Wk5: Schizophrenia: An Overview

Schizophrenia Overview: Clinical Characteristics, Epidemiology, Genetics, Neuroscience, and Psychopharmacology

Schizophrenia is a common and severe mental illness encountered regularly by clinicians.
This review provides an overview of schizophrenia's clinical characteristics, epidemiology, genetics, neuroscience, and psychopharmacology.

Clinical Presentation and Diagnosis

Diagnosis is based on clinical assessment, with codified criteria replacing early narrative descriptions.
- Positive Symptoms: Delusions and hallucinations are common reasons for seeking clinical help.
- Negative Symptoms: Amotivation and social withdrawal.
- Cognitive Symptoms: Deficits in working memory, executive function, and processing speed.
Earlier conceptualizations emphasized negative symptoms as core features.
Negative and cognitive symptoms contribute significantly to the long-term burden of the disorder.

Epidemiology and Burden

Typically appears in early adulthood, often preceded by a prodromal period.
Lifetime prevalence is approximately 1%.
High healthcare burden with annual costs in the U.S. estimated at over $150 billion.
The high cost is due to early onset and long-term impairments in social and occupational function.
Reduced life expectancy: approximately 15 years shorter than the general population.
Lifetime suicide risk is 5% to 10%.

Theme 1: Convergence of Genetic and Early Environmental Risk Factors on Neurodevelopment

Schizophrenia's pathogenesis begins early in neurodevelopment.
- Increased rates of in utero adversity such as maternal infections and starvation during pregnancy.
- Obstetric complications, including preterm birth and preeclampsia.
- Skin markers of altered ectodermal development.
- Mild cognitive and motor impairments in childhood, potentially manifesting as falling behind peers in schoolwork.
Twin and other studies show a large genetic component, with heritability estimated at around 80%.
- Heritability indicates the variability of the trait in the population attributable to genetic variation but doesn't estimate individual risk or specific genetic loci.
Genome-wide association studies (GWAS) identify loci associated with schizophrenia using an unbiased, data-driven approach.
- GWAS show multiple common variants, each with a small effect, associated with schizophrenia.
- After adjusting for the number of tests, more than 100 loci are significantly associated with schizophrenia.
- Schizophrenia is a polygenic disorder in most patients.

Polygenic Risk Scores and Copy-Number Variants

Polygenic risk scores provide a genetic risk summary based on the number of risk alleles an individual has, weighted by the odds ratio associated with each allele.
Copy-number variants (deletion or duplication of sections of DNA) are associated with a greatly increased risk of schizophrenia but are only found in 2% to 3% of people with schizophrenia.
- Deletion at chromosome 22q11.2 is associated with a 30% to 40% lifetime risk of developing schizophrenia.
Many genetic variants associated with schizophrenia may also be associated with other psychiatric disorders, indicating overlap in risk factors and potentially mechanisms.
Even among identical twins, pairwise concordance for schizophrenia is only around 50%.
- Highlights the importance of environmental factors and their interactions with genetic factors to increase schizophrenia risk.
The risk for schizophrenia explained by polygenic risk scores was 5 times greater in those who had experienced perinatal complications, indicating an interaction between genetic and obstetric risk factors.
In those who did not experience any obstetric complications, the risk score did not differentiate patients and control participants.
Genes highly expressed in the placenta accounted for these findings, suggesting some schizophrenia risk variants act by increasing the outcomes or likelihood of environmental risks, such as obstetric complications, that may then disrupt brain development.

Molecular Pathways from GWAS Findings

Gene expression data from more than 500 brains compared individuals with and without schizophrenia.
- Relevant genes identified by examining how gene expression data mirrored the loci implicated by GWAS, and these genes were then tested in model systems to assess functional relevance.
- This process identified genes involved in the regulation of the postsynaptic membrane, synaptic transmission, and voltage-gated potassium channels as associated with schizophrenia.
A complementary data-driven approach mapped the GWAS results onto gene expression profiles from different neuronal cell types to identify which cell types might be affected by the schizophrenia variants.
- These results showed that genes associated with schizophrenia risk are not expressed across all neuronal populations but instead are expressed specifically in hippocampal pyramidal cells, medium spiny neurons, and cortical interneurons.
A third, hypothesis-driven approach investigated the complement 4 (C4) locus within the major histocompatibility complex, one of the loci most strongly associated with schizophrenia.
- Together with subsequent work, this indicates that disrupted complement-mediated synaptic elimination by microglia occurs in individuals with schizophrenia.

