CNS Pharmacology — Antidepressants and Antipsychotics

Depression and Mood Disorders

• Monoamine Hypothesis: Deficiency of serotonin (5-HT), norepinephrine (NE), and/or dopamine in brain regions (prefrontal cortex, limbic system) underlies depressive symptoms
• Decreased presynaptic reuptake of monoamines leads to reduced postsynaptic receptor signaling
• Chronic antidepressant use causes downregulation of autoreceptors and increased postsynaptic receptor sensitivity (explains 2-4 week lag to therapeutic effect)
• Altered HPA axis function with elevated cortisol and CRH in depression
• Neuroinflammation and altered neuroplasticity (decreased BDNF) contribute to depressive pathology

Psychotic Disorders

• Dopamine Hypothesis: Hyperactivity in mesolimbic dopamine pathways causes positive symptoms (hallucinations, delusions)
• Hypoactivity in mesocortical dopamine pathways causes negative symptoms (apathy, reduced speech, anhedonia) and cognitive dysfunction
• Antipsychotics block D2 dopamine receptors in mesolimbic pathways, reducing positive symptoms; blockade in nigrostriatal pathways causes extrapyramidal side effects (EPSE)
• Serotonin dysfunction and glutamate abnormalities also implicated in psychosis

Major Depressive Disorder (MDD)

• Depressed mood or anhedonia (loss of pleasure) present for ≥2 weeks with ≥5 of 9 DSM-5 criteria (sleep, appetite, guilt, fatigue, concentration, psychomotor changes, suicidality, worthlessness)
• Persistent negative thoughts, hopelessness, and suicidal ideation (especially in adolescents and young adults)
• Psychomotor retardation or agitation; social withdrawal and occupational dysfunction
• May present with somatic complaints (pain, fatigue) rather than mood symptoms in some populations

Anxiety Disorders (treated with antidepressants)

• Generalized anxiety disorder (GAD): worry, restlessness, muscle tension
• Panic disorder: sudden onset panic attacks with autonomic symptoms
• Social anxiety disorder and obsessive-compulsive disorder (OCD)

Psychotic Disorders (Schizophrenia, Schizoaffective, Brief Psychotic Disorder)

• Positive symptoms: Auditory hallucinations (command hallucinations, persecutory voices), delusions (paranoid, grandiose), disorganized speech and behavior
• Negative symptoms: Flat affect, alogia (poverty of speech), avolition (lack of motivation), anhedonia
• Cognitive symptoms: Difficulty with working memory, executive function, attention
• Affective symptoms: May include depression or mania in schizoaffective disorder
• Patient often lacks insight into illness (anosognosia)

Depression

• DSM-5 criteria: ≥5 symptoms for ≥2 weeks including depressed mood or anhedonia (one must be present)
• Rule out secondary causes: Thyroid dysfunction (TSH, free T4), vitamin B12/folate deficiency, substance use, medical conditions (malignancy, endocrine disorders, neurological disease)
• Screening tools: PHQ-9 (Patient Health Questionnaire-9), HAM-D (Hamilton Depression Rating Scale)
• Assess suicidal ideation and intent; determine severity (mild, moderate, severe, with/without psychotic features)

Anxiety Disorders

• Clinical history and symptom duration; use GAD-7 or PSYCH-4 screeners
• Differentiate from medical causes (hyperthyroidism, caffeine toxicity, substance withdrawal)

Psychotic Disorders

• DSM-5 criteria: ≥2 psychotic symptoms for ≥1 month (or ≥1 month total if one symptom is bizarre) plus social/occupational dysfunction
• Rule out organic causes: Brain imaging (MRI/CT) for structural lesions, metabolic panel, drug screen, syphilis, HIV, EEG if seizure suspected
• Duration determines diagnosis: Brief psychotic disorder (<1 month), schizophreniform (<6 months), schizophrenia (≥6 months)
• Assess mood symptoms to differentiate from schizoaffective or mood disorders with psychosis

ANTIDEPRESSANTS

First-Line Agents (SSRIs/SNRIs)

• Selective Serotonin Reuptake Inhibitors (SSRIs): Block serotonin reuptake; preferred due to safety and tolerability
• Examples: sertraline (50-200 mg/day), escitalopram (10-20 mg/day), paroxetine (20-40 mg/day), fluoxetine (20-80 mg/day)
• Onset: 2-4 weeks for mood effect; 6-8 weeks for anxiety
• Side effects: Sexual dysfunction, SIADH, GI upset, activation/sedation (agent-dependent), serotonin syndrome (rare)

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Block both serotonin and norepinephrine reuptake
• Examples: venlafaxine (75-375 mg/day), duloxetine (30-120 mg/day)
• Particularly effective for pain syndromes and depression with fatigue
• Dose-dependent noradrenergic effects; hypertension risk at higher doses
• Discontinuation syndrome more common than SSRIs (use tapered withdrawal)

Second-Line Agents

• Tricyclic Antidepressants (TCAs): Block serotonin and norepinephrine reuptake; older class
• Examples: amitriptyline, nortriptyline, imipramine (150-300 mg/day typical)
• Efficacy equal to SSRIs but more side effects (anticholinergic: dry mouth, urinary retention, constipation; orthostatic hypotension; cardiac conduction delays; sedation)
• Contraindications: Cardiac conduction abnormalities, acute MI, narrow-angle glaucoma, urinary retention
• Used for: Chronic pain, neuropathy, migraine prophylaxis despite limited antidepressant indication

