand, a lack of motivation to engage in social contact will reinforce deficits in social cognition. Deficits in neurocognition, in particular, the higher-level operations indicated, will aggravate NS, such as mechanisms required for acquisition of reward. The paranoia of positive symptoms may also provoke (secondary) NS. Anxiety is often co-morbid with schizophrenia: it is also provoked by positive symptoms and impending treatment, and may aggravate NS. Further, social anxiety will more directly impact NS, especially social withdrawal. Depression is associated with deficits in effort-related behaviours which, together with anhedonia, will further deteriorate motivation. These observations suggest that NS may, to a certain extent, channel the deleterious influence of other symptoms into poor functional outcome with which NS are strongly correlated. Note that impaired social cognition may also aggravate (provoke) positive symptoms (paranoia and delusions) due to faulty and hasty (jumping to conclusions) interpretation of the actions and intentions of others. | PAR.CX, Parietal cortex. | Millan, M. J., Fone, K., Steckler, T., & Horan, W. P. (2014). Negative symptoms of schizophrenia: Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. European Neuropsychopharmacology, 24(5), 645–692. https://doi.org/https://doi.org/10.1016/j.euroneuro.2014.03.008

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.
Actionable factors that cause or contribute to secondary negative symptoms.Notes: *Including Huntington’s disease, multiple sclerosis, Parkinson’s disease, traumatic brain injury, chronic pain, sleep apnea, temporal lobe epilepsy. | Correll CU, Schooler NR. Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment. Neuropsychiatr Dis Treat. 2020;16:519-534

Diagnosis

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

Physical care algorithm: adapted from NICE guidelines | Adams CE. Schizophrenia. Full national clinical guideline on core interventions in primary and secondary care London: Gaskell and the British Psychological Society, 2003

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:

DSM-5 has identified five “defining” symptoms for the diagnosis of schizophrenia, which should become apparent in the course of appropriate observation and interviews. Negative symptoms, together with hallucinations and delusions (positive symptoms), psychomotor dysfunction (agitation, retardation, catatonia) and disorganisation. Depressed mood, mania and cognitive impairment (which subsumes impaired social cognition) are additional criteria to be considered, but they are not diagnostic per se. Note that neurocognitive dysfunction usually requires the use of specific tests for its characterisation as opposed to impairment in social cognition and negative symptoms which should be apparent during the course of the interview and from other forms of interaction. | Millan, M. J., Fone, K., Steckler, T., & Horan, W. P. (2014). Negative symptoms of schizophrenia: Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. European Neuropsychopharmacology, 24(5), 645–692. https://doi.org/https://doi.org/10.1016/j.euroneuro.2014.03.008

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
Neuron-glia interactions in the cerebral cortex: key neural substrates for the pathology of schizophrenia: In the cerebral cortex, interneurons (inhibitory neurons) regulate the output of pyramidal neurons (excitatory neurons). Many studies have reported abnormalities of interneurons (in particular parvalbumin-positive interneurons) and deficits of dendritic spines in the pyramidal neurons in the pathology of schizophrenia. Imbalance of excitatory and inhibitory neurons may be a key feature that underlies the pathology. Recent neurobiology indicates that astrocytes and microglia play key a role in maintenance and pruning of the dendritic spines, in association with immune inflammatory response in the brain. Oligodendrocytes create the myelin sheath, which is crucial for signal transmission inside the axon. Abnormalities of these glial cells have also been reported in schizophrenia. | Owen, M. J., Sawa, A., & Mortensen, P. B. (2016). Schizophrenia. Lancet (London, England), 388(10039), 86–97. https://doi.org/10.1016/S0140-6736(15)01121-6

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.

Schizophrenia has positive, negative , and cognitive symptom domains. | The Hippocampus and Nucleus Accumbens as Potential Therapeutic Targets for Neurosurgical Intervention in Schizophrenia – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Schizophrenia-has-positive-negative-and-cognitive-symptom-domains_fig1_26321097 [accessed 23 Nov, 2020]

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)
Pharmacological treatment algorithm | Taylor D, Kerwin R, Paton C. The Maudsley 2005-2006 prescribing guidelines, 8th ed. London: Taylor and Francis, 2005

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.
Psychotherapeutic approaches | Crismon L, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GC, et al., editors. 1Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, New York: McGraw-Hill; 2014. pp. 1019–1046.

Summary

Schizophrenia is a psychiatric disorder that often debuts in adolescence before the onset of psychotic symptoms in adulthood. | Schizophrenia. Nat Rev Dis Primers 1, 15069 (2015). https://doi.org/10.1038/nrdp.2015.69

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