Pharmacology Recent Advances

Study Notes

Comprehensive Study Notes

SECTION 1: NEWER ANTIDEPRESSANTS

1.1 Vortioxetine (Multimodal Antidepressant)

Class: Serotonin modulator and stimulator (SMS)

Brand: Trintellix

Approved: FDA 2013 for Major Depressive Disorder (MDD)

Mechanism of Action: The Multimodal Profile

Vortioxetine is unique because it acts at multiple serotonin receptor subtypes simultaneously, not just as a reuptake inhibitor.

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Pharmacokinetics

• Oral bioavailability: ~75%
• Protein binding: >98%
• Metabolism: CYP2D6 primary; also CYP3A4/5, CYP2C19
• Half-life: ~66 hours (allows once-daily dosing)
• Dose: 5–20 mg/day
• No dose adjustment for renal impairment; caution in hepatic impairment

Clinical Evidence

• FOCUS trial and CONNECT trial: Demonstrated cognitive benefits beyond mood improvement
• Meta-analyses show moderate superiority over placebo on MADRS
• Cognitive benefits (processing speed, executive function) shown in multiple RCTs
• VORTEX study: Comparable efficacy to duloxetine with better tolerability

Distinguishing Features

• Cognitive benefits, superior to placebo and comparable/better than other ADs on neurocognition
• Sexual dysfunction, significantly lower rates than SSRIs/SNRIs (~25% vs ~60%)
• Weight neutral, minimal weight gain
• No significant QTc prolongation
• No discontinuation syndrome (long half-life)

Side Effects

• Nausea (most common, dose-dependent), usually transient
• Constipation, vomiting
• Vivid dreams at higher doses
• Pruritus (itching), unique to vortioxetine, mechanism unclear

Dose Titration Strategy

• Start 5–10 mg/day
• Increase to 20 mg after 2–4 weeks if tolerated
• CYP2D6 poor metabolizers: max 10 mg/day
• Strong CYP2D6 inhibitors (paroxetine, fluoxetine): halve the dose

1.2 Vilazodone

Class: Serotonin partial agonist and reuptake inhibitor (SPARI)

Brand: Viibryd

Approved: FDA 2011 for MDD

Mechanism

• SERT inhibitor (like SSRIs)
• 5-HT1A partial agonist (like buspirone)
• The 5-HT1A partial agonism may explain faster onset and reduced anxiety/insomnia at initiation

Pharmacokinetics

• Must be taken with food (bioavailability increases 147–160% with food)
• Half-life: ~25 hours
• CYP3A4 metabolism
• Dose: 10 mg x 7 days → 20 mg x 7 days → 40 mg maintenance

Clinical Profile

• Comparable efficacy to SSRIs on HAMD-17 and MADRS
• Lower rates of sexual dysfunction compared to SSRIs
• Lower rates of weight gain
• Nausea and diarrhea common (GI adverse effects)

Key Differentiator from Vortioxetine

• Vilazodone: SPARI (SERT + 5-HT1A partial agonist)
• Vortioxetine: SMS (SERT + multiple 5-HT receptor modulation)
• Vilazodone has NO 5-HT3 antagonism, 5-HT7 antagonism
• Vilazodone REQUIRES food for absorption

1.3 Esketamine / Intranasal Ketamine

Background

Ketamine (a racemic mixture) has been used off-label for treatment-resistant depression (TRD) since ~2000. Esketamine is the S-enantiomer, more potent at NMDA receptors.

Brand: Spravato (intranasal esketamine)

FDA Approval: 2019 for TRD; 2020 for MDD with acute suicidal ideation or behavior (MDSI)

Mechanism of Action

Primary: NMDA (N-methyl-D-aspartate) receptor antagonism

• Blocks glutamate binding at NMDA receptors
• Rapid disinhibition of downstream glutamatergic activity
• Surge of AMPA receptor activation → BDNF release → synaptic plastogenesis

The AMPA surge hypothesis:

Additional mechanisms:

• Opioid receptor modulation (controversial, recent data suggests partial role)
• GABA-A modulation
• HCN1 channel blockade (explains analgesic effects)

REMS (Risk Evaluation and Mitigation Strategy)

REMS requirements:

1. Only dispensed in certified healthcare settings, not at pharmacy
2. Patient must be monitored for 2 hours after each administration
3. Monitoring for: dissociation, sedation, blood pressure changes, abuse
4. Patient cannot drive on day of administration
5. Healthcare setting must enroll in REMS program
6. ETASU (Elements To Assure Safe Use) components

Administration Protocol

• Intranasal delivery (84 mg device = 2 devices × 28 mg each)
• Doses: 56 mg or 84 mg
• Induction phase: Twice weekly for 4 weeks
• Maintenance phase 1: Once weekly for 4 weeks
• Maintenance phase 2: Once weekly or every 2 weeks

Clinical Evidence

• TRANSFORM-2 trial: Significant improvement in MADRS vs placebo intranasal + standard-of-care AD
• SUSTAIN-1 trial: Maintenance of remission, reduced relapse rates
• Onset of action: Within hours to days (vs weeks for conventional ADs)

Side Effects

Contraindications

• Aneurysmal vascular disease (risk of BP spikes)
• Arteriovenous malformation
• History of intracerebral hemorrhage
• Current psychosis (worsens dissociation)
• Hypersensitivity to ketamine/esketamine

Ketamine vs Esketamine

1.4 Brexanolone (Postpartum Depression)

Brand: Zulresso

FDA Approval: 2019, first drug specifically approved for postpartum depression (PPD)

Class: Neuroactive steroid / GABA-A receptor positive allosteric modulator (PAM)

Mechanism

The peripartum hormone crash:

• During pregnancy: allopregnanolone (progesterone metabolite) levels rise dramatically
• After delivery: abrupt fall → triggers PPD in vulnerable individuals
• Brexanolone = synthetic allopregnanolone

Mechanism: Positive allosteric modulation of both synaptic and extrasynaptic GABA-A receptors

• Synaptic GABA-A (γ2-containing): phasic inhibition
• Extrasynaptic GABA-A (δ-containing): tonic inhibition, critical for brexanolone's unique mechanism

Clinical Features

• Continuous IV infusion over 60 hours (2.5 days)
• Administered in certified healthcare facility (REMS program)
• Rapid onset: significant improvement within 24–48 hours
• Sustained effect: response maintained at 30-day follow-up

REMS Program

• Risk of excessive sedation and sudden loss of consciousness
• Monitor oxygen saturation continuously
• Patient must be accompanied home

Limitations

• IV only, impractical for widespread use
• Cost: ~$34,000 per treatment course
• Zuranolone (oral formulation) now available, FDA approved 2023, first oral neuroactive steroid for MDD and PPD

Zuranolone (Zurzuvae):

• Oral, 30 mg or 50 mg nightly for 14 days
• Same GABA-A PAM mechanism
• Does NOT require REMS
• First oral neuroactive steroid approved

1.5 Dextromethorphan-Bupropion (Auvelity)

Brand: Auvelity

FDA Approval: 2022 for MDD, first new MDD mechanism in decades

Components

1. Dextromethorphan (DXM): Uncompetitive NMDA antagonist + sigma-1 receptor agonist
2. Bupropion: CYP2D6 inhibitor (increases DXM levels) + NDRI

Why the Combination?

• Dextromethorphan alone is rapidly metabolized by CYP2D6 (extensive metabolizers)
• Bupropion inhibits CYP2D6 → increases DXM levels 8-fold → therapeutic concentrations achieved
• Bupropion also contributes antidepressant activity independently

Mechanism

• NMDA antagonism → similar to ketamine pathway (AMPA surge, BDNF, synaptogenesis)
• Sigma-1 agonism → neuroprotection, neuroplasticity
• NDRI component → dopaminergic/noradrenergic antidepressant effect

Clinical Evidence

• GEMINI trial: 45 mg/105 mg twice daily significantly improved HAMD-17 at week 6 vs placebo
• Faster onset than typical ADs (significant benefit by week 1)
• Response rates: ~54% vs ~34% placebo

Dosing

• Start: 45 mg DXM/105 mg bupropion once daily for 3 days
• Increase to twice daily thereafter

Side Effects

• Dizziness, headache, diarrhea, somnolence
• Risk of dissociation (lower than esketamine)
• No REMS required
• Abuse potential of DXM, schedule uncontrolled currently

1.6 Gepirone (Exxua)

Class: 5-HT1A partial agonist (azapirone, like buspirone)

FDA Approval: 2023 for MDD (after multiple prior rejections)

Mechanism

• Selective 5-HT1A partial agonist, no SERT inhibition
• Pre-synaptic autoreceptor agonism → anxiolytic
• Post-synaptic 5-HT1A agonism → antidepressant

Key Features

• No sexual dysfunction
• No weight gain
• No discontinuation syndrome
• Extended-release formulation, once daily
• Absence of significant drug interactions compared to SSRIs

Clinical Evidence

• Multiple trials showing efficacy in MDD
• Delayed approval due to concerns about effect size consistency
• Approved for patients who require antidepressant therapy without sexual side effects

SECTION 2: NEWER ANTIPSYCHOTICS

2.1 Lumateperone (Caplyta)

FDA Approval: 2019 for schizophrenia; 2021 for bipolar depression (both I and II)

Mechanism: Truly novel, simultaneous modulator of dopamine, serotonin, and glutamate

Mechanism of Action

Pharmacokinetics

• Dose: 42 mg once daily (at bedtime with or without food)
• Half-life: ~18 hours
• CYP3A4 primary metabolism
• No dose titration required

Clinical Profile

• Minimal weight gain, weight-neutral in trials
• Minimal metabolic effects, no significant glucose/lipid changes
• Low EPS, very low extrapyramidal burden
• Low sedation at therapeutic doses
• Prolactin-sparing, does not raise prolactin

Unique Indication: Bipolar Depression

• One of few antipsychotics with evidence for BOTH schizophrenia AND bipolar depression
• Effective in bipolar I and bipolar II depression (most drugs only approved for bipolar I)

2.2 Pimavanserin (Nuplazid)

FDA Approval: 2016, first drug approved specifically for Parkinson's Disease Psychosis (PDP)

Class: 5-HT2A inverse agonist/antagonist; 5-HT2C inverse agonist

Why Pimavanserin for PDP?

