Comprehensive Guide to Antipsychotic Side Effects: Metabolic, Movement, and Hormonal Management

Introduction and philosophy of Clinical Practice

• Presenters: The session is led by Raj Mago, MD (Clinical Professor and editor of simpleandpractical.com) and Andrew Cutler, MD.

• Faculty Mentions: The faculty includes individuals such as Tom Schwartz (Chairman), Roger, Lester Trom, and David Goodman, associated with the Neuroscience Education Institute (NEI).

• Clinical Philosophy: Dr. Mago emphasizes a "simple and practical" approach to clinical psychiatry. He notes that clinical practice requires balancing the efficacy of medications against their significant side effects, which impact patient health and adherence.

Metabolic Side Effects of Second-Generation Antipsychotics (SGAs)

• Definition of Metabolic Syndrome: Often referred to visually as the "evolution to McDonald’s man," this includes three primary components:     * Weight Gain: A primary driver of other metabolic disturbances.     * Hyperglycemia: Primarily due to insulin resistance. This is monitored via serum glucose and Hemoglobin A1c ($HbA1c$), which represents a $3$-month average of glucose levels.     * Dyslipidemia: Characterized by changes in lipid profiles. Dr. Mago uses a mnemonic: LDL is "Lousy" (should be low), and HDL is "Happy" (should be high).         * The condition is termed "dyslipidemia" rather than "hyperlipidemia" because while LDL and Triglycerides go up, the "happy" HDL goes down.

• Specific Lipid Markers:     * LDL (Low-Density Lipoprotein) is considered the most important single number for cardiovascular risk.     * Triglycerides typically increase.     * Total cholesterol should generally be ignored in favor of the specific lipid fractions.

Monitoring Guidelines for Metabolic Health

• Current Practice Gap: Long-term studies indicate that most clinicians are not monitoring patients on SGAs according to established guidelines.

• Baseline and Annual Monitoring: All patients should have the following checked at baseline and at least once per year:     * Body Mass Index ($BMI$).     * Wait Circumference.     * Blood Pressure.     * Fasting Plasma Glucose or $HbA1c$.     * Fasting Lipid Profile.

• Frequent Monitoring Exceptions:     * BMI: Should be checked at every visit for the first $6$ months because early weight gain is a highly reliable predictor of long-term weight trajectors.     * Critical Threshold: A weight increase of $5\,\%$ within the first month of treatment necessitates immediate clinical action.

Risk Stratification for Weight Gain

• High-Risk Medications: Clozapine, Iloperidone, and Olanzapine.

• Low-Risk and Mitigated Options:     * Olanzapine/Samidorphan: While lower risk than Olanzapine alone, it still carries significant metabolic risk:         * $25\,\%$ of patients gain $7\,\%$ or more of their body weight within $4$ weeks.         * $25\,\%$ increase their waist circumference by $5\,cm$ or more in $6$ months.         * $42\,\%$ of patients with normal baseline glucose levels develop hyperglycemia ($HbA1c$ shifts to abnormal) within $6$ months.         * The advantage of the Samidorphan combination is that weight gain tends to level off after the initial period, which is not true for Olanzapine monotherapy.

• High-Risk Populations:     * Non-white patients.     * Children and adolescents (who are particularly sensitive to metabolic shifts and are frequently over-prescribed SGAs).     * Individuals with a higher weight at baseline. The "rich get richer" phenomenon applies: those already overweight are more likely to gain more weight on SGAs than those who are underweight.

Pharmacological Interventions for Metabolic Side Effects

Metformin

• Efficacy: Research shows it can reduce weight by approximately $7.5\,\%$. It is effective even in patients whose glucose levels are normal; clinical trials often specifically excluded diabetic patients to prove its efficacy for SGA-induced weight gain.

• Clinical Timing: It should be started early (within $1$ to $3$ months of starting an SGA) rather than waiting for significant obesity to set in.

• Contraindications: Elderly patients (typically $> 75$ years old), and those with renal failure, liver failure, or heart failure.

• Safety Precautions: Avoid heavy alcohol use due to the risk of lactic acidosis. Monitor Vitamin $B_{12}$ levels annually as Metformin can cause deficiency.

• Titration Schedule:     * Start at $500\,mg$ after the largest meal of the day (to improve GI tolerability).     * Increase by $500\,mg$ each week until a target dose of $2000\,mg$ is reached ($1000\,mg$ is often insufficient).     * Formulation Note: Extended Release (ER) typically releases lower in the GI tract (more diarrhea), whereas Immediate Release (IR) releases higher (more nausea). Switching formulations can help manage specific GI side effects.

