Pharmacological Interventions for Psychosis

Pharmacological Interventions for Psychosis

Outline

• Psychotic Disorders and Schizophrenia: What is it?

• Causes of Schizophrenia

• Genes & Environment

• Biochemical Theories of Schizophrenia

• Anti-psychotic Drugs

Learning Objectives

• Define psychosis

• List the positive and negative symptoms of schizophrenia

• Explain the biochemical theories of schizophrenia

• Identify the common first and second-generation antipsychotics, and describe how they work

Psychotic Disorders

• Definition: The term ‘psychotic disorders’ refers to a range of mental disorders that involve symptoms of psychosis.

• Psychosis: A condition characterized by loss of contact with reality, impacting one’s ability to think, feel, and act.

• Examples of Psychotic Disorders:

  • Schizophrenia

  • Schizoaffective disorder (manic depression)

  • Substance-induced psychotic disorder

Schizophrenia

• Definition: Schizophrenia is a severe psychotic disorder diagnosed when an individual exhibits two or more symptoms from the main clusters (positive, negative, cognitive) for at least six months.

• Core Symptoms:

  • Positive Symptoms: Mental phenomena that are not present in healthy individuals, including hallucinations and delusions.

  • Negative Symptoms: Represent a loss or impairment of normal psychological functions, such as loss of motivation and social withdrawal.

  • Cognitive Symptoms: Impairments in concentration, disorganized thinking, and poor memory.

Causes of Schizophrenia

Gene x Environment Interactions in Schizophrenia

• The risk of developing schizophrenia is significantly influenced by genetic factors.

• Genetic Vulnerability: Predisposing genetic factors interact with various environmental factors that can induce neurochemical and structural changes leading to schizophrenia, typically manifesting in early adulthood.

• Note: Specific genes do not need to be memorized for this material.

Biochemical Theories of Schizophrenia

• Core Concept: Schizophrenia is proposed to be a biochemical brain disease involving neurotransmitter dysregulation.

• Key Neurotransmitters affecting schizophrenia:

  • Dopamine

  • Glutamate

  • Serotonin

  • GABA (Gamma-Aminobutyric Acid)

Biochemical Theories Overview

1. Dopamine Hypothesis

2. Glutamate Hypothesis

3. Serotonin (5-HT) Hypothesis

Neuro 101 Aside

• Classification of Neurons: Neurons can be classified based on the neurotransmitter they release:

  • Glutamate → glutamatergic

  • GABA → GABAergic

  • Dopamine → dopaminergic

  • Acetylcholine → cholinergic

• Some neuronal classes are grouped together:

  • Catecholamines (dopamine, noradrenaline, and adrenaline) → catecholinergic

  • Monoamines (dopamine, noradrenaline, serotonin) → monoaminergic

• Note: While not required for this lecture, this foundation will be essential for upcoming lectures.

General Neuronal Behavior

• Neurons typically release a single neurotransmitter (e.g., GABA neurons exclusively release GABA).

• However, neurons may express receptors for various neurotransmitters (e.g., glutamatergic neurons may have receptors for glutamate, GABA, and dopamine).

Dopamine Hypothesis

• Key Proposition: Schizophrenia symptoms are attributable to hyperactivity in the dopamine system.

• Supporting Evidence:

  • Drugs elevating synaptic dopamine levels (e.g., amphetamines, cocaine) produce delusions and hallucinations at high doses.

  • Antipsychotic drugs that block dopamine receptors are effective as treatment (First Generation Antipsychotics).

Dopamine Neurons & Pathways

• Location: Major dopamine-producing neurons reside in the midbrain (ventral tegmental area and substantia nigra).

• Mesocortical/Mesolimbic System:

  • Dopamine neurons in the ventral tegmental area project to the striatum and prefrontal cortex.

  • Functions include mediating memory, learning, affect, and organization of thought.

  • Hyperactivity in this system contributes to psychotic symptoms.

  • Blocking dopamine transmission effectively treats positive symptoms of schizophrenia.

Dopamine Receptors

• Type: Dopamine receptors are G-Protein coupled receptors classified into:

  • D1 Receptors: Stimulate adenylate cyclase via Gs protein and activate cAMP-dependent protein kinases but are less related to the therapeutic impact of many antipsychotics.

  • D2 Receptors: Inhibit adenylate cyclase activity; blocking these receptors correlates directly with clinical anti-psychotic potency.

Side Effects of Dopamine Antagonism

• While inhibiting dopamine transmission can reduce schizophrenia symptoms, it also leads to unwanted side effects due to non-specific inhibition of pathways:

  • Nigrostriatal System: Dopamine neurons in the substantia nigra project to the striatum, critical for movement initiation. Inhibition of this pathway can cause extrapyramidal symptoms (movement disorders) such as tardive dyskinesia after prolonged use of antipsychotics.