Traditional antipsychotics block D2 receptors. In Parkinson's, dopaminergic pathways are already depleted, D2 blockade worsens motor symptoms catastrophically.

Pimavanserin:

• No D2 binding, does not worsen motor symptoms
• Selective 5-HT2A/2C inverse agonism, reduces psychotic symptoms via serotonergic pathway

Mechanism

• Inverse agonist at 5-HT2A, constitutively active receptors are silenced even without serotonin
• Different from antagonist: reduces basal activity below baseline, not just blocks incoming signal

Clinical Evidence

• ACP-103-020 trial: Significant reduction in SAPS-PD (Scale for Assessment of Positive Symptoms in PDP)
• Improved neuropsychiatric inventory (NPI) scores
• No worsening of UPDRS motor scores

Limitations and Safety

• FDA Black Box Warning: Increased mortality in elderly with dementia-related psychosis
• QTc prolongation, avoid with other QTc-prolonging agents
• Dose: 34 mg once daily
• No dose titration required

Extended Use

• Investigated for Alzheimer's Disease Agitation (ADVANCE trial, negative primary endpoint but secondary benefits)
• Combination with citalopram studied for dementia-related psychosis

2.3 Cariprazine (Reagila/Vraylar)

FDA Approval: 2015 for schizophrenia and bipolar I disorder (mania and depression)

Class: Partial agonist at D2, D3, and 5-HT1A; antagonist at 5-HT2A, 5-HT2B

The D3 Distinction

This is the defining feature of cariprazine.

Why does D3 matter?

• D3 receptors are concentrated in: mesolimbic system, prefrontal cortex, hippocampus
• D3 modulation → improved negative symptoms of schizophrenia
• D3 involved in reward processing, motivation, cognition
• Cariprazine's D3 selectivity is the proposed mechanism for its unique efficacy on negative symptoms

Clinical Evidence

Negative symptoms:

• PANSS-ND (negative symptoms subscale) improved vs risperidone in RCTs
• Statistically significant superiority to risperidone on PANSS negative symptom factor scores
• RGH-MD-16 study: Cariprazine 3–6 mg vs risperidone, negative symptom advantage confirmed

Bipolar depression:

• Multiple RCTs showing efficacy on MADRS
• Unique among antipsychotics: efficacious at LOW doses (1.5 mg) for bipolar depression vs higher doses for mania

Pharmacokinetics

• Active metabolite: DCAR (desmethyl-cariprazine) with similar pharmacology
• Active metabolite: DDCAR (didesmethyl-cariprazine), very long half-life (~1–3 weeks)
• Total effective half-life: 2–4 weeks
• Implication: After discontinuation, pharmacological effect persists for weeks

Dosing

• Schizophrenia: 1.5–6 mg/day
• Bipolar mania: 3–6 mg/day
• Bipolar depression: 1.5–3 mg/day (lower than mania)

Side Effects

• Akathisia, highest among newer APs
• Weight gain, moderate (less than olanzapine/clozapine)
• Metabolic: moderate
• Minimal prolactin elevation (partial agonist)

2.4 Brexpiprazole (Rexulti)

FDA Approval: 2015 for schizophrenia and adjunctive treatment of MDD

2023 Approval: Agitation associated with Alzheimer's dementia (first drug for this indication)

Class: Serotonin-dopamine activity modulator (SDAM)

Mechanism

Key comparison with aripiprazole:

• Brexpiprazole: LOWER intrinsic activity at D2 (more antagonist-like behavior)
• Lower risk of akathisia than aripiprazole
• More potent 5-HT1A partial agonism

Alzheimer's Dementia Agitation

• RAISE trial: Brexpiprazole 2–3 mg significantly reduced CMAI agitation scores
• First FDA approval specifically for this indication
• Important caveat: Still carries dementia-related mortality warning

Adjunctive MDD

• Add-on to SSRI/SNRI in partial responders
• Doses: 1–3 mg/day (lower than for schizophrenia)

2.5 Long-Acting Injectable Antipsychotics (LAIs)

Why LAIs Matter

• Non-adherence is the #1 cause of relapse in schizophrenia
• ~50% of patients are non-adherent within 1 year of discharge
• LAIs bypass the daily decision to take medication
• Eliminates covert non-adherence
• Continuous therapeutic blood levels without peaks/troughs

Paliperidone Palmitate 3-Monthly (PP3M / Invega Trinza)

PP3M requirements:

• Must be adequately treated with PP1M for at least 4 months
• Last two PP1M doses must be same dose (stable)
• PP3M dose = 3.5x the PP1M dose

Paliperidone palmitate 6-monthly (PP6M / Invega Hafyera):

• FDA approved 2021
• Every 6 months injection
• Gluteal only

Aripiprazole Lauroxil (Aristada)

Initiation strategy (NCD, No Confirmation Day):

• Aristada Initio 675 mg (deltoid) + oral aripiprazole 30 mg on same day
• Followed by regular Aristada the next day
• Avoids the 21-day wait for oral overlap

SECTION 3: NEWER ANXIOLYTICS AND HYPNOTICS

3.1 Orexin Receptor Antagonists (DORAs)

The Orexin System

Orexins (hypocretins 1 and 2) are neuropeptides produced in the lateral hypothalamus. They are wake-promoting neurotransmitters.

DORA mechanism: Block both OX1R and OX2R simultaneously → "turn off" the wake drive → natural sleep architecture preserved

Contrast with older hypnotics:

• Benzodiazepines and Z-drugs: enhance GABA inhibition (suppress all brain activity)
• DORAs: specifically suppress wake-promoting drive only

Suvorexant (Belsomra)

FDA Approval: 2014

Doses: 5, 10, 15, 20 mg (usual: 10–20 mg)

Schedule: Schedule IV controlled substance

Mechanism: Dual OX1R + OX2R antagonist

Clinical Profile:

• Reduces sleep onset latency and wake after sleep onset (WASO)
• Preserves sleep architecture (REM, SWS proportions maintained)
• Less residual sedation than benzodiazepines
• No rebound insomnia upon discontinuation (key differentiator)

Side Effects:

• Somnolence, abnormal dreams
• Sleep paralysis, hypnagogic/hypnopompic hallucinations
• Cataplexy-like symptoms (rare, dose-dependent)
• Next-day impairment, warn about driving

Drug Interactions:

• Strong CYP3A4 inhibitors: reduce dose to 5 mg (ketoconazole, clarithromycin)
• CYP3A4 inducers: reduce efficacy (rifampin, carbamazepine)

Lemborexant (Dayvigo)

FDA Approval: 2019

Doses: 5 mg and 10 mg

Differences from suvorexant:

• Higher binding affinity at OX2R (more selective wake-off switch)
• Longer half-life: ~17–27 hours (suvorexant ~12 hours)
• Better sleep maintenance data in elderly
• SUNRISE-1 and SUNRISE-2 trials vs placebo + SUNRISE-2 vs zolpidem
• Lemborexant 5 mg showed better subjective sleep parameters than zolpidem at 1 month

Side Effects:

• Similar to suvorexant
• Somnolence, headache
• Caution: complex sleep behaviors (sleepwalking, sleep driving), black box warning added for all Z-drugs and now DORAs

Daridorexant (Quviviq)

FDA Approval: 2022

Doses: 25 mg and 50 mg

Key features:

• Shortest half-life among approved DORAs (~8 hours)
• Least next-day sedation, specifically designed for daytime functioning
• ESADA-1 and ESADA-2 trials: Improved subjective and objective sleep parameters + daytime functioning scores
• No dose adjustment for CYP3A4 interactions at approved doses (unlike suvorexant)

SECTION 4: PSYCHEDELICS IN PSYCHIATRY

4.1 Psilocybin

Source: Psilocybe cubensis and related mushrooms

Active metabolite: Psilocin (after dephosphorylation by alkaline phosphatase)

Mechanism of Action

• Primary: 5-HT2A agonist, binding in prefrontal cortex, thalamus, limbic system
• Secondary: 5-HT2C, 5-HT1A activity
• No direct effects on dopamine system

Neural effects of 5-HT2A agonism:

1. Disruption of thalamo-cortical gating → enhanced sensory processing → hallucinations
2. Default Mode Network (DMN) disruption → ego dissolution
3. Increased global brain connectivity, "hyperconnected" brain state
4. Neuroplasticity induction via BDNF and mTOR pathways

Clinical Trials

Treatment-Resistant Depression (TRD):

• COMPASS Pathways Phase 2b (COMP360):
• 25 mg psilocybin (single dose) → significant response at 3 weeks
• Rapid, sustained antidepressant effect
• ~29% remission at 3 weeks with 25 mg dose
• Adverse effects: headache, nausea, dizziness, transient anxiety during session

Major Depression:

• Johns Hopkins study (2021, JAMA Psychiatry):
• 2 sessions of psilocybin (20 mg + 30 mg, 1 week apart)
• ~71% response, ~54% remission at 4 weeks
• Maintained at 1-year follow-up

Existential Distress (Cancer):

• NYU and Johns Hopkins trials (2016):
• Single-dose psilocybin in cancer patients with anxiety/depression
• Dramatic, sustained reductions in existential distress
• ~60–80% meeting criteria for clinically significant antidepressant response at 6 months

Alcohol and Smoking Cessation:

• Pilot studies showing promise, larger RCTs ongoing

Regulatory Status

• Schedule I in US, India, no accepted medical use currently
• FDA granted Breakthrough Therapy Designation for:
• Psilocybin for TRD (COMPASS Pathways, 2018)
• Psilocybin for MDD (Usona Institute, 2019)
• Australia: ARTG approved psilocybin for TRD (July 2023), first country to reschedule for medical use

