NEUROBIOLOGY OF

SCHIZOPHRENIA

Dr.hareesh krishnan k r25/9/2014

SCHIZOPHRENIA

• Schizophrenia is a clinical syndrome of variable, but profoundly disruptive ,psychopathology that involves cognition,emotion,perception and other aspects of behaviour.

• The disorder usually begins before age 25yrs,persists throughout life and affects persons of all social classes.

FEATURES OF SCHIZOPHRENIA

Positive symptomsDelusionsHallucinations

Cognitive deficitsAttentionMemoryVerbal fluencyExecutive function (eg, abstraction)

Functional ImpairmentsWork/school

Interpersonal relationshipsSelf-care

Negative symptomsAnhedoniaAffective flatteningAvolitionSocial withdrawalAlogia

Mood symptomsDepression/AnxietyAggression/HostilitySuicidality

DisorganizationSpeech

Behavior

Genetic factors

Dopamine hypothesis and other biochemical factors

Brain structure

Associated factors – Birth complications/Viral

neuroimmunology & neuroendocrinology

Neurodevelopmental hypothesis

Evolution and schizophrenia

GENETIC FACTORS

GENETICS• Several genes appear to make a contribution

• nine linkage sites: 1q, 5q, 6p, 6q, 8p, 10p, 13q, 15q, and 22q

• Further analyses of these chromosomal sites have led to the identification of specific candidate genes, and

• the best current candidates are alpha-7 nicotinic receptor, DISC 1, GRM 3, COMT, NRG 1, RGS 4, and G 72

Dystrobrevin (DTNBP1) and neureglin 1

NEGATIVE SYMPTOMS

BIOCHEMICAL FACTORS

DOPAMINE HYPOTHESIS

• The theory evolved from two observations. • First, the efficacy and the potency of typical

antipsychotics are due to antagonism of D2 receptors

• Second, cocaine and amphetamine (increase dopamine) have psychotomimetic effects.

• The basic theory does not elaborate on whether the dopaminergic hyperactivity is due to • too much release of dopamine, • too many dopamine receptors, • hypersensitivity of the dopamine receptors to

dopamine, • or a combination of these mechanisms

• Mesocortical and Mesolimbic tracts are most often implicated

• Later studies(primates) showed that a reduction in dopamine activity in PFC is associated with cognitive deficits such as those found in schizophrenia.

Imbalance of dopamine

transmission

Subcortical regions

PFC regions

Normal Level of In The Human Brain

Elevated Level of Dopamine In The

Brain of a Schizophrenic Patient

• Evidence comes from – studies with drugs –post mortems –pet scans

Brain of schizophrenic patients produces more

dopamine than normal brains

ROLE OF DRUGS• Amphetamines and cocaine lead to increase in DA levels. Large

quantities lead to delusions and hallucinations.

• If drugs are given to schizophrenic patients their symptoms get worse.

• Drugs which block dopamine (Phenothiazines) also seem to reduce the symptoms of schizophrenia.

• People with Parkinson's disease develop schizophrenic symptoms if they take too much L-dopa

POST MORTEMS

• Falkai et al 1988Autopsies have found that people with

schizophrenia have a larger than usual number of dopamine receptors.

Increase of DA in brain structures and receptor density (left amygdala and caudate nucleus, putamen)

Concluded that DA production is abnormal for schizophrenia.

PET SCANS• Lindstroem et al (1999)

• Radioactively labelled a chemical L-Dopa • Administered to 10 patients with schizophrenia

and 10 with no diagnosis• L-Dopa taken up quicker with schizophrenic

patients vs controls• Suggests they were producing more DA than the

control group

• Increase in D2 receptors in the caudate nucleus of drug-free patients with schizophrenia.

ROLE OF SEROTONIN

• Current hypothesis states serotonin excess as a cause of both +ve and –ve symptoms in Schizophrena.

• Second Generation Antipsychotics (Clozapine) decreases +ve as well as –ve symptoms and has robust Serotonin antagonist activity.

