CNS Drugs

Why they matter

• Ubiquity: antidepressants and benzodiazepine receptor agonists are among the most prescribed drug classes in US ambulatory practice, so their interactions appear in stems about any organ system.
• Narrow margins: lithium, phenytoin, and valproate require therapeutic drug monitoring; small pharmacokinetic perturbations (dehydration, a new CYP inducer, an NSAID) produce toxicity.
• Iatrogenic syndromes: serotonin syndrome, neuroleptic malignant syndrome, tardive dyskinesia, and benzodiazepine withdrawal seizures are drug-caused emergencies that must be recognized without a serum level.

Epidemiology worth recalling

• Major depressive disorder: the most common psychiatric indication, with a lifetime prevalence in the US of roughly one in six adults and a female-to-male ratio near 2:1; the USPSTF recommends screening all adults, including pregnant and postpartum patients, for depression.
• Schizophrenia: affects approximately 1% of the population worldwide, with onset in the late teens to twenties in men and roughly a half-decade later in women — the reason antipsychotic metabolic burden accrues over decades.
• Epilepsy: affects on the order of 1% of Americans, with a bimodal incidence peaking in young children and again after age 60; new-onset seizures in an older adult should prompt a search for stroke, tumor, or metabolic cause rather than reflexive labeling as idiopathic.
• Benzodiazepines in the elderly: the AGS Beers Criteria list benzodiazepines as potentially inappropriate in older adults because of falls, fractures, and delirium, yet prescribing in this group remains common.
• Pregnancy exposure: valproate carries the highest teratogenic risk of the common anticonvulsants, and ACOG and AAN guidance favors lamotrigine or levetiracetam in people who may become pregnant.

SSRIs

• Molecular target: selective blockade of the presynaptic serotonin transporter (SERT), raising synaptic 5-HT. The therapeutic effect tracks not with acute reuptake blockade but with desensitization of somatodendritic 5-HT1A autoreceptors, explaining the 2–6 week latency to response despite immediate transporter occupancy.
• Pharmacokinetics that change decisions: fluoxetine has the longest half-life and an active metabolite (norfluoxetine), so it self-tapers and is least likely to cause discontinuation syndrome but requires a long washout before an MAOI. Paroxetine and fluoxetine are potent CYP2D6 inhibitors (blunt tamoxifen activation, raise TCA levels); fluvoxamine inhibits CYP1A2. Sertraline and escitalopram have the cleanest interaction profiles.

Antipsychotics

• D2 blockade by pathway: mesolimbic → reduced positive symptoms; nigrostriatal → extrapyramidal symptoms; tuberoinfundibular → loss of dopaminergic inhibition of prolactin release; mesocortical → potential worsening of negative/cognitive symptoms.
• Atypicality comes from added 5-HT2A antagonism plus lower-affinity, faster-dissociating D2 binding (clozapine, quetiapine). Aripiprazole is a D2 partial agonist, which is why it raises prolactin least.

Benzodiazepines

• Bind the allosteric site between α and γ subunits of the GABA-A receptor, increasing the frequency of chloride channel opening (barbiturates increase duration). Because they require endogenous GABA, there is a ceiling effect and relative safety in isolated overdose.
• Lorazepam, oxazepam, temazepam ("LOT") undergo glucuronidation only — no oxidative metabolism, no active metabolites — making them preferred in hepatic disease and the elderly.

Anticonvulsants

• Use-dependent Na+ channel blockade: phenytoin, carbamazepine, lamotrigine. T-type Ca2+ channel blockade in thalamic neurons: ethosuximide. SV2A binding: levetiracetam. Valproate acts by multiple mechanisms.
• Phenytoin shows zero-order (saturable) kinetics; carbamazepine autoinduces its own metabolism. Phenytoin, carbamazepine, and phenobarbital induce CYP450 (failure of oral contraceptives, warfarin); valproate inhibits metabolism and doubles lamotrigine levels.