Set and Setting

• Therapeutic psilocybin is not standalone, it is psilocybin-assisted psychotherapy
• Preparation sessions (psychotherapy)
• Drug sessions (monitored, therapist present)
• Integration sessions (processing experience)
• Physical environment matters: comfortable room, music, eye shades

Safety Profile

• Non-addictive, no withdrawal syndrome, no physical dependence
• Low abuse potential (tolerance develops rapidly to self-limiting)
• Transient adverse effects: headache, nausea, transient anxiety, confusion
• Serious risks: Challenging experiences ("bad trips"), managed with therapist presence
• Contraindications: Personal/family history of psychosis, schizophrenia, bipolar I (manic episodes), unstable cardiovascular disease
• HPPD (Hallucinogen Persisting Perception Disorder), rare

4.2 MDMA-Assisted Therapy for PTSD

Full name: 3,4-methylenedioxymethamphetamine

Schedule I (US), Breakthrough Therapy Designation (2017) for PTSD

Mechanism of Action

• Primary: Releases serotonin (massive), dopamine, and norepinephrine from presynaptic terminals
• Inhibits reuptake of all three monoamines
• Oxytocin release, social bonding hormone
• Net effect: Empathic, prosocial state with reduced fear response

Why MDMA is uniquely suited for PTSD:

• Fear extinction is impaired in PTSD (amygdala hyperactivation)
• MDMA: reduces amygdala reactivity to threat
• MDMA: increases prefrontal cortical control
• MDMA: creates a state of openness, trust, reduced defensiveness
• Allows trauma processing without the normal overwhelming fear response

Clinical Evidence

• MAPS Phase 3 trials (MAPP1 and MAPP2):
• 71% of MDMA group no longer met PTSD diagnostic criteria at 18-week primary endpoint
• 48% in placebo group lost PTSD diagnosis
• Response rates: ~67% (MDMA) vs ~32% (placebo)
• Well-tolerated: transient nausea, jaw clenching, insomnia on dosing night

Regulatory Status (2024)

• FDA advisory committee voted against approval (June 2024), concerns about functional unblinding and trial design
• FDA declined to approve (August 2024), requested additional Phase 3 trial
• Not currently approved
• Australia: TGA approved for PTSD treatment (July 2023), first country

Protocol

• 3 MDMA sessions (80–120 mg doses) over ~18 weeks
• Each session 8 hours long
• Therapist dyad (male + female co-therapists recommended by MAPS)
• Extensive preparation and integration therapy

4.3 Ketamine Clinics

Status: Legal, operating in US and India

Administration: IV infusion (most common), IM, intranasal (compounded)

Typical protocol:

• Series of 6 infusions over 2–3 weeks
• 0.5 mg/kg IV over 40 minutes
• Maintenance infusions as needed (monthly, bimonthly)

Indications:

• Treatment-resistant depression
• PTSD (off-label)
• Chronic pain / CRPS
• OCD (emerging data)

Limitations:

• Not standardized (dose, frequency, preparation)
• No regulatory oversight for non-REMS ketamine infusions
• Short duration of effect (days to weeks), necessitates repeat infusions
• Cost: $400–800 per infusion, not usually insured

4.4 Microdosing

Definition: Sub-perceptual doses (1/10th to 1/20th of a full dose)

• Psilocybin: 0.1–0.3 g dried mushroom or ~1–3 mg psilocybin
• LSD: 5–15 mcg (full dose 100–200 mcg)

Proposed benefits (largely anecdotal):

• Improved focus, creativity, mood
• Reduced anxiety
• No psychedelic effects

Evidence base:

• Mostly observational studies and self-reports
• RCTs difficult due to legality
• Imperial College London PNAS study (2021): Microdosing improved well-being, mindfulness scores, but expectation effects (placebo) could explain results
• No RCT-level evidence for clinical use

Regulatory status: Illegal in most jurisdictions including India

4.5 Regulatory Landscape Summary

SECTION 5: PRECISION PSYCHIATRY

5.1 Pharmacogenomics

Definition: How genetic variation affects drug metabolism, efficacy, and adverse effects

CYP450 Enzyme Polymorphisms

CYP2D6, most clinically relevant in psychiatry

Key CYP2D6 substrates in psychiatry:

• Antidepressants: fluoxetine, paroxetine, vortioxetine, nortriptyline, clomipramine, desipramine
• Antipsychotics: haloperidol, perphenazine, risperidone, aripiprazole
• Note: Fluoxetine and paroxetine are BOTH substrates AND inhibitors of CYP2D6

CYP2C19

Key CYP2C19 substrates:

• Citalopram, escitalopram (higher levels in PMs, QTc concern)
• Sertraline
• Diazepam, clonazepam
• Venlafaxine

HLA-B*1502 and Carbamazepine:

• Carriers of HLA-B*1502 allele at dramatically increased risk of Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) with carbamazepine
• Frequency: ~10% in Han Chinese, Thai, Filipino
• MANDATORY testing before carbamazepine initiation in patients of Asian ancestry
• FDA label requires this testing
• National Institute of Mental Health India guidelines echo this recommendation

HLA-A*3101:

• Carbamazepine hypersensitivity in European and Japanese populations
• Associated with SJS, DRESS, maculopapular exanthema

HLA-B*5701 and Abacavir:

• Not psychiatric but important model, HIV drug causing hypersensitivity

Pharmacogenomic Testing: Clinical Use

GeneSight and similar commercial panels:

• Tests: CYP2D6, CYP2C19, CYP2C9, CYP1A2, SLC6A4 (5-HTTLPR), MTHFR, HTR2A
• Color-coded report: Use as directed / Use with caution / Use with caution and more frequent monitoring / Not recommended

Limitations:

• Evidence for clinical utility is mixed
• PRIME Care trial (2022): GeneSight testing did not significantly improve HAMD-17 outcomes vs treatment as usual in primary care MDD
• GUIDED trial (2019): Positive results for GeneSight in MDD
• Not routinely recommended by NICE/APA guidelines currently

5.2 Therapeutic Drug Monitoring (TDM)

Indications for TDM in psychiatry:

1. Suboptimal response at adequate doses
2. Suspected non-adherence
3. Suspected toxicity despite therapeutic doses
4. Polypharmacy with potential interactions
5. Special populations (pregnancy, renal/hepatic disease, elderly)
6. Drugs with narrow therapeutic windows

5.3 Biomarker-Guided Treatment

Current approaches:

1. HPA axis markers: Cortisol non-suppression on DST → may predict antidepressant response
2. Inflammatory markers: High CRP (>1 mg/L) → may prefer anti-inflammatory antidepressants; low CRP → may prefer serotoninergic
3. EEG biomarkers: Alpha-wave asymmetry, theta-wave patterns, investigational
4. Neuroimaging: Anterior cingulate cortex activity on fMRI/PET → predict response to CBT vs medication

CANMAT recommendations: Biomarker-guided treatment not yet standard of care, promising but needs more RCT evidence

5.4 Computational Psychiatry

Definition: Application of mathematical models and computational algorithms to understand brain function, mental illness, and treatment prediction

Key concepts:

1. Predictive Coding / Active Inference: Brain as Bayesian inference machine, mental illness = aberrant precision-weighting of prediction errors
2. Reinforcement Learning Models: Anhedonia, addiction modeled as disrupted reward learning
3. Dynamic Causal Modeling: Inferring effective connectivity from fMRI data

Clinical applications (emerging):

• Digital phenotyping (smartphone data) to predict relapse
• Machine learning to predict treatment response
• Network analysis of symptom dimensions

SECTION 6: SEROTONIN SYNDROME

6.1 Pathophysiology

Serotonin syndrome results from excess serotonergic activity at central and peripheral 5-HT receptors.

Receptors involved:

• 5-HT1A: Agitation, tachycardia, hypertension, diaphoresis, hyperthermia
• 5-HT2A: Clonus, hyperreflexia, rigidity (mild), myoclonus, temperature dysregulation (severe)

The triad:

6.2 Hunter Criteria (Diagnostic Standard)

The Hunter Serotonin Toxicity Criteria are the most accurate clinical diagnostic criteria.

Requirement: Serotonergic drug must be present PLUS one of the following:

1. Spontaneous clonus
2. Inducible clonus + (agitation OR diaphoresis)
3. Ocular clonus + (agitation OR diaphoresis)
4. Tremor + hyperreflexia
5. Hypertonia + temperature >38°C + ocular or inducible clonus

Sensitivity: 84% Specificity: 97% (vs Sternbach criteria)

6.3 Culprit Drug Classes

Highest risk combination: MAOI + SSRI/SNRI, potentially fatal

6.4 Clinical Features

Onset: Rapid, within 24 hours of drug initiation/increase/combination (typically within 6 hours)

Course: Usually resolves within 24–72 hours if causative drug stopped

6.5 Management

Step 1: Discontinue all serotonergic drugs

Step 2: Supportive care (IV fluids, cooling measures, benzodiazepines for agitation)

Step 3: Cyproheptadine (5-HT antagonist), 12 mg loading, 2 mg every 2 hours PRN

Step 4: Severe cases: ICU admission, intubation for airway, neuromuscular paralysis

Cyproheptadine:

• H1 antihistamine with 5-HT2A antagonism
• NOT available IV, oral/NG only
• Evidence base: case reports and series, no RCTs
• Alternative: Chlorpromazine (5-HT2A antagonist, but risk of hypotension/seizure threshold lowering)

SECTION 7: NEUROLEPTIC MALIGNANT SYNDROME (NMS)

7.1 Definition and Pathophysiology

NMS is an idiosyncratic, potentially life-threatening reaction to antipsychotic drugs (and other dopamine antagonists).