ROLE OF NE

• Neuronal degeneration in NE system may account for anhedonia _ the impaired capacity for emotional gratification and the decreased ability to experience pleasure.

• Akathisia in Schizoaffective disorder was found to be associated with increased levels of norepinephrine (Agronin and Maletta, 2006)

ROLE OF GABA

• Inhibitory neurotransmitter

• Regulatory effect on dopamine activity.

• Loss of inhibitory GABA ergic neurones leads to hyperactivity of dopaminergic neurones symptoms of schizophrenia.

• Loss of GABAergic neurons in hippocampus has been demonstrated in patients with schizophrenia.

• GAD 67# _ reductions in GAD67 m RNA levels in PFC of schizophrenia.

Decreased muscarinic and nicotinic receptors in the caudate-putamen, hippocampus, and selected regions of the prefrontal cortex may directly impact cognition.

Source - http://www.schizophreniaresearch.org.au/category/research-news/2006-research-news/

There is also decreased muscarinic receptor in the STG responsible for auditory hallucinations in Sz (up to 48 per cent less muscarinic receptorsin the STG of schizophrenia brains than in healthy brains)

Acetyl choline

ROLE OF GLUTAMATE

• Glutamate has been implicated because ingestion of phencyclidine, a glutamate antagonist(NMDA R#), produces an acute syndrome similar to schizophrenia.

• Abnormally low levels of glutamate receptors are found in postmortem brains of people previously diagnosed with schizophrenia (Konradi and Heckers, 2003).

• The hypotheses proposed about glutamate include those of NMDA _hypoactivity, neurodevelopmental disorder and glutamate-induced neuro- toxicity.( neurodegeneration)

• Neurodevelopmental hypothesis_ NMDA receptors are causal in the migration of neurons to their proper final places during neurodevelopment .

• Neurodegenerative theory_ the excitatory neurotransmission exceeds the normal limits and becomes excitotoxic, killing the neurones and causing neurodegeneration.

NEUROPATHOLOGY

CEREBRAL VENTRICLES• Swayze (1990) reviewed 50 studies

of schizophrenics and found that many had abnormally large amounts of liquid in the cavities of the brain.

• Suddath, who supports this found the same enlarged cavities when using MRI scans on schizophrenic twins.

• Beng-Choon Ho (2010) in a longitudinal correlational study of 211 schizophrenics found that antipsychotic drugs have measurable influence on brain tissue loss over time.

• CT scans of patients with schizophrenia have consistently shown lateral and third ventricular enlargement and some reduction in cortical volume.

Whether an active pathological process is continuing to evolve in schizophrenia patients is still uncertain. Some studies indicate progression, while others do not.

ASYMMETRY AND LOBE FINDINGS

• There is a reduced symmetry in several brain areas in schizophrenia, including the temporal, frontal, and occipital lobes. • This reduced symmetry is believed by some

investigators to originate during fetal life and to be indicative of a disruption in brain lateralization during neurodevelopment.• High density of white matter in the right frontal

and parietal lobe.• Small amount of grey matter in the temporal

lobes.

LIMBIC SYSTEM

• PM findings and MRI -> decrease in the size of the limbic system including the amygdala, the hippocampus, and the parahippocampal gyrus

• Hippocampus is small, functionally abnormal and has disorganized neurons

Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon. Arch Gen Psychiatric. 1991;48:415

PREFRONTAL CORTEX

• PM studies show anatomical abnormalities in the PFC.

• Functional deficits have also been demonstrated.

• It has long been noted that several symptoms of schizophrenia mimic those found in persons with prefrontal lobotomies or frontal lobe syndromes.

THALAMUS

• Volume shrinkage or neuronal loss, in particular subnuclei

• The medial dorsal nucleus of the thalamus, which has reciprocal connections with the prefrontal cortex, has been reported to contain a reduced number of neurons

• Number of neurons, oligodendrocytes, and astrocytes is reduced by 30 to 45 % in schizophrenic patients Photomicrographs of Nissl-stained frontal sections through

the anterior (A), middle (B), and posterior (C) levels of the mediodorsal nucleus

BASAL GANGLIA AND CEREBELLUM

• #Many patients with schizophrenia show odd movements, even in the absence of medication-induced movement disorders.Examples are akathisia, facial grimacing, stereotypies.

