Schizophrenia Overview and Symptoms

Schizophrenia

• Chronic and complex psychiatric disorder that affects how a person thinks, perceives reality, manages emotions, and interacts with others.
• Affects young people and is often chronic and disabling
• Affects 1% of the population

Symptoms of Schizophrenia

• Delusions: False, irrational beliefs not shared by cultural reality (e.g., persecution, special powers)
• Hallucinations: Sensory experiences without external stimulus, typically auditory (hearing voices)
• Disorganized thinking: Confused, incoherent speech or difficulty organizing thoughts logically
• Disorganized or catatonic behavior: Unpredictable, bizarre, or repetitive behaviors (lack of response to stimuli to hyperactivity)
• Negative symptoms: Diminished emotional and social capabilities (apathy, flat affect, social withdrawal, lack of motivation)
• Other symptoms: Anxiety, guilt, depression, self-punishment, suicide attempts (50% of cases), difficulty with "selective attention".

Etiology of Schizophrenia

• Multifactorial disorder
• Genetics: Strong familial predisposition
• Environmental factors: Perinatal complications, viral infections during pregnancy, early psychological trauma
• Neurobiology: Dysregulation in the dopaminergic system and neurotransmitter imbalances

Dopaminergic Dysregulation in Schizophrenia

• Hyperactivity of dopamine transmission in the mesolimbic pathway causes positive symptoms (hallucinations, delusions).
• Dopaminergic hypoactivity in the mesocortical pathway is linked to negative symptoms (flat affect, anhedonia) and cognitive deficits.

Glutamate Dysregulation in Schizophrenia

• Hypofunction of NMDA (N-methyl-D-aspartate) receptors, particularly in the prefrontal cortex and hippocampus.
• Reduced NMDA receptor activity contributes to positive and negative symptoms, as well as cognitive dysfunction.

Dopaminergic Pathways Relevant to Antipsychotics

• Mesolimbic pathway: Involved in emotional regulation and motivation. Hyperactivity in this pathway is linked to positive symptoms. Antipsychotics reduce hyperactivity, alleviating hallucinations and delusions.
• Mesocortical pathway: Associated with cognitive and affective functions. Dopamine hypoactivity is linked to negative symptoms and cognitive deficits. Atypical antipsychotics may improve symptoms through serotonergic modulation.
• Nigrostriatal pathway: Controls motor function. D2 receptor blockade in this pathway leads to extrapyramidal side effects (EPS).
• Tuberoinfundibular pathway: Regulates prolactin secretion. D2 receptor blockade here increases prolactin levels, causing hyperprolactinemia (menstrual disturbances, galactorrhea, sexual dysfunction).

Antipsychotic Drugs

• Two groups:
  • First generation (typical or conventional): Primarily block D2 receptors, reducing positive symptoms but often causing significant motor side effects. (Chlorpromazine, Haloperidol, Fluphenazine, Flupentixol, Clopentixol)
  • Second generation (atypical): Block both D2 and 5-HT2A receptors, offering a more balanced treatment of positive and negative symptoms with a lower risk of EPS, but carry a risk of metabolic issues. (Clozapine, Risperidone, Sertindole, Quetiapine, Amisulpride, Aripiprazole, Zotepine, Ziprasidone)

Current Treatment for Schizophrenia: Drawbacks

• Not all patients respond (30% do not).
• Most are ineffective in relieving negative and cognitive impairments.
• Wide variety of side effects: Extrapyramidal motor, endocrine, and sedative effects.
• May shorten survival due to cardiac (pro-arrhythmic) effects.
• Abrupt cessation can lead to psychotic episode.

Mechanism of Action of Typical Antipsychotics

• Block D2 receptors in the dopaminergic system, reducing positive symptoms of schizophrenia (hallucinations, delusions)
• Blocking D2 receptors in other pathways, such as the nigrostriatal pathway, can lead to EPS (rigidity, bradykinesia, tremors)
• Blocking D2 receptors in the tuberoinfundibular pathway can cause hyperprolactinemia (increased prolactin levels, leading to galactorrhea and sexual dysfunction)

Adverse Drug Reactions (ADRs) of Typical Antipsychotics

• Severe EPS: Acute dystonia, akathisia, tardive dyskinesia, and parkinsonism
• Sedation
• Weight gain
• Galactorrhea and sexual dysfunction
• Hypotension, due to blocking other receptors (e.g., H1, α1, M1)

Mechanism of Action of Atypical Antipsychotics

• Act on a wider range of receptors, less likely to cause EPS
• Block both D2 and 5-HT2A receptors
• Blockade of 5-HT2A receptors in the prefrontal cortex helps reduce negative symptoms and cognitive deficits.
• Modulates dopamine activity in other pathways, minimizing the risk of EPS
• Partial D2 receptor blockade reduces positive symptoms while minimizing dopamine blockade in other pathways.

Advantages of Atypical Antipsychotics

• Cause fewer EPS and have a lower risk of tardive dyskinesia
• More effective in treating negative symptoms and cognitive impairments than first-generation drugs

ADRs of Atypical Antipsychotics

• Metabolic syndrome (weight gain, hyperglycemia, dyslipidemia)
• Anticholinergic effects (dry mouth, constipation, blurred vision)
• Risk of QT prolongation (alteration in cardiac electrical activity)

Effect of Antipsychotics on Muscarinic Receptors

• Some antipsychotics are also muscarinic antagonists.
• Blocking D2 receptors enhances overproduction of acetylcholine and muscarinic activation.
• Combining antipsychotics with antimuscarinic drugs may improve the side effect profile.
• Side effects: Constipation, dry mouth, blurred vision

Other Side Effects of Antipsychotics

• Jaundice
• Antipsychotic malignant syndrome: Muscle rigidity, rapid increase in body temperature and mental confusion, usually reversible, but death from renal or cardiovascular failure occurs in 10-20% of cases

Pharmacokinetics of Antipsychotics

• At least 40% of schizophrenic patients fail to take drugs as prescribed.
• Acute toxicity of antipsychotic drugs is slight.
• Plasma half-life: 15-30h, can be given orally or by intramuscular (IM) injection in urgent situations.
• Slow-release (depot) preparations are available. IM injection provides 2-4 weeks of action.

Clinical Uses of Antipsychotics

• Behavioural emergencies: Control hyperactive psychotic states (Chlorpromazine, Haloperidol, Olanzapine, Risperidone). IM dose is lower than oral dose.
• Schizophrenia: First-generation antipsychotic drugs, depot injections (e.g., Flupentixol decanoate) for better compliance, newer antipsychotic drugs, Clozapine (can cause agranulocytosis, effective against negative features of schizophrenia).