Pathophysiology:

• Abrupt D2 receptor blockade in:
• Striatum → rigidity, EPS
• Hypothalamus → hyperthermia
• Mesocortex/mesolimbic → cognitive changes

Predisposing factors:

• High-potency typical antipsychotics (haloperidol most associated)
• Rapid dose increase
• IM depot injections
• Dehydration
• Agitation, physical restraint
• Prior NMS episode (10–15x increased risk)
• Young male patients
• Brain pathology (dementia, Parkinson's)

7.2 Clinical Features: FEVER + RIGIDITY Mnemonic

Lab findings:

• Elevated CK (diagnostic hallmark), >1000 U/L typical
• Leukocytosis (WBC 10,000–40,000)
• Metabolic acidosis
• Elevated LFTs
• Myoglobinuria → renal failure risk
• Low serum iron (<12 μmol/L), specific for NMS

Onset: Slower than SS, hours to days after starting/changing antipsychotic

Duration: Without treatment: 1–2 weeks; with DAergic agonists: shorter

7.3 SS vs NMS vs Malignant Catatonia vs Malignant Hyperthermia

7.4 NMS Management

Immediate:

1. Stop antipsychotic
2. Supportive care: hydration, cooling, monitoring
3. Benzodiazepines for rigidity and agitation

Pharmacological:

1. Dantrolene (0.25–2 mg/kg IV q6h): Blocks calcium release from SR → reduces muscle rigidity and hyperthermia
2. Bromocriptine (2.5–5 mg TID): D2 agonist → reverses dopamine blockade
3. Amantadine (100 mg BD): NMDA antagonist + dopaminergic properties

ECT: For refractory NMS and malignant catatonia (can be diagnostically confounding)

Re-challenge with antipsychotic:

• Wait minimum 2 weeks after NMS resolution
• Start with low-potency atypical antipsychotic (clozapine, quetiapine)
• Low doses, gradual titration
• Avoid precipitating factors (dehydration, IM depot)
• Close monitoring

SECTION 8: DRUG INTERACTIONS IN PSYCHIATRY

8.1 Pharmacokinetic Interactions

CYP450-Mediated Interactions

Major CYP450 enzymes in psychiatry:

Smoking and CYP1A2:

Fluvoxamine as CYP1A2 inhibitor:

• Fluvoxamine strongly inhibits CYP1A2
• Combined with clozapine → clozapine levels increase 2–10 fold
• Can cause clozapine toxicity even at normal doses
• Some clinicians use low-dose fluvoxamine to increase clozapine levels in treatment-resistant cases (intentional interaction)

P-glycoprotein (P-gp) Interactions

• P-gp is an efflux transporter in the blood-brain barrier
• P-gp inhibitors → increase CNS penetration of substrates
• Quetiapine: P-gp substrate
• Verapamil: P-gp inhibitor

8.2 High-Risk Drug Combinations

Lithium + NSAIDs

Mechanism: NSAIDs reduce renal prostaglandin synthesis → reduced renal blood flow → decreased lithium clearance → lithium toxicity

Magnitude of interaction:

• Indomethacin, diclofenac, ibuprofen: 50–100% increase in lithium levels
• Aspirin (low dose): minimal effect
• COX-2 inhibitors (celecoxib): similar risk to NSAIDs

Management: Avoid NSAIDs with lithium. If unavoidable, monitor lithium levels closely, reduce dose, use aspirin as alternative.

Other drugs that raise lithium levels:

• ACE inhibitors / ARBs: reduce renal excretion
• Thiazide diuretics: sodium depletion → lithium retention
• Dehydration/low-sodium diet: same mechanism

MAOIs + SSRIs/SNRIs/TCAs

Mechanism: Combined serotonergic activity → severe serotonin syndrome

Risk: POTENTIALLY FATAL

Washout periods:

After stopping MAOI: Wait 2 weeks before starting any serotonergic drug

Clozapine + Carbamazepine

Mechanism: Carbamazepine induces CYP1A2 and CYP3A4 → reduces clozapine levels

Additional risk: Both drugs are independently associated with agranulocytosis, ADDITIVE risk

Combination: ABSOLUTELY CONTRAINDICATED

If mood stabilizer needed with clozapine:

• Valproate (preferred, though monitor for sedation)
• Lithium (monitor levels)
• Lamotrigine (adjunct for negative symptoms, some evidence)

Clozapine + Benzodiazepines

Mechanism: CNS depression, respiratory depression

Risk: Case reports of sudden death and respiratory collapse with IM clozapine + benzodiazepines

IMPORTANT: Avoid IM benzodiazepines within hours of clozapine administration; caution with oral combination

Lithium + Antipsychotics (High-Dose)

Risk: Neurotoxicity, enhanced adverse effects even at therapeutic levels

Most reported with: Haloperidol

Features: EPS, confusion, fever, delirium

Historical note: Early reports (1970s) linked haloperidol + lithium to irreversible brain damage, "Loulis and Hurley syndrome"

SECTION 9: LITHIUM: COMPREHENSIVE

9.1 Pharmacology

Mechanism of Action (Multiple):

1. Inositol depletion hypothesis: Inhibits inositol monophosphatase → depletes inositol → reduces PKC-mediated signaling in overactive cells
2. Glycogen Synthase Kinase-3 (GSK-3β) inhibition: Reduces phosphorylation cascade → neuroprotective, anti-apoptotic
3. Neurotrophin effects: Increases BDNF, promotes neurogenesis
4. Serotonin potentiation: Enhances 5-HT synthesis and release (basis for augmentation)
5. Anti-glutamatergic: Reduces NMDA receptor signaling
6. Epigenetic: Histone deacetylase (HDAC) inhibition

Pharmacokinetics:

• Complete GI absorption (100%)
• No protein binding
• Renal excretion (competitive with sodium, depleted sodium leads to lithium retention)
• Half-life: ~24 hours (acute); 36–48 hours (chronic, with renal accumulation)
• Steady state: 5–7 days
• No hepatic metabolism, ideal for patients with liver disease

9.2 Therapeutic Drug Monitoring

Monitoring protocol:

• Level drawn 12 hours after last dose
• Baseline: Renal function (Cr, BUN, eGFR), thyroid (TSH, FT4), calcium, ECG, pregnancy test (women of reproductive age)
• Frequency: Every 5–7 days during initiation; then monthly × 6 months; then every 3–6 months when stable

9.3 Lithium Toxicity

Signs by Level

Precipitants of toxicity:

• NSAIDs, ACE inhibitors, diuretics
• Dehydration (febrile illness, surgery, low-sodium diet)
• Renal impairment
• Drug-drug interactions (CKD patients particularly vulnerable)

Management:

1. Stop lithium
2. IV normal saline (aggressive hydration and sodium correction)
3. Hemodialysis if:
4. Level >4 mmol/L
5. Level >2.5 mmol/L with severe symptoms
6. Severe renal failure preventing excretion
7. Sodium polystyrene sulfonate, evidence limited
8. Activated charcoal: NOT effective (lithium not absorbed by charcoal)

9.4 Long-Term Effects

Renal effects:

• Nephrogenic diabetes insipidus (NDI): Lithium blocks vasopressin effect on collecting duct → polyuria, polydipsia
• Occurs in ~40% of patients
• Management: reduce to once-daily dosing, amiloride (blocks ENaC channel that lithium uses to enter cells), indomethacin (short-term)
• Chronic kidney disease: Irreversible tubular atrophy with long-term use (>10–15 years)
• Risk factors: older age, higher levels, episodes of toxicity
• Monitoring: eGFR trend annually

Thyroid effects:

• Hypothyroidism: ~20–40% of long-term users
• Less commonly, hyperthyroidism (Graves' disease, autoimmune)
• Monitor TSH annually, treat with levothyroxine (do NOT stop lithium)

Cardiac effects:

• T-wave flattening/inversion, benign
• Sinus node dysfunction, rare
• Avoid in sick sinus syndrome

Parathyroid effects:

• Hyperparathyroidism → hypercalcemia
• Mechanism: lithium increases set point for calcium-mediated PTH suppression

9.5 Lithium in Pregnancy

Teratogenicity:

• Historical concern: Ebstein's anomaly (tricuspid valve malformation)
• Updated estimates (2017 NEJM): Absolute risk increases from 0.6/1000 to 2.1/1000, much lower than previously thought
• Risk ratio ~2.66, significant but not as catastrophic as older estimates

CANMAT/NICE guidance:

• Benefit-risk discussion individualized
• For moderate-high risk patients: lithium may be continued with monitoring
• Fetal echocardiogram at 16–18 weeks if lithium continued
• Lithium levels increase in first trimester (increased renal clearance), then levels spike post-partum (renal clearance falls)
• Peri-partum: Dose reduction by 25–50% at 36 weeks; re-titrate after delivery
• Breastfeeding: Excreted in breast milk (40–50% of maternal level), generally advised against; discuss carefully

SECTION 10: CLOZAPINE: COMPREHENSIVE

10.1 Indications

TRS Definition (TRRIP consensus):

• Adequate trials of ≥2 antipsychotics (one should be an SGA)
• Each at adequate dose (e.g., >600 mg chlorpromazine equivalents)
• For adequate duration (≥6 weeks each)
• With documented adherence
• With persistent positive symptoms (CGI-S ≥4)

Time to clozapine:

• Average in real world: 5–10 years after first psychosis
• Evidence supports earlier use after 2 failed adequate trials
• NICE guidelines: After 2 failed antipsychotics

10.2 Clozapine Monitoring: The ANC Protocol

ANC = Absolute Neutrophil Count

Monitoring frequency:

• Weeks 1–26: Weekly ANC
• Weeks 27–52: Every 2 weeks
• After 1 year: Monthly

Agranulocytosis risk:

• Overall: ~0.8–1% (with monitoring)
• Peak risk: Weeks 6–18
• Higher risk: Ashkenazi Jewish descent, BNL (Benign Ethnic Neutropenia in African descent)

Benign Ethnic Neutropenia (BEN):

• African/Caribbean descent: baseline ANC 1000–1500/mm³ common (not pathological)
• New protocol allows clozapine in BEN with adjusted ANC thresholds

