Antipsychotics & Mood Stabilizers ppt

Psychosis

• Functionally disruptive symptoms with abnormal psychomotor behaviors, negative symptoms, cognitive impairments, and emotional disturbances
• Presence of delusions or hallucinations without insight, or both
• Defining feature of Schizophrenia Spectrum Disorders
• Many psychiatric, neurodevelopmental, neurological, and medical conditions can cause psychosis

Positive and Negative Symptoms

• Positive (+) Symptoms:
  • Hallucinations (audio, tactile, visual)
  • Delusions (untrue, irrational, firm fixed beliefs)
• Negative (-) Symptoms:
  • Neglect personal hygiene
  • Need assistance with ADLs
  • Thought disorders (alogia, thought blocking, word salad, perseveration)
  • Flat affect
  • Avolition (decrease in initiation of goal-directed behavior)
  • Anhedonia (lack of pleasure in activities, social interactions)

Dopamine Hypothesis

• Hyperdopaminergic activity in the Mesolimbic system: (+) symptoms
• Hypodopaminergic activity in the Mesocortical pathway: (-) symptoms, cognition, and affect

Antipsychotics

• All reduce dopaminergic neurotransmission
• Do not erase delusions, but block dopamine to allow patients to work through symptoms
• Can cause dysphoria, which increases non-adherence

Antipsychotic Terminology

• Full agonist: binds to the receptor to induce a full biological response
• Full antagonist: binds to the receptor and blocks the action of the endogenous neurotransmitter
• Partial agonist: has lower intrinsic activity at the receptor than a full agonist
• D2 antagonists: block D2 receptors (1st and 2nd generation antipsychotics)

Antipsychotic Indications

• Schizophrenia/schizoaffective disorder
• Bipolar disorder
• Acute psychosis (mania)
• Major depressive disorder with psychotic features
• Borderline personality disorder
• Tourette syndrome

1st Generation Antipsychotics (FGAs)

• MOA: D2 receptor antagonists
• Antipsychotic effect: relief of positive symptoms
• Induction of extrapyramidal side effects (EPS)
• Other MOA: 5-HT2c receptor antagonist, alpha 1 antagonist, H1 antagonist, M1 antagonist

1st Generation Antipsychotic Adverse Drug Reactions (ADRs)

• Extrapyramidal side effects (abnormal, involuntary movements)
• Neuroleptic malignant syndrome
• Anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, confusion)
• Moderate weight gain
• Sedation
• Orthostatic hypertension
• Increased prolactin levels

2nd Generation Antipsychotics (SGAs)

• MOA: 5-HT2A/D2 antagonists
• First-line pharmacotherapy
• Less EPS (extrapyramidal symptoms)
• (+) Sx relief; impact (-) sxs by improving apathy, social withdrawal, decreased motivation, and cognitive impairment
• MOA: D2 receptor antagonists (+) Sx improvement; 5-HT2A antagonist (-) Sx improvement

2nd Generation Antipsychotic ADRs

• Moderate to severe weight gain
• Metabolic syndrome
• Sedation
• Increased QT prolongation
• Neuroleptic malignant syndrome
• Seizures
• Prolactin-elevation antipsychotics

3rd Generation Antipsychotics (TGAs)

• MOA: Partial D2/5-HT1 agonist/5HT2A antagonist
• Indications: Schizophrenia, Bipolar Mania, Major Depressive Disorder
• ADRs: Weight gain, headache, agitation, insomnia, anxiety

Treatment-Resistant Schizophrenia (TRS)

• Definition: Limited antipsychotic response, high burden to patients, families, and society
• Treatment recommendations: Clozapine, currently the only indicated and evidence-based pharmacologic treatment for TRS

Mood Stabilizers

• Definition: Treat episodic course, relatively stereotyped features with clear subtypes, or variable presentation

• Symptoms: Inability to remain in homeostasis, interaction of genetic, epigenetic, neurochemical, and environmental factors