• The movement disorders involving the basal ganglia (e.g., Huntington's disease, Parkinson's disease) are the ones most commonly associated with psychosis.

• Increase in the number of D2 receptors in the caudate, the putamen, and the nucleus accumbens.

EYE MOVEMENT DYSFUNCTION

Decreased rate of blinking Staring Lack of the blink reflex in response to a tap

on the forehead Poor visual pursuit movements Poor pupil reactions to light Abnormal eye movements in 50 to 85

percent of patients with schizophrenia

VIRAL CAUSES

• In recent years, there has been a build up of evidence supporting the role of viral infections in the development of schizophrenia, including the poliovirus, the flu virus and encephalitis lethargica virus.

• Data supporting a viral hypothesis • increased number of physical anomalies at birth, • an increased rate of pregnancy and birth complications,• seasonality of birth consistent with viral infection, • geographical clusters of adult cases, and • seasonality of hospitalizations

• But there is no data supports the genetic evidence of viral infection.

BIRTH-RELATED COMPLICATIONS

Complications during pregnancy, abnormal foetal growth and complications during delivery are significant risk factors in the development of schizophrenia.

Those that play a significant role in the development of schizophrenia include: bleeding, diabetes and pre-eclampsia.

PSYCHONEUROIMMUNOLOGY

• Several immunological abnormalities have been associated with patients who have schizophrenia.

• These include decreased T-cell interleukin 2 production, reduced number and responsiveness of peripheral lymphocytes,abnormal cellular and humoral reactivity to neurons and the presence of brain directed (antibrain) antibodies.

PSYCHONEUROENDOCRINOLOGY

• Dexamethasone suppression test have been reported tobe abnormal in various sub groups of patients with schizophrenia.

• Some data suggest decreased concentrations of LH/FSH perhaps, correlated with age of onset and length of illness.

NEURODEVELOPMENTAL HYPOTHESIS

• The neurodevelopmental hypothesis of schizophrenia suggests that the disruption of early brain development increases the risk of later developing schizophrenia.

• It focuses attention on critical periods of early brain development

• Two perspective epidemiological as well as genetic( candidate genes have also been linked to altered brain development.)

CORTICAL GABA INTERNEURONS

• In the cortex interneurons contribute approximately 20% total neuronal compliment .

• Postmortem studies in schizophrenic brain revealed an apparent reduction in inhibitory GABA neurons.

• Cortical GABAergic interneurons are born in the ganglionic eminence ,migrate tangentially into the cortical plate following well-defined pathways qnd then vertically into specific cortical layers.

• Different signalling systems and specific genes( differentially expressed in these cells ) play and important role in neuronal migration.

• ErbB4, Pcdhh8, Nr4a1, Rora

EVOLUTION AND SCHIZOPHRENIA

• Two apparently well established findings have corroborated the need for an evolutionary explanation of these disorders:• (1) cross-culturally stable incidence rates and • (2)decreased fecundity of the affected individuals.

• The rationale behind this relates to the evolutionary paradox that susceptibility genes for schizophrenia are obviously preserved in the human genepool, despite fundamental reproductive disadvantages associated with the disorders.

• T.J. Crow has suggested an evolutionary theory of schizophrenia that relates the disorders to an extreme of variation of hemispheric specialisation and the evolution of language due to a single gene mutation located on homologous regions of the sex chromosomes.

REFERENCES

• Kaplan & sadock’s synopsis of psychiatry 10th edition.

• Comprehensive textbook of psychiatry 9th edition.

• Psychiatric clinics of north America (September 2012,volume 35).

• Neuroscience and Biobehavioral Reviews 28 (2004) 41–53.

• Schizophrenia_ Daniel Weinberger&Paul J Harrison

Thank you