10.3 Clozapine Adverse Effects

Metabolic Effects (Severe)

• Weight gain: 4–10 kg average; most among all antipsychotics
• Diabetes mellitus: significantly increased risk
• Dyslipidemia: elevated triglycerides especially
• Mechanism: H1 antagonism (appetite increase), M1 antagonism (impaired insulin response)

Cardiovascular

• Myocarditis/Cardiomyopathy:
• Myocarditis: Occurs in first 4–8 weeks (peak weeks 2–4)
• Incidence: ~0.3–0.7% (higher in Australian data: ~1–3%)
• Features: fever, chest pain, fatigue, eosinophilia, elevated troponin, CRP
• Action if suspected: STOP clozapine immediately; echo, cardiac enzyme monitoring
• Re-challenge: controversial, avoided in most cases
• If absolutely necessary: very gradual titration, prophylactic aspirin (evidence weak)
• QTc prolongation: Moderate risk
• Orthostatic hypotension: Common especially during titration

Seizures

• Dose-dependent: 1–2% at doses <300 mg/day; up to 5% at doses >600 mg/day
• Generalized tonic-clonic (GTCS)
• Management:
• Reduce clozapine dose if possible
• Add valproate (drug of choice, also helps metabolic symptoms and reduces prolactin)
• Avoid carbamazepine (agranulocytosis risk) and lamotrigine (rash risk if valproate added)
• Gabapentin or clonazepam as alternatives

Other Side Effects

• Hypersalivation (sialorrhea): Very common, especially nocturnal. Anticholinergics (hyoscine), pilocarpine, or pirenzepine
• Sedation: Most common complaint, use sedation to advantage by dosing at night
• Constipation: Serious, ileus risk. Prevent with bowel regimen
• Urinary incontinence/retention
• Fever (within first few weeks): Often benign, rule out agranulocytosis and myocarditis

10.4 Clozapine Re-challenge Protocol

Indicated when: Benefits outweigh risks after previous adverse event (not agranulocytosis)

Contraindicated re-challenge: Agranulocytosis (ANC <500) or NMS

Protocol for re-challenge (after myocarditis, special centers only):

1. Cardiac clearance from cardiologist
2. Baseline troponin, CRP, echo
3. Very slow titration (6.25 mg every 1–2 weeks)
4. Daily monitoring of cardiac enzymes for first 4–8 weeks
5. Low-dose aspirin (evidence weak, sometimes used prophylactically)

SECTION 11: ANTIPSYCHOTIC SWITCHING STRATEGIES

11.1 Rationale for Switching

Reasons to switch antipsychotic:

1. Inadequate efficacy
2. Adverse effects (EPS, metabolic, sedation)
3. Adherence issues (preference for LAI, simplification)
4. Specific comorbidity (e.g., depression → add mood benefits)

11.2 Cross-Titration

Most common approach, gradual overlap:

Steps:

1. Start new drug at low dose
2. Gradually increase new drug
3. Gradually taper old drug
4. Complete switch when new drug at target dose

Best for: Most switching scenarios, especially between drugs of different receptor profiles

11.3 Plateau Strategy (Abrupt Switch)

Abrupt discontinuation of old drug + immediate full dose of new drug

Used for:

• Switching to clozapine (often done this way)
• Patient preference, clinical urgency
• Drugs with very long half-lives (no need for gradual taper)

Risk: Withdrawal effects, rebound psychosis

11.4 Overlap Strategy (Add and Maintain)

New drug started and maintained at therapeutic dose while old drug continued temporarily

Used for:

• Adding clozapine to partial responder (augmentation phase)
• Assessing response to new drug before committing

11.5 Special Considerations by Drug

Switching FROM clozapine:

• Very risky, "supersensitivity psychosis" risk
• Very gradual taper (3–6 months)
• Bridge with other antipsychotic at full dose
• Clinical deterioration expected in many patients

Switching TO clozapine:

• Usually abrupt switch (clozapine requires titration from scratch anyway)
• Previous drug maintained briefly while clozapine titrated up, then tapered

Switching from depot:

• Cannot abruptly stop depot
• Plan based on half-life of specific depot (weeks to months)
• Start oral drug at appropriate time point in injection cycle

SECTION 12: AUGMENTATION STRATEGIES

12.1 Lithium Augmentation of Antidepressants

Evidence: Level I, most evidence-based augmentation strategy for treatment-resistant depression

Mechanism:

• Enhances serotonin synthesis and release
• Potentiates 5-HT1A autoreceptor desensitization
• Potentiates mood-stabilizing effects

Protocol:

• Add lithium to current antidepressant
• Target level: 0.5–0.8 mmol/L for augmentation (lower than bipolar)
• Response expected: 2–4 weeks
• Continue 6–12 months if response achieved

Evidence:

• Multiple RCTs and meta-analyses confirm efficacy
• NNT approximately 5 for augmentation
• Effective across SSRIs, TCAs, MAOIs

12.2 Triiodothyronine (T3) Augmentation

Mechanism: T3 sensitizes serotonin receptors; potentiates TCA activity

Evidence:

• Strong evidence for TCA augmentation
• Weaker evidence for SSRIs
• Meta-analysis: 24% response vs 14% placebo when added to TCAs

Dose: T3 25–50 mcg/day (low dose, below replacement threshold)

Duration: 3–4 week trial; continue 6–12 months if response

Adverse effects: Tachycardia, anxiety, osteoporosis risk (long-term)

Contraindicated: Cardiac disease, hyperthyroidism

12.3 Atypical Antipsychotic + SSRI

Most evidence:

Mechanisms:

• 5-HT2A antagonism (AP) + SERT inhibition (SSRI) → greater serotonin throughput
• Partial D2 agonism (aripiprazole) → improves motivation, reduces anhedonia
• Noradrenergic enhancement

12.4 Clozapine Augmentation Strategies

For ultra-treatment-resistant schizophrenia (inadequate response to clozapine alone):

Aripiprazole + clozapine: Well-studied, reduces weight, metabolic effects; modest improvement in psychopathology

SECTION 13: DISCONTINUATION SYNDROMES

13.1 SSRI Discontinuation Syndrome

Incidence: 20–40% of patients stopping SSRIs abruptly

Clinical features, FINISH mnemonic:

• Flu-like symptoms (malaise, myalgia, chills)
• Insomnia, vivid dreams
• Nausea, GI disturbance
• Imbalance (dizziness, vertigo)
• Sensory disturbances (electric shock sensations, paresthesias, pathognomonic)
• Hyperarousal, anxiety

Onset: 1–4 days after abrupt discontinuation

Duration: 1–2 weeks; can persist longer

Risk by half-life:

Management:

1. Gradual taper (minimum 2 weeks; often 4–8 weeks for long-term use)
2. If already stopped: reinstate low dose, taper slowly
3. Switch to fluoxetine for easier taper
4. Liquid formulations allow micro-tapering

13.2 Benzodiazepine Withdrawal

Mechanism: Chronic BZD use → downregulation of GABA-A receptors → upon discontinuation, excess CNS excitability

Clinical features:

• Mild: Anxiety, insomnia, tremor, sweating, irritability
• Moderate: Tachycardia, hypertension, perceptual disturbances
• Severe: Seizures, delirium (benzodiazepine withdrawal delirium)
• Risk of death (unlike most drug withdrawals; similar to alcohol withdrawal)

Timeline:

• Short-acting BZDs (lorazepam, oxazepam): Onset 12–24 hours
• Long-acting BZDs (diazepam, clonazepam): Onset 2–4 days

Management:

1. Substitution with long-acting BZD (diazepam or chlordiazepoxide) and gradual taper
2. Rule of 10%: Reduce dose by 10% every 1–2 weeks (Ashton manual)
3. Adjuncts: Carbamazepine, valproate (reduce seizure risk, help with psychological symptoms)
4. Propranolol for autonomic symptoms
5. Thiamine for those with alcohol co-dependence

13.3 Antipsychotic Withdrawal (Discontinuation)

Supersensitivity psychosis:

• Dopamine receptor upregulation after chronic D2 blockade
• Abrupt discontinuation → dopaminergic rebound → florid psychosis within days-weeks
• Can appear even in patients who did not have primary psychotic illness
• Distinction from relapse: onset within days of discontinuation; often more severe and atypical

Cholinergic rebound:

• Especially after stopping low-potency APs (clozapine, quetiapine) with high M1 antagonism
• Features: nausea, vomiting, diarrhea, headache, insomnia
• Onset: 24–48 hours after discontinuation

Management of AP discontinuation:

1. Gradual taper (months, not weeks, for chronic use)
2. Especially slow for clozapine (3–6 months)
3. Clinical monitoring for re-emergence of psychosis

SECTION 14: POLYPHARMACY IN PSYCHIATRY

14.1 Evidence-Based Combinations

Combinations with strong evidence:

14.2 Irrational Polypharmacy

High-risk irrational combinations:

1. Two antipsychotics simultaneously (except specific situations): increased side effects, no added efficacy
2. Two antidepressants without rationale: Limited evidence for most combinations
3. Benzodiazepine + Z-drug: Additive CNS depression
4. Multiple anticholinergics: Cognitive impairment, peripheral toxicity

Rational for two APs (limited evidence):

• Clozapine + amisulpride/aripiprazole: Evidence exists
• During cross-titration (temporary)
• Depot (stability) + oral (breakthrough), not ideal

14.3 Deprescribing

Principles:

1. Identify medications that are: no longer needed, duplicative, cause harm
2. Prioritize: Start with highest risk/burden medication
3. Gradual taper (especially for psych meds)
4. Shared decision-making with patient
5. Explicit stop dates and review points

HIGH-YIELD for deprescribing in psychiatry:

• Anticholinergics (for EPS that may have resolved)
• Sleep aids (evaluate and potentially discontinue benzodiazepines)
• Antipsychotics in dementia (when behavior has improved)
• PRN antipsychotics that have become regular
• Redundant mood stabilizers in stable bipolar disorder