Additional Side Effects

• Tuberoinfundibular System: Dopamine neurons in the arcuate nucleus control hormone release in the pituitary gland. Dopamine release here suppresses the secretion of prolactin and growth hormone. Long term antipsychotic use may result in hyperprolactinemia, which is linked to effects such as amenorrhea, decreased libido, and infertility.

Glutamate Hypothesis

• Core Proposition: Symptoms of schizophrenia may stem from reduced glutamate signaling, especially in the cerebral cortex.

• Supporting Evidence:

  • NMDA antagonists such as PCP (phencyclidine) and ketamine can induce hallucinations and delusional thoughts.

• Current theory posits that NMDA receptors on GABA interneurons in the cortex show hypofunction, leading to overactivation of the downstream glutamate signaling pathway to the ventral tegmental area.

Serotonin Hypothesis

• Core Proposition: Schizophrenia symptoms may be resultant of heightened serotonin signaling.

• Supporting Evidence:

  • Some serotonin (5-HT) agonists, like LSD, exhibit hallucinogenic properties.

  • 5-HT antagonists show improvement in positive schizophrenia symptoms.

  • Activation of 5-HT2A receptors in the prefrontal cortex is theorized to enhance glutamate neuron excitation, which potentially activates the mesolimbic dopamine system and leads to hallucinations.

  • 5-HT2A antagonists can counteract glutamate release in the cortex, thereby alleviating hallucinations and other positive symptoms.

Antipsychotic Drugs

• Classification: Two primary groups of antipsychotic drugs include:

  1. First Generation Antipsychotics (Typical)

  • Target both D1 and D2 dopamine receptor classes, with primary efficacy related to D2 receptor antagonism.

  • Examples include: Haloperidol, Chlorpromazine.

  1. Second Generation Antipsychotics (Atypical)

  • Primarily antagonistic to both 5-HT and D2 receptors.

  • Due to a looser binding affinity to dopamine receptors than the first generation, they typically exhibit fewer dopamine-related side effects, although they may still cause other adverse effects.

  • Examples include: Clozapine, Risperidone.

Therapeutic Margin

• Receptor Occupation: An occupancy rate between 60-80% of D2 receptors is necessary to achieve an antipsychotic effect with both typical and atypical antipsychotic medications.

• Side Effects Threshold: Exposure of approximately 80% D2 receptor occupancy may lead to side effects like Parkinson-like symptoms (extra pyramidal symptoms including tardive dyskinesias) and elevated prolactin levels (hyperprolactinemia).

  • Atypical antipsychotics are linked to fewer dopamine-related side effects.

Kinetic Hypothesis for Side Effects

• The interaction of ligands and receptors can be described as follows: $L + R \rightleftharpoons LR$

  • Equilibrium Constants: The ratio of the rates of binding ($K<em>{on}$) and unbinding ($K</em>{off}$) informs the equilibrium constant ($K_d$).

• Two pathways affected:

  • Tuberoinfundibular Tract: Dopamine secretion into the bloodstream, reaching the pituitary gland through the hypophysial portal system.

  • Mesolimbic/Mesocortical and Nigrostriatal Pathway: Dopamine is released in the synaptic cleft, binding to receptors on the postsynaptic membrane; notable for having a high degree of receptor rebinding, which can intensify effects.

Kinetic Properties of Drug Compounds

1. Fast On, Slow Off Compounds:

   • Example: Haloperidol (1st generation).

   • High receptor binding potential at D2 in striatum/cortex and pituitary leading to increased extrapyramidal side effects and hyperprolactinemia.

2. Fast On, Fast Off Compounds:

   • Example: Chlorpromazine (1st generation).

   • High extrapyramidal symptoms due to rapid binding with normal prolactin release due to fast unbinding.

3. Slow On, Fast Off Compounds:

   • Examples: Clozapine or Risperidone (2nd generation).

   • Lower rebinding potential correlating with decreased extrapyramidal symptoms and normal prolactin release.

Receptor Occupancy and Side Effects

• Both first and second generation antipsychotics vary in their affinities to multiple receptors such as dopamine, serotonin, adrenergic, GABA, and glutamate, potentially resulting in adverse effects.

• Clozapine: exhibits a unique affinity for dopamine D4 receptors, which can lead to agranulocytosis (severe reduction in white blood cells). Consequently, clozapine is not considered a first-line therapy for schizophrenia.

Pharmacodynamic Treatment Considerations

• Antipsychotic medications may show effects within hours or days (i.e., achieving 65% dopamine receptor blockade quickly) but can take 4 to 6 weeks to realize full therapeutic effects.

• Treatment Resistance: Approximately 30% of individuals with schizophrenia remain treatment-resistant, showing no improvement after two or more trials with first-line antipsychotics.

• Side effects lead some patients (50% or more) to discontinue medication. Common side effects include:

  • First Generation: Extrapyramidal symptoms, dyskinesias, increased prolactin release.

  • Second Generation: Cardiovascular effects, metabolic syndrome, diabetes, and significant weight gain.

Questions?