Schizophrenia: Causes and Treatments

Psychosis and Schizophrenia

• Psychosis is a set of symptoms, not a disorder itself
• Schizophrenia is a specific disorder that may or may not be associated with other conditions like mania, depression, or cognitive disorders.
• Psychosis includes delusions, hallucinations, disorganized speech, disorganized behavior, and gross distortions of reality.
• Schizophrenia is characterized by a set of symptoms that define psychosis.
• Schizophrenia was once broadly considered "madness" in the early 20th century. Bleuler (1911) defined the condition.
• Schizophrenia does not equal "split personality," a disorder known as multiple personality disorder
• The onset of schizophrenia typically occurs in adolescence or early adulthood.

Learning Outcomes

• Students should be able to define the distinction between psychosis and schizophrenia.

• Students will be able to identify and describe the symptoms of schizophrenia. These include positive and negative symptoms.

• Students will get a historical overview of schizophrenia.

• Students will gain knowledge on the neuropathology, aetiology, and treatment of schizophrenia.

• Students can describe the advantages and disadvantages of different treatments for schizophrenia.

Reference Literature

• Stahl online: Chapters 4 and 5

The Scream

• Edvard Munch created the piece "The Scream."
• His account regarding the creation involved feeling unspeakably tired, extreme fear, and an infinite scream of nature.
• Munch depicted a sense of vulnerability and isolation.

Psychosis and Schizophrenia- Meaning of terms

• The term "psychosis" is difficult and misused within both the media and by healthcare professionals.
• Negative perceptions and stigma associated with psychosis contribute to the use of the pejorative term "crazy"
• Psychosis is a syndrome composed of symptoms.

Symptoms of Psychosis

• Delusions: fixed false beliefs, not based on reality
• Hallucinations: sensory experiences without external stimuli (auditory, visual, tactile)
• Disorganized speech: nonsensical or illogical communication
• Disorganized behavior: bizarre and inappropriate actions
• Gross distortions of reality: profound difficulties interpreting surroundings

Schizophrenia: Aetiology and Pathology

• Onset is typically during adolescence/early adulthood
• Lifetime risk for schizophrenia is ~1%
• Presentation of symptoms and outcome is highly variable across individuals
• Multiple contributing factors are responsible for the condition, which is not completely understood. There is no single, definable cause.
• Problems of definition: Subgroups exist within schizophrenia that share common symptoms and other characteristics.
• Higher incidence in lower socioeconomic groups
• Possible correlation with prior, impaired functioning

Genetics

• Schizophrenia often runs in families, but no single gene is solely responsible.
• It is more likely that multiple gene interactions create vulnerability to developing the condition. Possessing the genes doesn't guarantee development.
• Studies with identical twins support the genetic component. If one identical twin is diagnosed, the other has a 1 in 2 chance. This is true even if they have different upbringings.
• Non-identical twins with different genetic makeups show less correlation in the development of the disorder.

Schizophrenia: Neuropathology

• Cerebral blood flow is often reduced in association with reduced frontal function.
• Enlarged ventricles of the brain show up in scans
• Volume of the brain's temporal lobes displays reductions in those diagnosed with schizophrenia.
• Schizophrenia is not a progressively worsening condition.

Schizophrenia: Symptoms In Brief

• Positive symptoms describe new behaviours that were not present before diagnosis. These symptoms include delusions, hallucinations, disorganized speech, disorganized behaviour and agitation.
• Negative symptoms describe behaviours that have been lost. These include reduced emotional responsiveness, reduced interest and reduced social drive and poor grooming.

Schizophrenia: Aetiology

• Inherited genetic factors play a role, and increased risks are apparent if one family member is already diagnosed.
• Studies of twins, both identical and non-identical, indicate a genetic contribution. Identical twins have a higher risk of developing the disorder if one twin is impaired, in comparison to non-identical twins.
• Environmental factors are also significant and include birth complications, viral infections, inner-city living, changes in environment and drug abuse.

