Schizophrenia

lecture 8

how many people does schizophrenia effect

• 1 in 300

• 24 million globally

• m:f ratio is 1.4:1

age of schizophrenia onset

• 15-25 in males

• 25-25 in females

schizophrenia symptoms

• Positive symptoms (gaining something)

  • hallucinations

  • delusions

  • disorganises speech

• negative symptoms:

  • anhedonia → loss of pleasure

  • reduced motivation

  • reduced emotional state

• cognitive symptoms

  • memory issues

  • inability to process social cues

  • impaired sensory perception

diagnosis of schizophrenia

• DSM-5 criteria

• 2 or more symptims for a significant amount of time across a month period

  • must include one of:

    • delusions

    • hallucinations

    • disorganised speech

  • can also include:

    • disorganised/catatonic behaviour

    • negative symptoms

• impaired function at work, interpersonal relations or self care

• patients present differently

burden of schizophrenia

• less common than depression, anxiety and BPD

• high burden of diesase → many years with disability and around 20 years earlier death

genetic cause of schizophrenia

• 50% heritability in twins → not fully genetic

  • likely polygenetic and environmental factors

• DISC1 gene is disrupted

  • expressed on post-synaptic excitatory synapses to regulate form and function

  • mutations identified and implicates a risk factor of psychiactric illness

Environmental risk factors for schiziphrenia

• pre and preinatal

  • maternal infection

  • maternal nutrition → eg. famine

  • maternal stress

  • delivery complications

  • neglect

  • traffic-related air pollution

• adolescence

  • migration → even higher in traumatic migration (eg, refuge, higher in men than women)

  • social isolation

  • stress

  • recreational drug use

    • highest for cannabis → onset in first few years of use

    • some link for alcohol and other substances

developmental timecourse of schizophrenia

• possible genetic predisposition

• complex interraction with perinatal and adolescent environment

• symptems onset in early adulthood

• persists through lifespan

• possible higher risk of neurodegenerative diseases

dopamine hypothesis for schizophrenia

• Positive symptoms → hyperactivity of D2 receptors in subcorticol and limbic regions

• Negative and cognitive symptoms → hypofunction of d1 receptors in PFC

• all current treatment uses this hypothesis except for xanomeline-tropsium (muscarinic agonist and peripheral antagonist)

dopamine pathways in schizophrenia

• mesolimbic pathway

  • VTA → nucleus accumbens

  • reward

  • overactivity → positive symptoms

  • reduced by D2 antagonists

• mesocortical pathway

  • VTA → PFC

  • underactivity → negative symptoms

  • exacerbated by D2 antagonisys, so use D1 positive allosteric modulators (PAM)

• Niagrostriatal pathway

  • substantia nigra → striatum

  • movement

  • D2 antagonists cause extramyramidal parkinson-like movement disorder → bradykinesia, akinesia, termor

• Tuberoinfundibular pathway

  • hypothalamus → anterior pitutiary

  • inhibits prolactin

  • D2 antagonists elevates prolactin and causes undesired lactation in women

Schizophrenia treatments based on the dopamine hypothesis

• First generation antipsychotics (FGA)

  • haloperidol, chlorpromazine

  • D2 antagonists, reduce positive symptoms but not negative or cognitive symptoms

  • induce extrapyramidal side effects → poor patient compliance

• Second generation antypsychotics (SGA)

  • clozapine, olanzaoine

  • D2 antagonists but also blocks D3, D4, mACh, 5-HT2A and 5-HT6

  • less extrapyramidal sife effects but weight gain and type 2 diabetes

  • no more effective than FGA (CATIE 2005 trial)

• Third generation antipsychotics

  • aripiprazole, cariprazine

  • D2 and D3 partial agonists

  • slightly better

  • few extrapyramidal side effects

  • small effect on negative and cognitive symptoms

• Brilaroxazine

  • D2-4, 5-HT1A,2A,6 and 7, nACha4 and b2, SERT

  • recent phase III trial

  • soon to seek approval

support for dopamine hypothesis of schizophrenia

• Pharmacological:

  • amphetamines → inhibit DA uptake

    • cause psychosis in healthy induviduals

    • worsens symptoms in schizo patients

  • effective antyosychotic doses correlate with D2 occupancy

• post-mortem

  • elevated dopamine, DA metabolites and D2 receptors in striatum

  • measures are in patients who have been treated → changes could be caused by this

