L14 - Schizophrenia

Overview of Schizophrenia

• Chronic severe neurological disorder characterized by:

  • Distorted thinking

  • Distorted perceptions

  • Altered behavior and language

• Prevalence: Affects ilda1% of the population; ilda2.4 per 100,000 in Australia.

• Significant impact on quality of life:

  • Morbidity: Lost work productivity, personal relationships, high suicide rates.

Potential Causes of Schizophrenia

• Multifactorial origin: No single cause identified.

• Factors include:

  • Neurodevelopmental factors

  • Genetic factors (mutations in dopamine, glutamate, GABA pathways)

  • Environmental factors (perinatal complications, urban living, cannabis use)

• Changes in neurotransmission (dopamine, serotonin, glutamate) implicated.

Symptoms of Schizophrenia

• Divided into three categories:

  • Positive Symptoms:

  • Delusions

  • Hallucinations

  • Thought disorder

  • Disorganized behavior

  • Negative Symptoms:

  • Emotional flattening

  • Social withdrawal

  • Reluctance to perform tasks

  • Cognitive Symptoms:

  • Attention deficits

  • Memory impairments

  • Executive function deficits

The Dopamine Hypothesis

• One of the oldest hypotheses regarding schizophrenia.

• Dopamine role:

  • Hyperactivity of D2 receptors in mesolimbic pathway linked to positive symptoms. The overstimulation in this pathway leads to increased dopamine neurotransmission, causing symptoms such as hallucinations and delusions.

  • Hypofunctionality of D1 receptors in mesocortical pathway linked to negative and cognitive symptoms. Reduced dopamine activity in this area can impair cognitive functions and reduce emotional responses.

• Evidence:

  • Increased dopamine D2 receptor density in postmortem brain tissue of schizophrenia patients. Studies have shown a higher density of D2 receptors in the brains of schizophrenia patients, supporting the hypothesis that excessive dopamine activity contributes to the disorder.

• Psychomimetic effects: Caused by drugs that increase dopamine availability:

  • L-DOPA: A precursor to dopamine, which can exacerbate psychotic symptoms.

  • Cocaine: Blocks dopamine reuptake, increasing dopamine levels and potentially causing psychotic symptoms.

  • Amphetamines: Promote dopamine release, leading to increased dopamine levels and psychotic symptoms.

The Glutamate Hypothesis

• Reduced glutamate activity, particularly at NMDA receptors, may lead to cognitive dysfunction and contribute to symptoms. Glutamate is a major excitatory neurotransmitter, and its hypofunction can result in a range of schizophrenia-like symptoms.

• Evidence includes:

  • PCP and ketamine inducing schizophrenia-like symptoms. These drugs are NMDA receptor antagonists that block glutamate activity, leading to psychotic and cognitive symptoms.

  • Reduced glutamate and NMDA receptor expression observed in schizophrenia patients. Studies have found reduced levels of glutamate and NMDA receptors in the brains of individuals with schizophrenia.

Antipsychotic Drugs Overview

• Divided into two generations:

  • First Generation (Typical): Primarily D2 receptor antagonists. These drugs mainly block D2 dopamine receptors.

  • Second Generation (Atypical): D2 receptor antagonists and 5HT2A receptor antagonists. These drugs block both dopamine D2 receptors and serotonin 5HT2A receptors.

• Both groups target dopaminergic neurotransmission but differ in receptor affinity profiles, leading to different side effect profiles. The different affinities for dopamine and serotonin receptors result in varying effects on symptoms and side effects.

First Generation Antipsychotics

• Mechanism of Action: Block D2 receptors; effective when 65-80% occupancy is achieved. By blocking these receptors, they reduce dopamine neurotransmission, which is overactive in certain brain pathways in schizophrenia.

• Adverse Effects:

  • Extrapyramidal symptoms (EPS) due to blockade in nigrostriatal pathway. The blockade of D2 receptors in this pathway leads to motor-related side effects.

  • Other side effects due to receptor blockade: hypotension, sedation, anticholinergic effects. These effects are caused by the drugs blocking other receptors, such as adrenergic, histamine, and muscarinic receptors.

• Examples:

  • Chlorpromazine:

  • Indications: Schizophrenia, anxiety, nausea. Used to treat psychotic disorders, anxiety, and as an antiemetic.

