Antipsychotics and Mood Stabilizers in Behavioral Health

Schizophrenia Pathophysiology and Etiology

• Conceptual Overview: Schizophrenia displays marked "heterogeneity" and involves numerous etiologies.

• Nature vs. Nurture Model:

  • Genetic Diathesis (Nature): Involves specific risk genes such as:

    • ErbB4 risk gene.

    • DAO activator risk gene.

    • MTHFR risk gene.

    • Dysbindin risk gene.

    • DISC-1 risk gene.

    • NRG-1 risk gene.

    • COMT risk gene.

  • Epigenetic Environmental Stressors (Nurture): Factors include abusive childhood, virus or toxins, marijuana use, and traumatic experiences or learning patterns.

• Neurophysiological Progression:

  • Genetic predisposition + environmental stressors lead to a "biased" circuit.

  • This results in hypoactivation with malfunction, followed by unsuccessful compensation and decompensation after multiple life events.

  • Clinical manifestations: Delusions, hallucinations, and thought disorders.

• Theories of Pathophysiology: Postulated theories involve dopamine, serotonin, and glutamate, though current focus is heavily on the dopaminergic theory.

CNS Dopamine Tracts and Clinical Correlations

• Nigrostriatal Pathway:

  • Origin: Substantia nigra ($A9$ area).

  • Innervation: Dorsal striatum.

  • Function: Extrapyramidal system and movement.

  • Dopamine Antagonist Effect: Movement disorders (Extrapyramidal Symptoms).

  • Schizophrenia State: Normal functioning in schizophrenia patients.

• Mesolimbic Pathway:

  • Origin: Midbrain ventral tegmentum ($A10$ area).

  • Innervation: Nucleus accumbens, hippocampus, and amygdala.

  • Function: Emotional functioning and motivational behavior.

  • Schizophrenia State: High activity level leading to positive symptoms (hallucinations, delusions).

  • Dopamine Antagonist Effect: Relief of psychosis.

• Mesocortical Pathway:

  • Origin: Midbrain ventral tegmentum ($A10$ area).

  • Innervation: Frontal and prefrontal lobe cortex.

  • Functional Subdivisions:

    • To DLPFC (Dorsolateral Prefrontal Cortex): Schizophrenia state is LOW, leading to cognitive symptoms and negative symptoms.

    • To VMPFC (Ventromedial Prefrontal Cortex): Schizophrenia state is LOW, leading to affective symptoms and negative symptoms.

  • Dopamine Antagonist Effect: Relief of psychosis, but potentially causing akathisia.

• Tuberoinfundibular (Tuberohypophyseal) Pathway:

  • Origin: Hypothalamus.

  • Innervation: Pituitary gland.

  • Function: Regulates prolactin release.

  • Schizophrenia State: Normal functioning.

  • Dopamine Antagonist Effect: Increased prolactin concentrations.

General Antipsychotic Side Effects

• Cognitive and CNS Effects: Cognitive impairment and somnolence.

• Cardiovascular Effects: Orthostatic hypotension caused by $\alpha$-adrenergic blocking. Requires caution in elderly patients and those with dehydration.

• Anticholinergic Side Effects: Included dry mouth, constipation, blurred vision, and urinary hesitancy.

• Extrapyramidal Symptoms (EPS):

  • Acute dystonia.

  • Pseudoparkinsonism.

  • Tardive dyskinesia (TD).

  • Akathisia.

Management of Extrapyramidal Symptoms: Cogentin (Benztropine)

• Indications: Parkinson's disease and extrapyramidal reactions to phenothiazines or reserpine.

• Mechanism: Usually relieves drug-induced "pseudo-parkinsonism" including muscular rigidity, gait disturbances, tremors at rest, and drooling.

• Administration: Oral tablets or injection (when rapid response is essential, such as in acute dystonic attacks).

  • Injection supplied in $2\,cc$ ampules; each $cc$ contains $1\,mg$ of benztropine mesylate.

  • Tablets supplied in $0.5\,mg$ (scored) and $2\,mg$ (quartersected).

• Precautions: Use with caution in hot weather to minimize risk of anhidrosis. Monitoring for severe reactions is required.

• Side Effects: Anticholinergic and antihistaminic in nature.

  • Common: Dry mouth, blurred vision, nausea, nervousness.

  • Severe/Dose-related: Glaucoma, vomiting, urinary retention, constipation, mental confusion, visual hallucinations.

Cardiovascular Risks: QTc Prolongation and Torsades de Pointes

• IV Haloperidol Risks: Associated with Torsades de Pointes (TdP) in critically ill patients.

• Patient Characteristics in TdP (Sharma et al. 1998 Study):

  • Patient 1: $45M$, Dosage/Time: $9\,mg/7\,hr$, Max QTc: $638\,ms$.

  • Patient 2: $64F$, Dosage/Time: $115\,mg/10\,hr$, Max QTc: $605\,ms$.