• Predictors of good response: Prior response to a drug, absence of EtOH or drug abuse, acute onset/short duration of illness, affective symptoms, family history of affective illness, medication compliance### Bipolar Disorder Treatment

• Lithium and mood stabilizers are associated with an increase in gray matter volume

• Acute mania, acute depression, and reduction of future episodes are treated with maintenance regimens

• Mixed episodes are characterized by high highs and low lows

Maintenance Treatment

• Patients are at high risk of relapse for up to 6 months after remission of an acute episode
• Lithium, valproate, lamotrigine, carbamazepine, and oxcarbazepine are recommended for maintenance treatment
• Best empirical evidence supports the use of lithium and valproate in maintenance treatment

Mood Stabilizers

Lithium

• Indicated for 1st-line and maintenance treatment of bipolar disorder
• MOA: inhibits postsynaptic D2 receptor supersensitivity and alters cation transport in nerve and muscle cells
• Narrow serum therapeutic range: 0.6-1.2 mEq/L (0.4-0.8 mEq/L for elderly)
• Dosing considerations: abrupt discontinuation can lead to relapse
• Contraindications/precautions: severe cardiovascular disease, pregnancy (1st trimester), unstable renal function, dehydration, and sodium depletion
• Monitoring: check levels at steady state (5 days), before/after every dose change, and with change in other medications
• Warnings: suicide risk, nephrogenic diabetes insipidus, polyuria/polydipsia, hypercalcemia, and hyperthyroidism
• Adverse reactions: leukocytosis, dry mouth, hand tremor, confusion, vertigo, decreased memory, and EKG changes

Lithium Toxicity

• >1.2 mEq/L: nausea, diarrhea, tremor, ataxia, cognitive slowing
• >1.5 mEq/L: coarse tremor, dizziness, vomiting, diarrhea, ataxia, confusion
• >2.0 mEq/L: delirium, EEG changes, impaired renal function, arrhythmias, coma
• >2.5 mEq/L: ARF, seizures; treated with IVFs and monitoring, and dialysis if necessary

Valproic Acid

• Indicated for acute mania and maintenance treatment
• Effective serum levels: typically 50
• Adverse reactions: mild and transient LFT elevation, rare fatal hepatotoxicity, N/V/D, sedation, ataxia, tremor, weight gain, and thrombocytopenia
• Teratogenicity: neural tube defects in fetus
• DDI: weak inhibitor of CYP2C9 and CYP2C19, highly protein bound

Carbamazepine (Tegretol)

• Indicated as an anticonvulsant in lieu of lithium or valproic acid or as an adjunct
• DDI: protein bound, metabolized by liver, auto-inducer of own hepatic enzymes
• Adverse reactions: ↑ risk of SJS and TEN, HLA-B 15:02 allele in Asian ancestry, rare aplastic anemia and agranulocytosis, non-dose-related idiosyncratic hepatitis
• Pregnancy category D: risk of neural tube defects

Oxcarbazepine (Trileptal)

• Indicated as an anticonvulsant in lieu of lithium or valproic acid or as an adjunct
• No levels needed
• Adverse reactions: hyponatremia (25%), SJS (check HLA-B*15:02), ↓ estrogen OCP levels

Lamictal

• Indicated for bipolar maintenance and bipolar depression
• Dosing considerations: start low, go slow, target dose 100 mg/d
• Adverse reactions: rash, which may lead to SJS, especially in children

Mood Stabilizer Strategies

• Use a mood stabilizer in every phase of illness
• Tailor treatment to phase of illness
• Optimize proven treatments before trying unproven ones
• Renal disease: generally avoid lithium
• Liver disease: generally avoid valproate
• Sensitivity to EPS: generally avoid aripiprazole and risperidone
• Obesity: generally avoid olanzapine, quetiapine, and risperidone
• Women of childbearing age: avoid valproate