  • Side effects include EPS, sedation, hypertension. These are due to its effects on dopamine, histamine, and adrenergic receptors.

  • Haloperidol:

  • Indicated for schizophrenia, high affinity for D2 receptors. Primarily used to treat psychotic disorders due to its strong dopamine-blocking effects.

  • Side effects include EPS, hypotension. High D2 receptor affinity results in significant EPS risk.

  • Flupentixol:

  • Similar receptor profile with EPS, sedation, and hypotension as side effects. Shares similar effects and side effects due to its dopamine receptor antagonism.

Extrapyramidal Side Effects (EPS)

• Caused by D2 receptor blockade in the nigrostriatal pathway: The reduction of dopamine activity in this pathway leads to various motor-related side effects.

  • Symptoms include:

  • Pseudo-Parkinsonism: stooped posture, shuffling gait, tremors. Resembles Parkinson's disease symptoms due to dopamine reduction.

  • Acute dystonia: facial spasms, muscle spasms. Sudden, sustained muscle contractions often in the face, neck, or limbs.

  • Akathisia: restlessness. A state of motor restlessness and an inability to sit still.

  • Tardive dyskinesia: facial involuntary movements. Repetitive, involuntary movements, especially of the face and tongue, which can be irreversible.

• Generally more pronounced with first-generation antipsychotics. Due to their higher D2 receptor affinity and selectivity.

Second Generation Antipsychotics

• Mechanism of Action: D2 and 5HT2A receptor antagonism, with less risk of EPS. Blocking both dopamine and serotonin receptors helps to reduce both positive and negative symptoms of schizophrenia, with a lower risk of motor side effects.

• Indicated for treating schizophrenia and bipolar disorder, with mixed evidence regarding their efficacy for negative symptoms. These drugs are used for a range of mood and psychotic disorders, but their effect on negative symptoms is variable.

• Examples:

  • Risperidone:

  • High affinity for 5HT2A, moderate for D2, profile includes EPS risk, sedation, hypertension. Its mixed receptor affinity provides broad symptom control, but side effects can still occur.

  • Clozapine:

  • Lower D2 affinity, higher affinity for D4, used in treatment-resistant cases. Less likely to induce EPS. Its unique receptor profile makes it effective for patients who do not respond to other antipsychotics.

  • Adverse effects: agranulocytosis (1% of patients), seizures, hypertension, sedation. Requires regular blood monitoring due to the risk of agranulocytosis.

Clinical Efficacy of Antipsychotics

• Treatment:

  • Positive symptoms controlled effectively, but minimal effects on negative/cognitive symptoms. Antipsychotics primarily reduce hallucinations, delusions, and disorganized thought, but do not fully address negative and cognitive symptoms.

  • Response time delay and potential treatment resistance in 30% of patients. It can take several weeks to see the full effects, and some patients do not respond to treatment.

• Abrupt cessation: May lead to rapid psychotic relapse due to adaptive brain changes. The brain adapts to the presence of the drug, and sudden withdrawal can cause a rebound effect.

• Development of treatment-resistant schizophrenia complicates management. Requires alternative treatment strategies such as clozapine or experimental therapies.

Emerging Treatments and Research

• New investigations target neurotransmitter systems beyond dopamine (e.g., trace amine associated receptors, muscarinic receptors). Research is exploring other neurotransmitters to find new ways to treat schizophrenia.

• Ongoing trials for therapeutic options that do not focus on D2 antagonism are showing promise, highlighting a possible shift in treatment paradigms in the future. These new treatments may provide relief for patients who do not respond to traditional antipsychotics.

Summary

• Schizophrenia is a complex disorder influenced by genetic, environmental, and neurodevelopmental factors. Understanding the many contributing factors is crucial for effective treatment.

• Achieving therapeutic efficacy in schizophrenia remains challenging, with promising research indicating future developments in treatment strategies. New research is aimed at improving treatment outcomes and quality of life for patients.

• Current treatments primarily target the dopaminergic system but emerging therapies may offer new mechanisms for managing symptoms, particularly cognitive and negative symptoms. New treatment approaches may provide more comprehensive relief from the various symptoms of schizophrenia.