SECTION 15: CANNABIS-BASED MEDICINES

15.1 Cannabinoids: Overview

15.2 Nabilone

Regulatory status: Approved in India (Schedule H drug); FDA approved in US

Indications:

• Chemotherapy-induced nausea and vomiting (CINV) unresponsive to conventional antiemetics
• Chronic pain (off-label)
• PTSD nightmares (off-label, limited evidence)

Mechanism: Synthetic cannabinoid, CB1 and CB2 agonist

Dose: 1–2 mg BD; reduce dose in elderly

15.3 CBD Oil

Epidiolex: FDA-approved CBD (100% CBD, plant-derived)

• Approved for: Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex
• Mechanism: GABA-A PAM, CB1 inverse agonist, TRPV1 agonist, inhibits AEA reuptake

CBD for psychiatric conditions:

• Anxiety: Small RCTs and open-label studies suggest benefit for social anxiety; dose range 300–600 mg
• Psychosis: CBD as antipsychotic? Phase II trial showing CBD reduced positive symptoms in schizophrenia; mechanism may involve AEA-CB1 pathway normalization
• PTSD: Limited data; being studied

India regulatory status:

• Cannabis plants: NDPS Act 1985, Schedule I narcotics
• However: CBD products (under 0.3% THC) exist in a grey zone
• No approved CBD formulation for psychiatric use in India
• State government licenses required for research

15.4 Cannabinoid Hyperemesis Syndrome (CHS)

• Paradoxical cyclical vomiting in heavy, long-term cannabis users
• Typically relieved by hot showers (compulsive bathing behavior)
• Mechanism: CB1 receptor desensitization vs direct emetic effects
• Treatment: Cessation of cannabis; capsaicin cream (topical, for bathing behavior); haloperidol has evidence for acute management

SECTION 16: KEY EXAM TABLES AND SUMMARIES

16.1 Novel Mechanisms: Quick Reference

Total estimated word count: ~18,000 words

Model Answers

15 Model Answers

ANSWER 01

Discuss the pharmacology, indications, adverse effects, and monitoring of clozapine. How would you manage clozapine-induced agranulocytosis? (15 marks)

Introduction

Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS), the only antipsychotic with FDA approval for reducing suicidal behaviour in schizophrenia and schizoaffective disorder. Its unique pharmacological profile explains both its superior efficacy and its complex adverse effect burden.

Pharmacology

Clozapine is a dibenzodiazepine atypical antipsychotic with an unusually broad receptor binding profile:

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The key pharmacokinetic characteristic of clozapine is its dependence on CYP1A2 for metabolism, smoking and drugs that induce or inhibit this enzyme cause clinically significant level changes.

Clozapine's "fast-off" kinetics from D2 receptors (unlike haloperidol which binds tightly) are proposed to explain low EPS despite its antipsychotic efficacy (the "fast dissociation hypothesis," Kapur and Seeman).

Indications

1. Treatment-resistant schizophrenia (TRS): Defined as inadequate response after ≥2 adequate antipsychotic trials. Level I evidence; NNT approximately 6 compared to standard antipsychotics.
2. Suicidality in schizophrenia/schizoaffective disorder: FDA-approved specifically for this indication, the only antipsychotic to carry it.
3. Parkinson's disease psychosis: When pimavanserin is unavailable or ineffective, very low doses (12.5–50 mg) preserve motor function.
4. Refractory bipolar disorder: Off-label, evidence-based.
5. Chronic violence/aggression: Evidence for reducing aggression even independent of psychotic symptoms.

Adverse Effects

Haematological (potentially life-threatening):

• Agranulocytosis: ~0.8% lifetime risk. Peak onset weeks 6–18. Mechanism: toxic/immunological destruction of granulocyte precursors.
• Benign neutropenia: up to 3%, usually transient.

Cardiovascular:

• Myocarditis: 0.3–0.7% (Australian data suggests up to 3%). Peak weeks 2–4 of treatment. Features: fever, chest pain, eosinophilia, elevated troponin and CRP. Action: STOP immediately.
• Cardiomyopathy: later, dilated type.
• QTc prolongation: moderate risk.
• Orthostatic hypotension: especially during titration.

Metabolic:

• Weight gain: 4–10 kg average, highest among all antipsychotics.
• Type 2 diabetes mellitus.
• Dyslipidaemia: especially hypertriglyceridaemia.

Neurological:

• Seizures: dose-dependent (1–2% at <300 mg/day; up to 5% at >600 mg/day). Generalised tonic-clonic.
• Sedation: common, utilise by dosing at night.
• EPS: very rare.

Autonomic:

• Hypersalivation (sialorrhea): very common, especially nocturnal. Mechanism: M2 antagonism in salivary glands.
• Constipation: potentially severe, ileus risk.
• Urinary incontinence.

Monitoring Protocol

ANC thresholds:

• ≥1500/mm³: continue
• 1000–1499: continue with more frequent monitoring
• 500–999: interrupt, daily monitoring
• <500 (agranulocytosis): STOP, permanent contraindication to re-challenge

Management of Agranulocytosis

Definition: ANC <500/mm³

Immediate actions:

1. Stop clozapine immediately
2. Notify the clozapine registry (CPMS in India, REMS in US)
3. Admit patient
4. Reverse barrier nursing (infection precaution)
5. Daily FBC
6. Urgent haematology consultation

Medical management:

• G-CSF (Granulocyte Colony Stimulating Factor): filgrastim 300–480 mcg/day SC, stimulates granulocyte recovery. Now standard of care.
• Prophylactic antibiotics if fever or clinical infection
• Monitor for sepsis

Recovery: Usually 2–3 weeks with G-CSF; without G-CSF: 3–4 weeks.

Re-challenge: ABSOLUTELY CONTRAINDICATED after true agranulocytosis. The patient must be permanently registered as contraindicated in the clozapine registry.

Antipsychotic alternatives after agranulocytosis:

• Quetiapine, olanzapine, amisulpride
• Higher relapse risk, expect clinical deterioration
• Consider LAI for adherence

Conclusion

Clozapine remains irreplaceable in TRS despite its adverse effect burden. The mandatory monitoring system has reduced agranulocytosis mortality from >10% to <5%. The clinical decision to initiate clozapine should be made in a specialist setting with patient education, written consent, and enrolment in the monitoring registry.

ANSWER 02

Write a detailed note on serotonin syndrome: pathophysiology, clinical features, diagnosis, and management. Distinguish from neuroleptic malignant syndrome. (10 marks)

Introduction

Serotonin syndrome (SS) is a drug-induced syndrome caused by excess serotonergic activity at central and peripheral 5-HT receptors. It is a clinical diagnosis based on drug history and examination. Unlike NMS, it is predominantly pharmacological in origin and typically self-limiting.

Pathophysiology

Excess serotonin acts at two key receptors:

1. 5-HT1A: Mediates cognitive and autonomic effects, agitation, tachycardia, hypertension, hyperthermia
2. 5-HT2A: Mediates neuromuscular effects, clonus, myoclonus, hyperreflexia, and at high stimulation: life-threatening hyperthermia

The critical neuromuscular pathways:

• Spinal 5-HT2A receptors: clonus, hyperreflexia
• Brainstem 5-HT: temperature dysregulation
• Peripheral autonomic: tachycardia, diaphoresis

Clinical Features, The Classic Triad

Severity spectrum:

• Mild: tremor, tachycardia, diaphoresis, mydriasis, intermittent tremor
• Moderate: all above + clonus, hyperreflexia, hyperthermia <38.5°C, agitation
• Severe: hyperthermia >41°C, rhabdomyolysis, metabolic acidosis, renal failure, DIC, respiratory failure

Onset: Rapid, typically within 6 hours of causative drug exposure.

Diagnosis, Hunter Serotonin Toxicity Criteria

Requirement: Serotonergic agent present PLUS one of:

1. Spontaneous clonus
2. Inducible clonus + (agitation OR diaphoresis)
3. Ocular clonus + (agitation OR diaphoresis)
4. Tremor + hyperreflexia
5. Hypertonia + temperature >38°C + (ocular OR inducible clonus)

Sensitivity 84%, specificity 97%, superior to Sternbach criteria.

High-risk drug combinations: MAOI + SSRI (potentially fatal), MAOI + tramadol, MAOI + meperidine, SSRI + linezolid, SSRI + tramadol.

Management

SS vs NMS Distinction

Mnemonic to remember the clonus distinction: SS = Spastic and Spikey (hyperreflexia, clonus); NMS = Necrotic and Numb (rigidity, elevated CK).

ANSWER 03

Discuss the pharmacology, clinical evidence, REMS requirements, and place in therapy of esketamine nasal spray for treatment-resistant depression. (10 marks)

Introduction

Esketamine (Spravato, intranasal) received FDA approval in 2019, becoming the first truly novel antidepressant mechanism since the introduction of SSRIs in the 1980s. As the S-enantiomer of ketamine, it offers rapid onset of action via glutamatergic modulation, a departure from the monoamine-based framework that dominated psychiatry for six decades.

Pharmacology

Mechanism:

1. NMDA receptor antagonism (primary): Esketamine binds to the phencyclidine (PCP) site inside the NMDA receptor channel (open-channel block). This inhibits glutamatergic transmission acutely.

1. AMPA receptor disinhibition (downstream): NMDA blockade at interneurons (which tonically inhibit AMPA activity) leads to a burst of AMPA receptor activation. This triggers BDNF release from neurons, activating the TrkB-mTOR signalling cascade.

1. Synaptogenesis: mTOR activation drives rapid de novo protein synthesis → new synaptic spines form within hours → this is the cellular basis of the rapid antidepressant effect.

1. Additional mechanisms: Opioid receptor modulation has been proposed (controversial), HCN1 channel blockade, sigma-1 receptor interaction.