Aetiology: Dopamine Hypothesis

• Dopamine production, degradation, and transmission all form part of the dopamine hypothesis in the etiology of schizophrenia. Chemical processes are important in the production, degradation, and transmission of dopamine.

• The hypothesis suggests the hyperactivity of mesolimbic dopamine pathways might trigger cognitive and other positive symptoms.

• Conversely, the hypoactivity of mesocortical pathways may induce negative symptoms.

Aetiology: Glutamate Hypothesis

• A new hypothesis suggests that there are problems with glutamatergic neurotransmission which may contribute to schizophrenia
• The hypothesis states that altered glutamatergic neurotransmission might be associated with symptoms of schizophrenia.

Phencyclidine (PCP) on the NMDA Receptor

• PCP and ketamine can block NMDA receptors which have been noted as potentially important in the pathophysiology of schizophrenia.
• Blockade might impact glutamate-mediated excitation, contributing to the condition's pathogenesis.

Intracortical Glutamatergic Neurotransmission

• Intracortical glutamatergic neurotransmission is facilitated/moderated via GABAergic interneurons.

NMDA-R Hypofunction

• Hypofunction of NMDA receptors may lead to positive symptoms of schizophrenia.
• This happens when the glutamate pathways are affected.

In other terms

• Glutamatergic and GABAergic neurons have interactions that impact dopamine-related processes and cause symptoms of schizophrenia

Schizophrenia: Symptoms (Summary)

• Positive symptoms, including delusions, hallucinations, and disorganized speech, represent new behaviours.
• Negative symptoms, including reduced emotional responsiveness, reduced interest, and reduced social drive, represent lost behaviours.

Changes in Symptoms With Time

• Initially, schizophrenia may present with mild symptoms but as the condition progresses, often towards a chronic state, negative symptoms overpower positive symptoms.
• Early detection and intervention are important to better manage the condition.

Schizophrenia Outcomes

• Approximately 25% of patients experience a single episode of psychosis and recover.
• Factors contributing to successful recovery from a single episode include: no family history or pre-existing conditions; stable premorbid personality; acute onset; and preservation of emotional responsiveness along with early diagnosis and treatment.
• Symptoms of persistent schizophrenia frequently correlate with a patient's family history and include persistent, premorbid personality distortions; difficulties in forming relationships; and disrupted social or domestic life. Onset is often insidious, and the patient may experience loss of initiative and drive along with delayed diagnosis and treatment.

Treatments for Schizophrenia

• Treatment aims to control acute attacks and resolve underlying social and domestic factors.
• Rehabilitative care for patients with schizophrenia is critical due to the repercussions of psychosis. This includes the treatment and monitoring of mood, emotion, and behavior and begins after a comprehensive evaluation.

Schizophrenia: D2 Antagonists

• Psychotherapy is potentially helpful
• Antipsychotic (neuroleptic) medications, such as haloperidol and chlorpromazine, primarily target positive symptoms.
• The onset of action is typically delayed
• Approximately 30% of patients might not respond to this class of medication.
• Depot formulations of medication can improve compliance in affected individuals.

Treating Schizophrenia

• Reducing mesolimbic dopamine hyperactivity reduces positive symptoms.
• However, such treatments often increase negative symptoms because mesocortical dopamine tone is also reduced.

Therapeutic and Side Effects

• Antipsychotic drugs reduce dopamine hyperactivity, improving positive symptoms but may exacerbate negative symptoms.
• Medication can sometimes cause side effects: Extrapyramidal (EPS) such as extrapyramidal side effects, including acute dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia.

Side Effects: Extrapyramidal Symptoms

• Extrapyramidal symptoms (EPS) represent a common side effect of antipsychotic medications.
• These may manifest as involuntary movements affecting various body parts.
• Common EPS include acute dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia.

Side Effects: Prolactinaemia

• High prolactin levels can arise due to interference with dopamine pathways, leading to hormonal imbalances.