Mood and anxiety disorders

• SSRIs are first-line for major depression, generalized anxiety, panic disorder, PTSD, and OCD per the APA practice guideline for major depressive disorder; OCD characteristically requires higher doses and a longer trial (clomipramine is the TCA alternative).
• Benzodiazepines are adjuncts for panic or severe initial anxiety only while an SSRI takes effect; long-term use is discouraged, and the AGS Beers Criteria advise against them in older adults.
• Bipolar disorder: lithium or valproate for maintenance; valproate and atypical antipsychotics for acute mania. Lithium is the agent with the best evidence for reducing suicide risk.

Psychosis

• The APA 2020 schizophrenia guideline recommends an antipsychotic for all patients, with agent choice driven by side-effect profile rather than superior efficacy — except clozapine, which is indicated for treatment-resistant schizophrenia after adequate trials of two other antipsychotics and for persistent suicidality.
• Long-acting injectable formulations are recommended when nonadherence drives relapse.

Seizures

• Status epilepticus: the American Epilepsy Society guideline makes an IV benzodiazepine first-line (lorazepam IV, or midazolam 10 mg IM when no IV access in an adult), followed by a second-line agent — fosphenytoin, IV valproate, or IV levetiracetam, which performed comparably in head-to-head trial data.
• Focal seizures: levetiracetam, lamotrigine, or oxcarbazepine/carbamazepine.
• Generalized tonic-clonic: valproate or levetiracetam; lamotrigine.
• Absence: ethosuximide is first-line in childhood absence epilepsy, outperforming lamotrigine and matching valproate with fewer attentional adverse effects.
• Infantile spasms: ACTH or vigabatrin (vigabatrin preferred in tuberous sclerosis).

Other settings

• Alcohol withdrawal: symptom-triggered benzodiazepines; use lorazepam or oxazepam in cirrhosis.
• Insomnia: the AASM recommends CBT-I as first-line, with hypnotics short-term only.
• ADHD: AAP guidance supports stimulants (methylphenidate, amphetamine salts) as first-line pharmacotherapy in school-age children, with behavioral therapy first in preschoolers.

SSRIs

• Sexual dysfunction (most common cause of nonadherence), GI upset, insomnia, and SIADH-mediated hyponatremia — highest risk in elderly women on diuretics.
• Citalopram prolongs QT dose-dependently; the FDA caps the daily dose and lowers the ceiling in patients over 60, in hepatic impairment, and with CYP2C19 inhibitors.
• Bleeding risk rises with NSAIDs or antiplatelets because platelets cannot synthesize serotonin and depend on SERT-mediated uptake.
• Boxed warning: increased suicidal ideation in patients under 25 during initiation.
• Serotonin syndrome (with MAOIs, linezolid, tramadol, triptans): treat by stopping the agent, giving benzodiazepines and cooling; cyproheptadine, a 5-HT2A antagonist, is the antidote. Clonus and hyperreflexia distinguish it from the lead-pipe rigidity and bradyreflexia of NMS, which is treated with dantrolene and/or bromocriptine.

Antipsychotics

• EPS timeline: acute dystonia in hours–days (benztropine or diphenhydramine), akathisia in days–weeks (dose reduction, propranolol), parkinsonism in weeks–months, tardive dyskinesia after months–years (VMAT2 inhibitors valbenazine or deutetrabenazine).
• Metabolic syndrome with olanzapine and clozapine; the ADA/APA consensus recommends baseline and serial weight, BP, fasting glucose/A1c, and lipids.
• Clozapine: severe neutropenia requiring ANC monitoring under a REMS program, plus myocarditis, seizures, sialorrhea, and life-threatening constipation/ileus.
• Boxed warning: increased mortality when any antipsychotic is used for dementia-related psychosis.

Benzodiazepines

• Respiratory depression, especially with opioids — an FDA boxed warning on both classes. Flumazenil reverses sedation but can precipitate refractory seizures in chronic users or mixed overdose, so it is not routine.

Anticonvulsants

• Phenytoin: gingival hyperplasia, hirsutism, nystagmus/ataxia, DRESS, osteopenia; IV infusion causes hypotension and purple glove syndrome.
• Carbamazepine: agranulocytosis/aplastic anemia, SIADH; FDA advises **HLA-B*1502 testing** in patients of Asian ancestry before starting because of SJS/TEN risk.
• Lamotrigine: SJS with rapid titration or valproate co-therapy.
• Valproate: hepatotoxicity, pancreatitis, hyperammonemic encephalopathy (levocarnitine), neural tube defects.
• Lithium toxicity: hemodialysis is definitive.