Pharmacokinetics:

• Intranasal bioavailability: ~48% (higher than expected due to direct CNS access via olfactory pathways)
• Tmax: 20–40 minutes
• Half-life: ~7–12 hours
• Metabolism: hepatic (CYP3A4, CYP2B6) to noresketamine (active)
• Dose: 56 mg or 84 mg intranasally

Clinical Evidence

Onset of action: Antidepressant effects within 2–4 hours; clinically meaningful by 24–48 hours. Peaks at 1–4 weeks.

REMS Requirements

Esketamine carries a mandatory REMS (Risk Evaluation and Mitigation Strategy) programme, one of approximately 60 drugs in the US with this requirement.

Key REMS elements:

1. Certified healthcare settings only: Cannot be dispensed at a pharmacy for home use
2. On-site supervision: Patient must receive each dose in a certified healthcare facility
3. Post-dose monitoring: Minimum 2 hours observation for:
4. Dissociation (most common, occurs in >50%)
5. Sedation
6. Blood pressure elevation (systolic rise of 20–40 mmHg common)
7. Perceptual disturbances
8. No driving on dosing day: Patient requires escort
9. ETASU certification: Healthcare settings must register with the REMS programme
10. Pregnancy registry: Women of childbearing age

Why REMS? Abuse potential (Schedule III), dissociation risk, BP elevation risk, not safe for unsupervised self-administration.

Administration Protocol

• Induction: 56 mg or 84 mg twice weekly × 4 weeks
• Maintenance Phase 1: Once weekly × 4 weeks
• Maintenance Phase 2: Once weekly or every 2 weeks thereafter
• Taken as 2 × 28 mg devices (one nostril each), 5 minutes apart

Place in Therapy

Advantages over IV ketamine:

• FDA-approved (ketamine: off-label)
• Standardised dose and route
• REMS monitoring built-in
• S-enantiomer: more potent at NMDA receptor per mg

Limitations:

• Does not replace ongoing antidepressant treatment
• Duration of effect limited (days to weeks per infusion session)
• Cost: ~$800–900 per treatment session
• Long-term maintenance data still accumulating
• High rates of dissociation at each session

ANSWER 04

Describe the pharmacology of newer antipsychotics with particular reference to cariprazine and lumateperone. What is the clinical significance of D3 receptor selectivity? (10 marks)

Introduction

Third-generation antipsychotics have moved beyond simple D2 blockade toward receptor-selective approaches that target specific dopamine receptor subtypes and multiple neurotransmitter systems. Cariprazine and lumateperone represent two distinct advances in this evolution.

Cariprazine, D3-Selective Partial Agonist

Receptor profile:

Clinical significance of D3 selectivity:

D3 receptors are concentrated in the mesolimbic system, prefrontal cortex, and hippocampus, regions governing reward, motivation, and cognition. Negative symptoms of schizophrenia (avolition, alogia, anhedonia) are linked to hypodopaminergic tone in these circuits.

Partial D3 agonism is proposed to:

• Restore reward salience (reduced avolition)
• Improve working memory (PFC D3 modulation)
• Reduce anhedonia

RCH-MD-16 study: Cariprazine 3–6 mg demonstrated statistically significant superiority over risperidone 3–6 mg on PANSS negative symptom factor scores, a landmark finding, as no previous drug had shown this against an active comparator.

Pharmacokinetics: Active metabolites (DCAR and DDCAR) have a combined effective half-life of 2–4 weeks. Clinical implication: drug effects persist weeks after discontinuation.

Clinical use:

• Schizophrenia: 1.5–6 mg/day (negative symptom benefit at 3 mg)
• Bipolar mania: 3–6 mg/day
• Bipolar depression: 1.5–3 mg/day (only antipsychotic effective at sub-mania doses for bipolar depression)

Adverse effects: Akathisia (highest among newer APs), weight gain (moderate), metabolic effects (moderate).

Lumateperone, Multimodal Novel Mechanism

Receptor profile:

What makes lumateperone truly novel:

1. D1 agonism in the PFC: While all other antipsychotics either block or have no activity at D1, lumateperone activates prefrontal D1 receptors. This is predicted to improve cognition and negative symptoms.

1. Dual D2 activity: Pre-synaptic agonism normalises dopamine synthesis in hypo-dopaminergic states (relevant for negative/cognitive symptoms); post-synaptic antagonism reduces excessive mesolimbic signalling (relevant for positive symptoms).

1. SERT inhibition: Contributes to antidepressant and mood-stabilising properties, explains bipolar depression efficacy.

1. NMDA NR2B modulation: Reduces excitotoxic glutamate signalling, a mechanism shared with ketamine, potentially explaining mood and cognitive benefits.

Clinical evidence:

• Schizophrenia: Phase III trials (ITT-301, -302) showing significant PANSS reduction vs placebo
• Bipolar I depression AND Bipolar II depression: Multiple RCTs positive, one of very few drugs approved for both
• Weight-neutral in clinical trials, a practical advantage over most APs

Dosing: 42 mg once daily (no titration required)

Comparison

ANSWER 05

Discuss lithium pharmacology, monitoring, toxicity management, and use in pregnancy. (10 marks)

Introduction

Lithium remains the most evidence-based mood stabiliser for bipolar disorder after more than 70 years of clinical use. It is the only psychiatric drug with Level I evidence for suicide prevention in bipolar disorder, and the only drug with proven anti-suicidal effects independent of mood stabilisation.

Pharmacology

Mechanisms of action (multiple, interacting):

1. Inositol depletion: Inhibits inositol monophosphatase and bisphosphatase → depletes inositol from hyperactive neural circuits → selectively dampens overactive phosphoinositide signalling (the "inositol depletion hypothesis").

1. GSK-3β inhibition: Glycogen synthase kinase-3β is a key regulator of neuronal apoptosis, neurogenesis, and synaptic plasticity. Lithium inhibition → neuroprotective, reduces apoptosis, promotes BDNF.

1. Serotonin potentiation: Increases synthesis and release of 5-HT → basis for augmentation of antidepressants and anti-suicidal effect.

1. HDAC inhibition: Epigenetic mechanism, histone deacetylase inhibition → altered gene expression → long-term neuroprotection.

1. Anti-glutamatergic: Reduces NMDA receptor-mediated excitotoxicity.

Pharmacokinetics:

• Oral absorption: 100% (complete)
• No protein binding, no hepatic metabolism
• Distribution: total body water
• Renal excretion (competes with sodium reabsorption in proximal tubule)
• Half-life: ~24 hours (acute); 36–48 hours (chronic)
• Steady-state: 5–7 days

Narrow therapeutic index: This drives the mandatory monitoring protocol.

Monitoring Protocol

Baseline investigations:

• Renal function: creatinine, BUN, eGFR, urinalysis
• Thyroid: TSH, FT4
• Serum calcium (parathyroid effects)
• ECG (especially >50 years)
• Pregnancy test (women of reproductive age)
• Weight, BMI

Serum level targets (12-hour post-dose sample):

Monitoring frequency:

• Initiation: every 5–7 days until stable
• Stable: monthly × 6 months → every 3–6 months

Long-term monitoring: Renal function (eGFR) annually; TSH annually; calcium annually.

Toxicity

Precipitating factors:

• NSAIDs (reduce renal clearance)
• ACE inhibitors/ARBs (reduce glomerular filtration)
• Thiazide diuretics (sodium loss → lithium retention)
• Dehydration, fever, vomiting
• Renal disease
• Low-sodium diet

Clinical features by level:

Management:

1. Stop lithium
2. IV normal saline 0.9%, aggressive hydration (promotes renal excretion and corrects sodium deficit)
3. Haemodialysis if: level >4 mmol/L; level >2.5 with severe symptoms; severe renal failure
4. Activated charcoal: NOT effective
5. Sodium polystyrene: limited evidence
6. Supportive: seizure management, airway

Use in Pregnancy

Teratogenicity, updated estimates:

Earlier reports dramatically overstated the risk of Ebstein's anomaly (tricuspid valve malformation). A 2017 NEJM cohort study revised the absolute risk:

• Background risk: 6/10,000 births
• With lithium: 21/10,000 births (relative risk ~2.66)

This is a real risk, but much lower than the 1-in-10 figures quoted previously.

Clinical decision framework:

• Women with severe bipolar disorder: lithium may be continued given that untreated mania/depression also poses foetal risks
• Women at lower risk: taper lithium during first trimester; restart after organogenesis

Peripartum management:

• Renal clearance increases in first trimester → levels may fall (increase dose to maintain therapeutic level)
• Post-partum: renal clearance falls → level spikes → REDUCE dose 25–50% at 36–38 weeks, re-titrate after delivery
• Monitor fortnightly in third trimester

Neonatal effects (if continued):

• Neonatal lithium toxicity: hypotonia ("floppy baby"), cyanosis, bradycardia
• Resolve within days as lithium is excreted

Fetal monitoring:

• Anomaly scan with foetal echocardiogram at 16–18 weeks
• Growth scans third trimester

Breastfeeding: Excreted in breast milk at 40–50% of maternal serum level. Generally advised against; if continued, monitor infant lithium levels and renal function.

ANSWER 06

Enumerate and explain the strategies for augmentation of antidepressants in treatment-resistant depression. Which has the strongest evidence base? (10 marks)

Introduction

Treatment-resistant depression (TRD) is conventionally defined as inadequate response to ≥2 adequate antidepressant trials. Approximately 30% of patients with MDD meet this criterion. Augmentation, adding a second agent to an existing antidepressant, is distinct from switching strategies and is the recommended approach when partial response exists.

Augmentation Strategies, Evidence Hierarchy

Tier 1 (Strongest evidence, Level I):

1. Atypical antipsychotic augmentation (FDA-approved combinations)

Mechanism: 5-HT2A antagonism by AP + SERT inhibition by AD → enhanced serotonin throughput; partial D2 agonism → improved motivation and anhedonia (aripiprazole).

