Antipsychotics

Schizophrenia Physiopathology

• Healthy brains exhibit a balance between excitatory and inhibitory neuronal activity. Cortical pyramidal cells' excitatory output is controlled by GABAergic interneurons. This interplay creates gamma oscillations, crucial for slow, functional brain network fluctuations.
• Schizophrenia involves altered cortical circuits. Reduced pyramidal cell dendritic spines decrease excitatory activity. Diminished excitatory input to GABAergic interneurons reduces inhibition of pyramidal cells. Reduced interneuron inhibition of pyramidal cells further hampers brain function leading to aberrant gamma activity, impacting functional networks, and contributing to schizophrenia's cognitive and negative symptoms.

Stress, Dopamine, and Psychosis

• Psychosocial stressors heighten the subcortical dopamine system's response to further triggers. Cortical deficits lead to impaired regulatory control. Subsequent triggers (like stress) cause inappropriate striatal dopamine release. This, in turn, leads to incorrectly determining stimuli's importance and the development of psychotic symptoms. Psychosis itself is stressful, potentially further dysregulating the system.

First-Generation Antipsychotics

• Chlorpromazine: A phenothiazine antipsychotic, its action likely involves long-term brain adaptation to dopamine receptor blocking. Used as an antiemetic and for intractable hiccups.

  • Mechanism of Action (MoA): Dopamine receptor (D1-D4), serotonin (5-HT1, 5-HT2), histamine (H1), muscarinic (M1/M3), dopamine reuptake inhibition. Has anxiolytic, anti-depressive and anti-aggressive properties.
  • Adverse Effects (AE): weight gain, cardiovascular (hypotension, syncope, QT changes), genitourinary (breast engorgement, ejaculatory disorders, priapism), corneal deposits, visual impairment, drowsiness, dystonia, extrapyramidal reaction, neuroleptic malignant syndrome, dermatitis, photosensitivity, skin pigmentation.

• Haloperidol: A phenyl-piperidinyl-butyrophenone, primarily for schizophrenia and other psychoses. Also used for delusional disorders, ballism, and Tourette syndrome. Powerful antiemetic.

  • MoA: inhibits dopamine effects by tightly binding to dopamine D2 receptors, blocking dopamine neurotransmission.
  • AE: CNS (extrapyramidal reactions, parkinsonism, dystonia, drowsiness, akathisia), GI (constipation, abdominal pain, sialorrhea), neuromuscular (hyperkinetic activity, tremor, bradykinesia), diaphoresis, hyperglycemia, hyponatremia, genitourinary (breast engorgement), cardiovascular (sudden death, QT-prolongation, Torsades de Pointes), cataracts, retinopathy, visual disturbances, and neuroleptic malignant syndrome. Liver and skin issues are also possible.

Second-Generation Antipsychotics (SGAs)

• Clozapine: A tricyclic dibenzodiazepine, used for treatment-resistant schizophrenia.

  • MoA: Selective monoaminergic antagonist, high affinity for 5HT2, D2, alpha 1/2 adrenergic, and H1 receptors.
  • AE: Tachycardia, hypertension/hypotension, drowsiness, sedation, dizziness, insomnia, weight gain, constipation, nausea, vomiting, dyspepsia, fever, increased transaminases (liver), agranulocytosis, leukopenia, toxic delirium, grand mal seizures.

• Risperidone: A pyridopyrimidine; Paliperidone is a primary active metabolite.

  • MoA: Decreases dopaminergic and serotonergic pathway activity; high affinity for 5-HT2A receptors compared to D2 receptors.
  • AE: Hyperprolactinemia, galactorrhea, gynecomastia, weight gain, increased appetite, constipation, abdominal pain, sedation, extrapyramidal symptoms, akathisia, infections (nasopharyngitis, cough).

• Quetiapine: A treatment for schizophrenia, and acute manic episodes.

  • MoA: Dopamine (D1/D2), alpha 1/2 adrenergic, and serotonin (5-HT1A/5-HT2) receptors.
  • AE: Increased blood pressure, peripheral edema, hypertension/hypotension, syncope, drowsiness, headache, agitation, dizziness, extrapyramidal symptoms, skin rash, acne, hyperprolactinemia, nausea, abdominal pain.

• Lithium: A mood stabilizer for bipolar disorder, often considered first-line therapy.

  • MoA: Myoinositol pathway, IP3 pathway, GSK-3, GABA modulation, cAMP and BDNF regulation.
  • AE: Nausea, vomiting, loss of appetite, diarrhea, low thyroid, heart problems, electrolyte imbalances, nephrotoxicity, tremor.
  • Drug interactions: Thiazides, ACE inhibitors, NSAIDs, and lithium toxicity.
  • Pregnancy/Breastfeeding considerations: Use carefully, stop 2-3 days before delivery; breastfeeding not recommended

• Important Considerations for all medications: Adverse effects, treatment duration, maintenance treatment, treatment resistance, and potential for relapses. Clozapine is often the treatment of choice in treatment-resistant cases, following a trial of other medications.

This quiz delves into the physiopathology of schizophrenia, focusing on the balance between excitatory and inhibitory neuronal activity. It explores how altered cortical circuits contribute to cognitive and negative symptoms, along with the role of stress and dopamine in psychosis. Test your understanding of these complex interactions and their implications for brain function.