Postmortem Studies

Several pathways identified by genetic studies have also been implicated by postmortem studies, including findings of lower levels of synaptic proteins, dendritic spines, and gamma-aminobutyric acid (GABA)–ergic and glutamatergic markers in individuals with schizophrenia relative to control participants.
Aberrant functioning of complement and microglial systems in schizophrenia may lead to the loss of dendritic spines.
Genetic and early environmental risk factors disrupt brain development, particularly in some neuronal subtypes and brain regions, increasing the risk of developing schizophrenia.

Theme 2: Cortical Excitatory-Inhibitory Imbalance and the Development of Cognitive and Negative Symptoms

Schizophrenia typically develops in early adulthood and is rare before age 16 years.
Other factors act later to lead to the disorder, in addition to genetic and early developmental factors.
Cognitive deficits and negative symptoms begin before the onset of the first psychotic episode.
Cognitive function is considerably lower in people at risk of developing schizophrenia than matched control individuals.
Early neurodevelopment is characterized by the production of synaptic connections, which continues during childhood before a switch in adolescence to synaptic pruning, such that the number of synapses in an adult is about half that of a young child.
The macroscale consequences of this can be observed in reductions in gray matter volume over adolescence and early adulthood and the concomitant reorganization of both structural and functional brain networks.
These processes are disrupted in schizophrenia, leading to widespread impairments in neural communication and the development of cognitive deficits in individuals with the disorder.
Normal developmental trajectories are disrupted in schizophrenia, with increased gray matter loss and aberrant network organization apparent at illness onset, and this is associated with cognitive deficits.

Neural Circuits and Cognitive Processes

Many cognitive processes, such as working memory, are underpinned by synchronized neural oscillations, particularly those occurring at approximately 40 Hertz, which are termed gamma oscillations.
These oscillations underlie the slow fluctuations in neural activity observed using functional magnetic resonance imaging and, as such, play a major role in determining the architecture of functional brain networks.
In healthy individuals, these neural oscillations and functional networks have been linked with a wide range of cognitive abilities.
In schizophrenia, electrophysiological studies have consistently shown disrupted synchronization of neural oscillations in both patients with chronic schizophrenia and first-episode psychosis, and these abnormalities have been associated with cognitive and negative symptoms.
These oscillations occur secondary to a finely tuned balance between groups of inhibitory and excitatory neurons.
GABAergic interneurons play a central role in regulating the fast firing of pyramidal neurons required for the generation of these high-frequency rhythms.

Molecular Alterations and Neural Oscillations

Postmortem studies have found a lower density of dendritic spines on pyramidal neurons.
Lower messenger RNA levels of parvalbumin and markers of other inhibitory interneuron subtypes.
Lower levels of glutamate decarboxylase 67 (GAD67) messenger RNA and GAD67 protein, an enzyme involved in GABA synthesis, which together suggest that inhibitory mechanisms are altered.
Microglia play a key role in pruning synapses, and there is some in vivo evidence for altered microglial markers in individuals with schizophrenia.
Disrupted synaptic pruning could contribute to the lower dendritic spine levels in affected individuals, which would in turn affect the excitatory activity of pyramidal cells.
Abnormalities of N-methyl-D-aspartate receptor function and glutamatergic signaling may also contribute to disrupted excitatory-inhibitory balance.
These disruptions have the potential to lead to abnormalities, such as altered gamma oscillations and disruption of coordinated brain function, leading to aberrant organization of functional brain networks.
This disrupted neural function may then contribute to the development of cognitive and primary negative symptoms.