• Clonus versus lead-pipe rigidity is the single discriminator examiners use: hyperreflexia with inducible clonus and diarrhea = serotonin syndrome (cyproheptadine); diffuse lead-pipe rigidity with markedly elevated CK and bradyreflexia = neuroleptic malignant syndrome (dantrolene ± bromocriptine). Both get benzodiazepines and cooling.
• Best next step in status epilepticus is an IV benzodiazepine, not a load of fosphenytoin. If no IV access, midazolam 10 mg IM in an adult. Only after adequate benzodiazepine dosing does the AES algorithm move to a second-line agent.
• Clozapine is the answer whenever a stem describes failure of two adequate antipsychotic trials, or persistent suicidality in schizophrenia — and the flu-like illness with chest pain in the first month of clozapine is myocarditis, not a viral syndrome.
• The valproate–lamotrigine interaction is the classic rash question: valproate inhibits lamotrigine glucuronidation, doubling levels and precipitating Stevens-Johnson syndrome unless the dose is halved and titration slowed.
• Phenytoin obeys zero-order kinetics — a small dose increase near saturation produces nystagmus, ataxia, and confusion. Free (unbound) phenytoin is the level to check in hypoalbuminemia or uremia.
• Lithium toxicity is usually iatrogenic: a new thiazide, ACE inhibitor, NSAID, or volume depletion reduces renal clearance. Severe toxicity is dialyzed; there is no pharmacologic antidote.
• Do not reflexively give flumazenil to an obtunded patient with suspected benzodiazepine overdose — in chronic users or mixed TCA ingestion it can unmask seizures. Supportive airway management is the answer.
• Common distractor: attributing hyperprolactinemia only to typical agents. Risperidone raises prolactin more than most typicals, while aripiprazole (D2 partial agonist) raises it least; galactorrhea plus amenorrhea in a patient on risperidone is the intended association.
• Do not use valproate in a person who could become pregnant when an alternative exists; ACOG and AAN favor lamotrigine or levetiracetam.

• Blood-brain barrier (BBB) limits drug entry; lipophilic drugs penetrate better than hydrophilic ones
• Antipsychotics block dopamine D2 receptors; atypicals have better tolerability but metabolic side effects
• SSRIs are first-line for depression/anxiety; serotonin syndrome occurs with MAOIs or tramadol co-administration
• Benzodiazepines potentiate GABA; high abuse potential and paradoxical reactions in elderly
• Antiepileptics have narrow therapeutic windows; many induce/inhibit CYP450 enzymes

• Neuroleptic malignant syndrome (NMS): fever, rigidity, autonomic instability, elevated CK after antipsychotic use
• Serotonin syndrome: agitation, tremor, hyperreflexia, hyperthermia with SSRI + MAOI
• Anticholinergic toxidrome: "hot as a hare, dry as a bone, mad as a hatter, red as a beet"
• Benzodiazepine withdrawal: seizures, tremor, autonomic hyperactivity (dangerous—taper slowly)

• Lithium drug interactions: NSAIDs and thiazides ↓ renal clearance → toxicity; ACE inhibitors also increase levels
• Antipsychotic choice: Typical agents cause more EPS; atypicals better for negative symptoms but worse metabolic profile—balance risk/benefit
• SSRI withdrawal: Abrupt discontinuation causes discontinuation syndrome (not true withdrawal), especially paroxetine; taper over weeks

• Depression: SSRIs (sertraline, citalopram) or SNRIs (venlafaxine)
• Anxiety/Panic: SSRIs or benzodiazepines (short-term only)
• Bipolar disorder: Lithium or valproate (mood stabilizers)
• Schizophrenia: Atypical antipsychotics (risperidone, olanzapine, aripiprazole)
• Seizures: Drug-specific (levetiracetam, lamotrigine—fewer interactions); phenytoin for acute seizures
• ADHD: Stimulants (methylphenidate, amphetamine) or atomoxetine