Psychopharmacology of Schizophrenia and Mood Stabilizers: Antipsychotics, Lithium, and Valproic Acid

First-Generation Antipsychotics (FGAs)

Strong D2 antagonists; treat positive symptoms; high EPS risk

Second-Generation Antipsychotics (SGAs)

D2 antagonists + 5-HT2A antagonists; treat positive + some negative symptoms; lower EPS, higher metabolic risk

Positive symptoms of schizophrenia

Hallucinations, delusions, disorganized speech

Negative symptoms of schizophrenia

Apathy, anhedonia, flat affect, social withdrawal

Dopamine hypothesis

Excess dopamine in mesolimbic pathway causes positive symptoms

Mesolimbic pathway

Overactive in schizophrenia → positive symptoms

Mesocortical pathway

Underactive → negative symptoms

Nigrostriatal pathway

D2 blockade → EPS

Tuberoinfundibular pathway

D2 blockade → ↑ prolactin

Haloperidol (Haldol)

FGA; high potency D2 blocker; high EPS risk; low anticholinergic effect

Fluphenazine (Prolixin)

FGA; high potency; high EPS

Chlorpromazine (Thorazine)

FGA; low potency; high sedation; anticholinergic; orthostasis

High-potency FGA

EPS high; sedation low; anticholinergic low

Low-potency FGA

EPS low; sedation high; anticholinergic high

Extrapyramidal Symptoms (EPS)

Dystonia, akathisia, parkinsonism, tardive dyskinesia

Acute dystonia

Muscle spasms; treat with benztropine or diphenhydramine

Akathisia

Inner restlessness; treat with propranolol

Parkinsonism

Tremor, rigidity; treat with anticholinergics

Tardive dyskinesia

Late irreversible choreiform movements; due to D2 upregulation

Neuroleptic Malignant Syndrome (NMS)

Rigidity, hyperthermia, autonomic instability; treat with dantrolene or bromocriptine

Clozapine (Clozaril)

Low D2 blockade; strong 5-HT2A block; best for treatment-resistant schizophrenia; risk agranulocytosis; REMS required

Clozapine unique risks

Agranulocytosis, myocarditis, seizures, weight gain, sialorrhea

Risperidone (Risperdal)

SDA; ↑ prolactin; dose-dependent EPS

Paliperidone (Invega)

Active metabolite of risperidone; ↑ prolactin

Olanzapine (Zyprexa)

High metabolic risk; weight gain; diabetes risk

Quetiapine (Seroquel)

Sedating; low EPS; used in bipolar depression

Ziprasidone (Geodon)

QT prolongation risk; lower metabolic risk

Aripiprazole (Abilify)

Partial D2 agonist; lower EPS; lower prolactin

Lurasidone (Latuda)

Used in bipolar depression; lower metabolic risk

Asenapine (Saphris)

Sublingual; bipolar disorder

Iloperidone (Fanapt)

QT prolongation risk

Brexpiprazole (Rexulti)

Partial D2 agonist

Cariprazine (Vraylar)

Partial D2/D3 agonist; bipolar disorder

SGA metabolic syndrome

Weight gain, hyperlipidemia, diabetes

Highest metabolic risk SGAs

Clozapine, olanzapine

Highest prolactin SGAs

Risperidone, paliperidone

Black Box Warning (Antipsychotics)

Increased mortality in elderly patients with dementia-related psychosis

Lithium (Lithobid, Eskalith)

Mood stabilizer; inhibits inositol monophosphatase; ↓ IP3 signaling; modulates second messenger systems

Lithium therapeutic level

0.6-1.2 mEq/L

Lithium toxicity level

>1.5 mEq/L

Lithium severe toxicity

>2.5 mEq/L

Lithium acute toxicity

Nausea, vomiting, diarrhea

Lithium chronic toxicity

Tremor, confusion, ataxia, seizures

Lithium monitoring

Renal function, thyroid function, levels

Lithium adverse effects

Hypothyroidism, nephrogenic diabetes insipidus, tremor, weight gain

Lithium teratogenic risk

Ebstein anomaly

Drugs that increase lithium levels

Thiazides, ACE inhibitors, NSAIDs

Lithium toxicity treatment

Hemodialysis if severe

Valproic Acid (Depakote)

Mood stabilizer; ↑ GABA; blocks Na+ channels; hepatotoxic; teratogenic

Carbamazepine (Tegretol)

Blocks Na+ channels; CYP inducer; agranulocytosis risk

Lamotrigine (Lamictal)

Blocks Na+ channels; bipolar depression; risk Stevens-Johnson syndrome

Oxcarbazepine (Trileptal)

Similar to carbamazepine; less enzyme induction

Valproate adverse effects

Hepatotoxicity, pancreatitis, neural tube defects

Carbamazepine adverse effects

Agranulocytosis, hyponatremia

Lamotrigine titration

Slow titration to avoid SJS

Bipolar I disorder

Manic episodes ± depression

Acute mania treatment

Lithium, valproate, antipsychotics

Bipolar depression treatment

Lamotrigine, quetiapine, lurasidone

Mechanism difference FGA vs SGA

FGA strong D2 block; SGA D2 + 5-HT2A block

Why SGAs cause less EPS

5-HT2A blockade increases dopamine in nigrostriatal pathway

Why D2 blockade causes hyperprolactinemia

Blocks dopamine inhibition of prolactin release

Tardive dyskinesia mechanism

Chronic D2 blockade → receptor upregulation

Clozapine monitoring

Weekly ANC initially

Mood stabilizer for suicide reduction

Lithium

Antipsychotic depot formulations

Long-acting injectables for adherence

QT prolongation antipsychotics

Ziprasidone, iloperidone

Most sedating antipsychotic

Clozapine, quetiapine

Least EPS antipsychotic

Clozapine, quetiapine

Highest EPS risk

Haloperidol, fluphenazine

Neuroleptic vs Serotonin syndrome

NMS slow onset rigidity; serotonin syndrome hyperreflexia + clonus