Theme 3: Subcortical Dopamine Dysregulation and the Onset of Psychosis

Several later environmental risk factors are associated with an increased risk of developing schizophrenia.
These associations are unlikely to result from genetic differences between members of different races/ethnicities or biases among clinicians and instead exert their influence via aberrant reactions within the stress-response circuity, particularly the amygdala and frontal cortex, which are thought to lead to sensitization of the subcortical dopamine system.
Other stressful psychosocial factors, such as life events, also increase the risk of developing schizophrenia.
Subcortical dopamine dysregulation has a role in the development of psychosis.
- Amphetamines and other drugs that release dopamine induce psychotic symptoms in healthy volunteers and worsen symptoms in patients with schizophrenia.
Molecular imaging studies show that striatal dopamine synthesis and release capacity is higher in patients compared with control participants.
Greater release of dopamine after amphetamine administration is directly associated with the worsening of psychotic symptoms in patients.
Higher striatal dopamine synthesis capacity is present in the prodromal phase, is specific to those individuals in prodromal states who develop psychosis, and worsens with psychosis onset.
Depleting striatal dopamine levels or blocking dopamine receptors reduces psychotic symptoms in patients, suggesting that dopamine dysregulation is likely a final common pathway to psychosis in most patients.

Mesostriatal Dopamine and Reward Prediction

Preclinical work has demonstrated that the activity of mesostriatal dopamine neurons is associated with the discrepancy between expected and actual rewards, which is termed a reward prediction error signal.
Dopamine neuron firing encodes aversive and other non-rewarding stimuli and is specifically involved in the updating of beliefs after meaningful as opposed to merely surprising stimuli.
Dopamine neurons can be considered as signaling the salience of stimuli for learning and updating cognitive models of the world.
Schizophrenia is associated with dysregulated firing of mesostriatal dopamine neurons, meaning that dopamine signaling becomes decoupled from salient stimuli.
- As a result, irrelevant objects may be marked as salient solely because they have been associated with aberrant dopamine signaling.
- Provides a neuroscientific explanation for clinical phenomena frequently described by patients.

Cognitive Biases and Delusional Beliefs

Early-life experiences, such as bullying or child abuse, may lead to cognitive biases, such as a tendency to view negative events as resulting from the hostile acts of others.
These cognitive biases are more common in people at risk of schizophrenia.
Dopamine signaling within the dorsal striatum has been associated with threat, because this is the site of greatest dopaminergic dysregulation in schizophrenia and therefore potentially contributes to the fact that delusions are often persecutory in content.

Theme 4: Current Treatments for Schizophrenia

All current pharmacological treatments for schizophrenia are dopamine D2-receptor blockers, and positron emission tomography (PET) studies in affected patients show that substantial occupancy of dopamine D2 receptors, generally more than 60% occupancy, is required for a high likelihood of response.
D2 blockade will dampen the consequences of dysregulated striatal dopamine release.
Movement-associated adverse effects become more likely with higher D2 occupancy, generally greater than 80%, providing an explanation for these common adverse effects and suggesting a therapeutic window for treatment.

Dopamine Receptor Occupancy and Therapeutic Window

PET studies investigating receptor occupancy and clinical response have generally studied short-term responses in patients over a few weeks.
It is unknown if the same level of D2-receptor occupancy used for short-term treatment is needed over months to reduce the risk of relapse.
Long-term treatment may induce changes in the dopamine system.
There is some evidence that long-term treatment with potent D2 blockers may be associated with upregulation of striatal D2-receptor levels in some patients.
However, this was observed in patients taking relatively high doses of first-generation antipsychotic drugs rather than the second-generation antipsychotic drugs generally used at present and has yet to be shown in prospective studies.

Antipsychotic Medications and Dopamine Function

Antipsychotic drugs appear to have little association with presynaptic dopamine function and may indeed sensitize the dopamine system.
Given the lack of any permanent association with underlying dopamine dysfunction, the high rates of relapse after antipsychotic medication discontinuation are expected, and long-term maintenance treatment is recommended in clinical guidelines.
There is little evidence that antipsychotic drugs substantially improve negative and cognitive symptoms other than in situations in which these are secondary to positive symptoms.
These symptoms most likely result from the disruption of cortical circuits rather than striatal dopamine signaling.