Narrow Therapeutic Range

• A narrow therapeutic range for certain antipsychotic medications suggests that achieving effective doses for treatment while minimizing side effects becomes challenging.

Other Actions of Conventional Antipsychotics

• Conventional antipsychotics may have multiple effects on various neurotransmitter receptors besides dopamine receptors.
• M1 antagonism has side effects: constipation, blurred vision.

Treating Schizophrenia: Serotonin Hypothesis and Atypical Antipsychotics

• Reducing mesolimbic dopamine hyperactivity leads to reduced positive symptoms.
• 5HT2A antagonism leads to increased dopamine tone, which reduces extrapyramidal symptoms (EPS).

Blocking 5-HT2A in Schizophrenia

• Blocking serotonin receptors in the cortex has been shown to increase dopamine secretion and decrease extrapyramidal symptoms (EPS)

Better Therapeutic Profile

• Atypical antipsychotics have a wider margin for treatment success versus side effects.

Binding Properties of Atypical Antipsychotics

• Atypical antipsychotics display varying binding affinities to different receptors.
• Some medications show strong binding activity, for instance, to 5HT1B/D and D2 receptors.

Atypical Antipsychotic Side Effects

• People with schizophrenia who take antipsychotic medications often smoke more.
• side effects include weight gain, diabetes and increased smoking, especially amongst those diagnosed with schizophrenia.
• The use of atypical antipsychotics can lead to metabolic syndrome.
• Older medications, like haloperidol, were often associated with weight loss effects.

Metabolic Syndrome

• Metabolic syndrome is closely associated with schizophrenia in certain individuals, mostly those currently taking antipsychotic medication

Treating Schizophrenia: D2 Antagonists/Partial Agonists atypical Antipsychotics

• Reducing mesolimbic dopamine hyperactivity reduces positive symptoms using dopamine partial agonists such as aripiprazole
• Partial agonist activity on D2 in the mesocortical pathway reduces negative symptoms

D2 Antagonists/Partial Agonists

• Partial agonists have different receptor effects than full agonists.
• Conventional antipsychotics block dopamine receptors.
• Partial agonists have both activating and blocking effects on dopamine receptors.

Antipsychotic Drugs

• Antipsychotics were developed in the 1950s and are mainly classified by their chemical structure.

• Typical antipsychotics primarily block dopamine receptors to primarily target positive symptoms.

• They include chlorpromazine, haloperidol, thioridaxine, and others

• Atypical antipsychotics target dopamine AND other receptors (e.g., serotonin).

Summary of Antipsychotic Drug Classes

• A summary table provides comparative data on the main types of antipsychotics and their affinities to various receptors.

New Anti-Psychotic Drug Tolerability

• A table shows side effect profiles of different antipsychotics, helping in their selection depending on patient needs and risk factors.

Quiz: Side Effects

• A quiz using diagrams to assess the knowledge of different side effects and how receptors are affected

How to Manage Side Effects

• Pharmacists should understand the pharmacology to predict side effects and implement strategies to minimize negative effects.

Quetiapine

• Quetiapine has multiple effects, including hypnotic, antidepressant, and antipsychotic actions, depending on the dosage.

Treatment Strategies

• Early intervention and maintenance treatment for acute episodes are often successful
• Strategies to manage relapses should be part of a comprehensive treatment plan.

Cannabis Psychosis

• Cannabis use can cause short-term psychotic episodes in certain individuals, particularly those with pre-existing mental health vulnerabilities.

Cannabis and Schizophrenia

• Cannabis use does not appear to increase the risk of schizophrenia but may induce or worsen psychosis in some individuals who are vulnerable or are already diagnosed with schizophrenia.

Drugs & Psychosis: Context

• Several illicit substances and even some prescription medications are associated with inducing or exacerbating psychotic episodes. For example, amphetamines, cocaine, MDMA, PCP.

Schizophrenia - Losing Control

• Images depict the experience of profound mental health struggles (a visual aid).

Revision Slides

• Revision slides covering previous topics summarized.