  • Patient 4: $71F$, Dosage/Time: $55\,mg/1\,hr$, Paced ECG.

  • Patient 8: $47M$, Dosage/Time: $400\,mg/24\,hr$, Max QTc: $574\,ms$.

• Clinical Pearl: Aripiprazole has been shown to have a lowering effect on QTc compared to other agents.

Patient Counseling and Dosing Principles

• Onset of Action: Quicker onset than antidepressants. Initial effects seen in days to $3\,weeks$, although full effect may take longer.

• Trial Period: Should trial a medication for at least $2\,weeks$.

• Dosing Strategy: Utilize the lowest effective dose.

• Discontinuation: Avoid abrupt cessation; use a slow taper over $2\text{--}4\,weeks$.

Second Generation Antipsychotics (SGAs): Specific Agents

• Aripiprazole (Abilify):

  • MOA: Dopamine $D2$/$5HT1$ partial agonist and $5HT2$ antagonist.

  • Side Effects: Low EPS risk but high incidence of akathisia.

  • Long-acting Injectables (LAI):

    • Abilify Maintena: administered every $4\,weeks$.

    • Aristada: administered every $4$, $6$, or $8\,weeks$.

• Olanzapine (Zyprexa):

  • Structure: Similar to clozapine but not associated with agranulocytosis.

  • Indications: Schizophrenia and bipolar depression (when combined with fluoxetine as Symbyax).

  • Side Effects: High risk for weight gain, sedation, and diabetes.

• Clozapine (Clozaril):

  • Advantages: Most effective agent for schizophrenia; low risk of movement disorders (primarily serotonergic); decreases risk of suicide.

  • Disadvantages: Significant risk of severe constipation and fatal ileus (bowel regimen mandated: Miralax, Senna, etc.); weight gain, sedation, diabetes, and agranulocytosis risk (requires REMS).

  • Prescribing Rule: Do NOT prescribe benztropine/Cogentin with Clozapine because Clozapine has inherently high anticholinergic effects and low EPS risk.

Comparison of Side Effect Profiles

• First Generation (FGAs):

  • Chlorpromazine: High sedation, high orthostatic hypotension, moderate anticholinergic.

  • Haloperidol: Very high EPS, low sedation, low orthostatic hypotension.

  • Fluphenazine: High EPS, low sedation.

  • Thioridazine: High QTc risk, high sedation, high anticholinergic.

• Second Generation (SGAs):

  • Clozapine: Very high weight gain, very high sedation, high anticholinergic, low EPS.

  • Olanzapine: Very high weight gain, high sedation, low EPS.

  • Quetiapine: Moderate weight gain, high sedation, low EPS.

  • Risperidone: Moderate EPS (dose-dependent), moderate weight gain.

  • Ziprasidone: Low weight gain, moderate QTc risk.

Bipolar Disorder and Adjunctive Medications

• Lithium: Primary mood stabilizer; Category $D$ in pregnancy; Dose range $900\text{--}1,200\,mg/day$.

• Lamotrigine (Lamictal):

  • Titration Schedule: Start $25\,mg$ qd (Weeks 1-2) $\rightarrow$ $50\,mg$ qd (Weeks 3-4) $\rightarrow$ $100\,mg$ qd (Week 5) $\rightarrow$ $200\,mg$ (Week 6 maintenance).

  • Interactions: Estrogen-containing contraceptives can decrease serum levels.

  • Safety: Discontinue at first sign of rash (Stevens-Johnson Syndrome risk).

• Other Anticonvulsants: Carbamazepine ($600\text{--}1,600\,mg/day$) and Valproic Acid ($750\text{--}2,000\,mg/day$).

Special Populations and Recommendations

• Geriatrics:

  • Black Box Warning: Increased mortality in elderly with dementia-related psychosis.

  • Strategy: "Start low, go slow." Watch for sedation, orthostatic hypotension, and QTc prolongation.

  • Preferred SGAs: Seroquel, Olanzapine, Risperidone, Abilify.

• Pregnancy (Categories):

  • Category B: Clozapine.

  • Category C: Chlorpromazine, Haloperidol, Aripiprazole, Olanzapine, Quetiapine, Risperidone, Ziprasidone, Lamotrigine.

  • Category D: Lithium, Carbamazepine, Valproate.

• PORT Recommendations (2009):

  • For first-episode schizophrenia: Use any agent OTHER than clozapine or olanzapine.

  • Consider long-acting formulations and prioritize smoking cessation.

• Cost Considerations: Brand name SGAs like Brexpiprazole or Lurasidone can cost up to $\$1300/mo$. Tardive dyskinesia treatments (Ingrezza, Austedo) can cost $\$75,000\text{--}90,000/year$.

Questions & Discussion

• Visual Aid Prompt: The transcript presents an image of "Normasaline (Saline Flush $10\,mL$ $NaCl\,0.9\%$)" labeled humorously as an FDA-approved treatment for the reduction and control of psychotic behaviors when antipsychotics are not working.