GLP-1 Receptor Agonists

• Semaglutide (Wegovy/Ozempic): Approved for obesity and diabetes. Works by increasing satiety and blunting post-prandial sugar spikes.

• Weight Loss Data: Patients lose an average of $20-35\,lb$. Over $50\,\%$ of patients in trials lost $10-50\,\%$ of their baseline weight.

• Indications: $BMI \ge 30$ (obesity) or $BMI \ge 27$ with at least one weight-related comorbidity (e.g., high blood pressure, diabetes, dyslipidemia).

• Tirzepatide (Mounjaro): A newer agent that may offer even greater weight loss than Semaglutide.

Drug-Induced Movement Disorders (DIMDs)

• Terminology: Dr. Cutler urges clinicians to abandon the general term "EPS" (Extrapyramidal Symptoms), as it is too non-specific. Instead, clinicians should use specific diagnoses.

• Classification:     * Acute: Akathisia, Drug-Induced Parkinsonism (DIP), and Dystonia.     * Tardive (Chronic): Tardive Dyskinesia (TD), Tardive Dystonia, and Tardive Akathisia.

Clinical Management of Akathisia

• Characteristics: Defined by a subjective sense of inner restlessness. Physical signs include shuffling, leg swinging while sitting, and rocking. Sit-to-stand movements often exacerbate the urge to move.

• High-Risk Medications: Aripiprazole, Asenapine, Cariprazine, Lurasidone, and Ziprasidone (drugs with high $D_2$ affinity).

• Low-Risk Medications: Clozapine, Iloperidone, Olanzapine, Quetiapine, and Lumateperone (which showed lower risk than placebo in some trials).

• Diagnostic Tip: Low serum ferritin can mimic or worsen akathisia; check ferritin levels.

• Treatment Options:     * Propranolol: A central beta-blocker. Start at $20\,mg$ twice daily. Titrate based on blood pressure and symptomatology. Note: Atenolol is ineffective as it does not cross the blood-brain barrier.     * Benzodiazepines: Clonazepam has demonstrated evidence.     * Mirtazapine: Effective at doses $\le 15\,mg$. Doses higher than this increase norepinephrine, which can worsen akathisia.

Drug-Induced Parkinsonism (DIP): Identification and Treatment

• Symptoms: Bradykinesia (slowing), cogwheel rigidity, masked face ("reptilian stare"), resting/postural tremor, drooling (hypersalivation), and micrographia (small writing).

• Differentiation from Idiopathic Parkinson’s Disease (IPD):     * DIP is usually bilateral and symmetrical; IPD is often unilateral at onset.     * IPD has non-motor symptoms occurring years earlier: constipation (due to alpha-synuclein in the GI tract), REM sleep behavior disorder, and hyposmia (loss of smell).

• The Spiral Test: A simple monitoring tool where a patient draws a spiral. Shaky lines indicate tremor; elegant, smooth lines indicate improvement after intervention.

• Medication Risk: High risk includes Lurasidone, Paliperidone, and Risperidone. Low risk includes Clozapine and Quetiapine.

• Treatment:     * Benztropine: Dose $1-6\,mg/day$. Dosing should be in the morning or afternoon, not at bedtime, because Parkinsonian symptoms vanish during sleep.     * Trihexyphenidyl: An alternative anticholinergic.     * Amantadine: Unique because it treats both acute DIP and Tardive Dyskinesia.     * Conversion Scale: $1\,mg$ Benztropine $= 2\,mg$ Trihexyphenidyl $= 50\,mg$ Diphenhydramine.

Hyperprolactinemia: Diagnosis, Monitoring, and Management

• Thresholds for Serum Prolactin:     * Males: Up to $20\,ng/mL$.     * Females: Up to $40\,ng/mL$.     * Pregnant Females: Up to $400\,ng/mL$ ($10\times$ normal).

• Clinical Warning: Do not check prolactin routinely. Only check if the patient is symptomatic (e.g., sexual dysfunction, menstrual changes, gynecomastia, or galactorrhea).

• Proper Testing Protocol: To avoid false positives (stress-induced/transient elevations), the test must be:     * Taken in the morning.     * Performed while fasting.     * Preceded by no strenuous exercise.     * Conducted when the patient is not under acute stress/needle phobia.

• Management Strategies:     * Rule out other causes: Polycystic Ovarian Syndrome (PCOS - suggested by acne and midline hirsutism), Hypothyroidism (check TSH), and Pituitary tumors.     * Lurasidone and Olanzapine: These are NOT prolactin-sparing and fall into the moderate-to-high risk category.     * Aripiprazole Addition: The primary strategy for treating SGA-induced hyperprolactinemia. The corrective dose is $10-20\,mg$ (not "low dose") for a duration of at least $3-4$ weeks before assessing efficacy.