Psychological Treatments for Psychosis

Psychological treatments can help individuals to address biased cognitive schema and reappraise psychotic symptoms.
This has the potential to break the cycle in which the stress of experiencing psychosis is itself an exacerbating and perpetuating factor.
High expressed emotion, a communication style characterized by critical comments, hostility, and emotional overinvolvement towards people with schizophrenia, is associated with increased rates of relapse, and therapies to address maladaptive family communication have also been shown to be effective.
Psychological treatments also appear to have minimal associations with cognitive and negative symptoms.

Outstanding Questions

Schizophrenia has been associated with several molecular and circuit-level alterations, such as impaired mismatch negativity, altered serotonergic systems, and altered redox systems, and additional abnormalities are seen in patients with dual diagnoses.
No model accounts for all of the alterations associated with schizophrenia, and, for many of them, it remains unknown if they are causal or potentially compensatory reactions to upstream dysfunction.
Studies of people at risk of schizophrenia and in the early stages of the illness, similar to ones that have been done for the dopamine system, will help clarify these issues.
While striatal hyperdopaminergia is a well-established finding in schizophrenia, the molecular mechanisms underlying this remain unclear.
Likewise, the exact mechanisms leading to disrupted excitatory-inhibitory balance remain unclear; for example, it remains uncertain whether changes in GABAergic interneurons are best understood as a primary pathology or as a compensatory mechanism for dendritic spine loss.
Moreover, while there is evidence that impaired cortical regulation could underlie mesostriatal dopamine dysregulation, causality has yet to be demonstrated in vivo.
Determining this could help identify new therapeutic targets for interventions.

Treatment Resistance and Heterogeneity

Dopamine-receptor blockers show a benefit in terms of positive symptoms for most patients, although even in this domain, efficacy is limited for some individuals.
This has been termed treatment-resistant schizophrenia and occurs in around one-third of individuals with chronic schizophrenia.
For these individuals, clozapine appears to be of particular benefit, but the mechanism underlying this remains poorly understood.
Lower striatal dopamine synthesis capacity, higher glutamate concentrations in the anterior cingulate cortex, and more pronounced gray matter changes are all associated with treatment resistance.
There is also some evidence that individuals with higher polygenic risk score are less likely to respond to antipsychotic treatment, although this appears to depend on the population studied.
So far, neither imaging nor genetic or clinical markers have sufficient accuracy to be suitable for prognostication at the individual patient level.
Greater understanding of the neurobiology of treatment resistance and other sources of heterogeneity has the potential to identify new treatment targets and potentially allow for personalized clinical treatments.

Symptom Clusters and Novel Treatments

Schizophrenia is a syndrome that includes several symptom clusters and subclusters.
Individual patients may differ markedly in their symptom profiles, and it is thus unsurprising that there is heterogeneity in neurobiological findings and treatment response.
One approach proposed to address this is to focus instead on the circuits and processes underlying specific symptoms or symptom clusters (for example, the research domain criteria approach).
All current licensed treatments for schizophrenia are D2-receptor blockers.
Several treatments using non-dopaminergic mechanisms have been tested.
There is some evidence that modulation of N-methyl-D-aspartate receptor function or α7 nicotinic receptor signaling could be beneficial in the treatment of negative and cognitive symptoms, but replicated evidence of efficacy remains elusive.
The research findings discussed suggest several novel potential treatment targets, such as microglia and the complement system (in attempts to prevent aberrant synaptic pruning) and the GABAergic system (to correct dysfunctional interneuron signaling).

Conclusions

Schizophrenia is a complex disorder with multiple symptoms clustered in 3 main domains and numerous interacting risk factors.
Genetic and environmental risk may converge to lead to aberrant functioning of cortical microcircuits and disinhibition of striatal dopamine signaling, which then together lead to the wide range of symptoms experienced.
Antipsychotic drugs are effective for positive symptoms for most patients but have little benefit for negative and cognitive symptoms, and essentially all use the same mechanism, blockade of the D2 receptor.
Recent developments in genetics, neuroimaging, and preclinical research have identified potential upstream treatment targets to address the mechanisms underlying these symptoms as well.
Integrating knowledge across these fields is vital to enable translation of these new findings into interventions of clinical benefit to individuals with schizophrenia.