• PET

  • little change in transporters and receptors in treatment naive patients

  • increased basal dopamine in striatum

  • decreased basal dopamine in PFC

  • scanning using raclopride (binds to D2) and amphetamine shows increased mesolimbic dopamine release in schizo patients

• genome wide association studies (GWAS)

  • single nucleotide polymorphisms (SNPs) at 287 genetic loci associated with schizo

    • impacts COMT gene → decreases dopamine metabolism

    • impacts D2 receptor locus

    • impacts postsynaptic kinases doenstream of DA receptors

limitations of dopamine hypothesis for schizophrenia

• inconsistent findings for several risk factors → COMT, presynaptic DA regulators and vesicular storage

• Risk genes like DISC1 are in DA and glutamatergic signalling

• unclear mechanism of dopamine dysfunction

• aound 30% of patients unresponsive to DA medication

Glutamate or excitation/inhibition imbalance hypothesis

• in a normal person:

  • glutamate activates NMDA receptors on GABAergic neurones

  • increases GABAergic activity

  • inhibits glutamatergic activity

• in schizophrenia:

  • not enough NMDA activation on GABAergic neurones

  • decreased GABAergic activity

  • disinhibition of glutamatergic activity → more active, cytotoxicity

support for excitation/inhibition imbalance hypothesis of schizophrenia

• Pharmacological

  • NMDA receptor antagonists (ketamine or PCP) causes psychosis on healthy individuals

• Post-mortem

  • loss of GABAergic markers in PFC and hippocampus (inc GABA synthesis enzyme, uptake transporter and Ca2+ binding proteins)

  • increased endogenous NMDA receptor antagonist NAAG → binds to glycine site on NMDA

  • decreased inhibitory annd increased excitatory hippocampal synapses

• Magnetic resonance spectroscopy (MRS)*

  • decreased glutamate, GABA and glutathione in anterior cingulate cortex

• PET*

  • reduced NMDA receptors in hippocampus

• * imaging studies on small cohorts not balanced for confounding variables or are stratified by a predominant symptom

clinical trials of drugs based on excitation/inhibition imbalance hypothesis of schizophrenia

• none have been successfull yet

• all work on glutamatergic mechanisms

• eg. NMDA agonists and glutamate agonists

Evidence for the inflammatory hypothesis of schizophrenia

• major histocompatability locus (chromosome 6) has highest association with schizo

  • encodes genes involved in immunity

• patients have elevated cytokines in blood

• envrionmental risks have links to inflammation → eg pollution

• inflammatory comorbidity → 19% of schizo patients have IBS

• stress and maternal immune activation increase risk by altering microglial function

• can have autoantibodies against NMDA receptors

treatments based on the inflammatory hypothesis of schizophrenia

• minocycline → antibiotic

  • inhibits microglial activation

• Celecoxib → non-steroidal anti-inflammatory (NSAID)

  • some promising results

• patient stratification needed for future trials → need to understand pateint genetics and history

  • plasma and imaging markers to identify likely responders

  • personalised medicine

Synaptic hypothesis of schizophrenia

• version 1

  • fienberg, 1982

  • too many or too few or wrong synapses eliminated in adolescence

• version 2

  • keshavan, 1994

  • excessive cortical pruning and insufficient subcortical pruning

• version 3 → intergrated hypothesis

  • howes and onwordi, 2023

  • genetic and environmental risks leading to abberant glial-mediated synaptic pruning

Intergrated hypothesis of schizophrenia

strengths, gaps and future directions of the integrated hypothesis of schizophrenia

• strengths

  • basis to develop disease modifying agents not just symptom relief

• gaps and future directions

  • synaptic loss alone doesnt account for all grey matter volume loss → also change in dendritic spine density, need imaging and marker studies

  • do synaptic alterations occur in the first episode of psychosis or earlier → need PET studies on high risk unmedicated individuals

  • does loss affect specific synapse types → need multimodal imaging ( eg. MRI and PET)

  • can SV2A (presynaptic protein) alterations be confirmed at a protein level post-mortem → relationship between SV2A and other synaptic markers