• Monoamine Oxidase Inhibitors (MAOIs): Block MAO enzyme; reserved for TRD (treatment-resistant depression)
• Examples: phenelzine, tranylcypromine, moclobemide (reversible MAOI)
• Major concern: Hypertensive crisis if combined with sympathomimetics, certain foods (tyramine-containing), or serotonergic agents
• Dietary restrictions required (aged cheeses, cured meats, fermented products)
• 2-week washout required before starting other serotonergic agents

• Atypical Antidepressants: Varied mechanisms
• Bupropion: Inhibits dopamine/norepinephrine reuptake; stimulating, improves cognition; no sexual dysfunction; lower seizure threshold (contraindicated in seizure disorder)
• Mirtazapine: Alpha-2 antagonist with 5-HT2A/2C antagonism; sedating; increases appetite (useful in depression with weight loss)
• Trazodone: 5-HT2A antagonist; heavily sedating; used off-label for insomnia at low doses

Treatment Approach

• Start first-line SSRI/SNRI at standard dose;

Serotonergic toxicity

• Serotonin syndrome: excess 5-HT at postsynaptic receptors, classically when an SSRI/SNRI is combined with an MAOI, linezolid, tramadol, triptans, or MDMA. Triad: autonomic instability, altered mental status, and neuromuscular hyperactivity with clonus and hyperreflexia greater in the lower extremities. Management is withdrawal of the offending agent, benzodiazepines, and cooling; cyproheptadine (5-HT2A antagonist) is the pharmacologic antidote.
• Hyponatremia/SIADH and increased GI/perioperative bleeding (impaired platelet 5-HT uptake, additive with NSAIDs/anticoagulants) are the SSRI toxicities that warrant lab and bleeding-risk monitoring, especially in the elderly.
• Discontinuation syndrome: flu-like symptoms, dizziness, "brain zaps" — worst with short half-life agents (paroxetine, venlafaxine), essentially absent with fluoxetine.

TCAs and MAOIs

• TCA overdose — the 3 C's: Coma, Convulsions, Cardiotoxicity. Fast sodium-channel blockade widens QRS; IV sodium bicarbonate is the antidote (raises extracellular Na⁺ and alkalinizes, displacing drug from the channel). Avoid physostigmine and class IA/IC antiarrhythmics.
• MAOI hypertensive crisis from tyramine-rich food or sympathomimetics; treat with a short-acting vasodilator or the alpha-blocker phentolamine. A 2-week washout (5 weeks after fluoxetine) is mandatory.
• Bupropion lowers seizure threshold — contraindicated in seizure disorder, bulimia, and anorexia.
• Trazodone: priapism (alpha-1 blockade) — a urologic emergency.

Antipsychotics

• Neuroleptic malignant syndrome: lead-pipe rigidity, hyperthermia, autonomic instability, markedly elevated CK; treat with dantrolene and dopamine agonists (bromocriptine).
• EPS timeline: acute dystonia (hours–days; benztropine/diphenhydramine), akathisia (propranolol or benzodiazepine), parkinsonism, then tardive dyskinesia (months–years; VMAT2 inhibitors valbenazine or deutetrabenazine).
• Metabolic syndrome (olanzapine, clozapine): ADA/APA consensus recommends baseline and serial weight/BMI, glucose or A1c, and lipids.
• QT prolongation (ziprasidone, IV haloperidol, thioridazine); FDA limits citalopram to 40 mg/day, 20 mg in the elderly or hepatic impairment.
• Clozapine: agranulocytosis (serial ANC monitoring per FDA labeling), myocarditis, seizures, sialorrhea, ileus.
• Boxed warnings: suicidality in patients <25 on antidepressants; increased mortality with antipsychotics in elderly patients with dementia-related psychosis.

• Clonus and hyperreflexia = serotonin syndrome; lead-pipe rigidity = NMS: this is the single most tested discrimination. Serotonin syndrome comes on within hours of a serotonergic addition and is hyperkinetic; NMS evolves over days after a D2 blocker and is hypokinetic with markedly elevated CK. Antidotes differ: cyproheptadine versus dantrolene.
• Widened QRS after an overdose in a depressed patient = TCA: best next step is IV sodium bicarbonate, not an antiarrhythmic. QRS widening — not the anticholinergic signs — predicts seizures and ventricular arrhythmia.
• Clozapine is the one agent for treatment-resistant schizophrenia (failure of two adequate antipsychotic trials) and the only one shown to reduce suicidality, per the APA schizophrenia guideline. The trade-off is agranulocytosis with mandatory ANC monitoring, plus myocarditis, seizures, and drooling in a sedated patient.
• New fever and sore throat in a patient on clozapine: check the ANC before anything else.
• Bupropion and mirtazapine spare sexual function; SSRIs, SNRIs, and TCAs do not. Bupropion also aids smoking cessation and causes weight loss, but is contraindicated with seizure disorder or an eating disorder. Mirtazapine's sedation and appetite stimulation are an advantage in the cachectic, insomniac elderly patient.
• Risperidone causes hyperprolactinemia (tuberoinfundibular D2 blockade → galactorrhea, amenorrhea, gynecomastia); olanzapine and clozapine cause the worst metabolic burden; ziprasidone prolongs QT; aripiprazole is a D2 partial agonist with the least weight gain.
• Common distractor — the 2–4 week lag: exam stems reward continuing an SSRI at an adequate dose for an adequate duration before switching or augmenting. Do not switch at week one for "no response."
• A new antidepressant in a young adult requires close follow-up for emergent suicidality (FDA boxed warning, ages <25), and screening for bipolar disorder first — an SSRI alone can precipitate mania.