2. Lithium augmentation

• Most evidence-based pharmacological augmentation, Level I evidence predating all AP augmentation trials
• Mechanism: enhances serotonin synthesis and release; potentiates 5-HT1A desensitisation
• Target level: 0.5–0.8 mmol/L
• Response rate: ~50% in previously treatment-resistant patients
• Time to response: 2–4 weeks
• NNT: approximately 5

Tier 2 (Good evidence, Level II):

3. Triiodothyronine (T3) augmentation

• Dose: 25–50 mcg/day (sub-replacement)
• Best evidence for TCA augmentation; weaker for SSRIs
• Meta-analysis: 24% response vs 14% placebo
• Mechanism: sensitises serotonin receptors; potentiates TCA activity

4. Mirtazapine added to SSRI/SNRI ("California Rocket Fuel")

• Mechanism: SNRI + NaSSA → combined noradrenergic + serotonergic + histaminergic action
• Evidence: multiple RCTs, generally positive though less robust than AP augmentation
• Practical: mirtazapine's sedation is often used therapeutically for insomnia comorbidity

5. Buspirone augmentation

• 5-HT1A partial agonist, augments SSRI action at autoreceptors
• Level II evidence; less potent than AP augmentation

Tier 3 (Emerging evidence):

6. Esketamine nasal spray

• FDA-approved for TRD (2019)
• Rapid effect (within 24–48 hours), uniquely useful in urgent situations
• Sustained maintenance with regular sessions

7. Thyroid hormone (levothyroxine, T4)

• Weaker evidence than T3 augmentation

8. Lamotrigine augmentation of antidepressants

• Case series and small RCTs; evidence for SSRI + lamotrigine in TRD
• May be particularly useful when bipolar spectrum features are present

9. Pramipexole (D3 agonist)

• Evidence for bipolar II depression and unipolar TRD
• Level II evidence

10. Modafinil/armodafinil

• Augment fatigue and hypersomnia in partial responders
• Does not improve core depression scores significantly

Strongest Evidence

Clinical decision guide: If partial response to SSRI/SNRI → first add atypical AP (if tolerability concern, aripiprazole; if insomnia comorbid, quetiapine; if better side-effect profile needed, brexpiprazole). If metabolic concerns preclude AP → lithium augmentation. If urgent response needed (severe suicidality) → esketamine.

ANSWER 07

Write a pharmacological note on orexin receptor antagonists. Compare the three approved agents. What is their mechanism of action and advantage over traditional hypnotics? (8 marks)

Introduction

Dual orexin receptor antagonists (DORAs) represent a paradigm shift in insomnia pharmacotherapy, from GABAergic sedation to targeted wake-drive suppression. Three agents are currently approved: suvorexant (2014), lemborexant (2019), and daridorexant (2022).

The Orexin System

Orexins (orexin-A/hypocretin-1, orexin-B/hypocretin-2) are neuropeptides produced by ~70,000 neurons in the lateral hypothalamus. They project widely to wake-promoting nuclei:

In narcolepsy (loss of orexin neurons): sudden sleep attacks, cataplexy.

In insomnia: orexin system overactivated → failure to "turn off" wake drive.

DORA mechanism: Simultaneously block OX1R and OX2R → suppress the wake drive without globally suppressing brain activity.

Advantage Over Traditional Hypnotics

Comparison of the Three DORAs

Suvorexant: First in class, most clinical experience, works for sleep onset and maintenance.

Lemborexant: Better than zolpidem on subjective sleep parameters at 1-month mark; longer half-life beneficial for sleep maintenance but raises next-day concern in some patients.

Daridorexant: Designed from the start with daytime functioning as co-primary endpoint; shortest half-life → best next-day profile.

Safety Notes

• Complex sleep behaviours (sleep-walking, sleep-driving, sleep-eating): Black box warning for all three, although incidence far lower than with Z-drugs.
• Respiratory depression: Minimal effect on respiratory drive (unlike BZDs), relatively safer in mild COPD/OSA. Caution in severe respiratory compromise.
• No abuse potential defined in clinical use patterns.
• Pregnancy: Avoid (insufficient data).

ANSWER 08

Discuss the role of pharmacogenomics in clinical psychiatry with special reference to CYP2D6 and CYP2C19. What is the clinical significance of HLA-B*1502 testing? (8 marks)

Introduction

Pharmacogenomics, the study of how genetic variation affects drug response, offers the promise of "right drug, right dose, right patient." In psychiatry, where drug selection has historically been empirical and trial-and-error, pharmacogenomics provides a biological framework for individualising treatment.

CYP2D6

CYP2D6 is the most clinically relevant enzyme in psychiatric pharmacogenomics, metabolising approximately 25% of all psychotropic drugs.

Phenotype classification:

Ethnic distribution:

• PMs: 7–10% Caucasians; 1–2% Asians; 3–7% Africans
• UMs: 1–2% Caucasians; up to 29% in Ethiopian populations

Key psychiatric CYP2D6 substrates:

• Antidepressants: nortriptyline, desipramine, clomipramine, vortioxetine, paroxetine, fluoxetine
• Antipsychotics: haloperidol, risperidone, aripiprazole, perphenazine
• Opioids: codeine (prodrug, PMs get no analgesia; UMs get excessive morphine)

Important: Paroxetine and fluoxetine are BOTH substrates AND potent inhibitors of CYP2D6. This creates phenoconversion, an EM becomes a functional PM when taking paroxetine.

CYP2C19

Ethnic distribution of PMs:

• 3–5% Caucasians
• 15–20% Asian populations (particularly Japanese, Chinese)

Key psychiatric substrates:

• Citalopram, escitalopram (PMs have elevated levels → QTc concern)
• Sertraline
• Diazepam, clonazepam
• Venlafaxine, amitriptyline

Clinical application: CYP2C19 PMs should receive lower doses of citalopram/escitalopram, the FDA already recommends a maximum 20 mg/day for CYP2C19 PMs based on QTc risk.

HLA-B*1502 and Carbamazepine

Background:

• Carbamazepine causes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), life-threatening mucocutaneous reactions, in rare individuals
• In 2004, a Taiwanese study demonstrated that nearly 100% of Han Chinese patients who developed SJS on carbamazepine carried the HLA-B*1502 allele

Allele frequency:

• Han Chinese: ~8–10%
• Thai, Filipino, Malaysian: 6–8%
• South Asian (Indian subcontinent): ~2–4% (varies significantly by region)
• Europeans: <1%
• Japanese: rare

Mechanism: HLA-B*1502 presents carbamazepine metabolites as neoantigens to cytotoxic T-cells → explosive T-cell activation → cutaneous cell death.

FDA mandate: Test for HLA-B*1502 before initiating carbamazepine in patients of Asian ancestry. If positive → DO NOT use carbamazepine.

India relevance:

• Indian Pharmacopoeia and CDSCO guidelines recommend HLA-B*1502 testing before carbamazepine
• Risk is real but lower than East Asian populations
• Oxcarbazepine also carries risk in HLA-B*1502 carriers

HLA-A*3101:

• Associated with carbamazepine hypersensitivity in European and Japanese populations
• Causes SJS, DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), and maculopapular exanthema
• Lower penetrance than B*1502 for severe reactions but broader population relevance in Europeans

Clinical decision algorithm:

ANSWER 09

Classify and discuss drug interactions in psychiatry. Which combinations are potentially fatal? How do you manage a patient who requires both an MAOI and SSRI? (8 marks)

Introduction

Drug interactions in psychiatry are clinically significant because polypharmacy is common, psychiatric drugs have narrow therapeutic windows, and many interactions can be fatal. Interactions are classified as pharmacokinetic or pharmacodynamic.

Classification

A. Pharmacokinetic Interactions (affect drug levels)

1. Absorption: Antacids reduce absorption of many psychotropics (less clinically significant)
2. Distribution: Displacement from protein binding (valproate + aspirin)
3. Metabolism (most important):
4. CYP450 inhibition → increased levels of substrate
5. CYP450 induction → decreased levels of substrate
6. Phase II (glucuronidation): valproate inhibits UGT → increases lamotrigine levels 2-fold
7. Excretion:
8. Lithium: renal excretion manipulated by NSAIDs, diuretics, ACE inhibitors
9. Renally cleared drugs affected by renal function changes

B. Pharmacodynamic Interactions (affect drug effects)

1. Additive: Two CNS depressants → excessive sedation
2. Synergistic: MAOI + SSRI → serotonin syndrome
3. Antagonistic: Anticholinergic drugs reduce effect of procognitive agents

Potentially Fatal Combinations

High-Risk Combinations: Detailed

Lithium + NSAIDs:

• Mechanism: NSAIDs inhibit renal prostaglandins → reduced renal blood flow → lithium retention
• Magnitude: 50–100% increase in lithium levels
• Management: Avoid; if unavoidable, reduce lithium dose 25–50%, monitor levels in 3–5 days, advise patient about dehydration risk

Clozapine + carbamazepine:

• Dual risk: carbamazepine independently causes agranulocytosis + induces CYP1A2 → reduces clozapine levels
• Absolutely contraindicated
• Alternative mood stabiliser: valproate (preferred with clozapine)

Fluvoxamine + clozapine:

• Fluvoxamine is a potent CYP1A2 inhibitor → can increase clozapine levels 2–10 fold
• Inadvertent prescribing can cause clozapine toxicity (seizures, respiratory depression)
• Some clinicians exploit this intentionally: low-dose fluvoxamine (25–50 mg/day) to increase clozapine levels while using lower clozapine doses (reduces metabolic burden)

Managing a Patient Requiring Both MAOI and SSRI

This situation should be avoided if at all possible. However, if sequential use is required:

Standard washout:

Stopping SSRI → starting MAOI:

• Fluoxetine: 5-week washout (long half-life + active norfluoxetine ~14 days)
• Other SSRIs/SNRIs: 2-week washout
• Venlafaxine: 2-week washout

Stopping MAOI → starting SSRI:

• ALL MAOIs: 2-week washout minimum
• Phenelzine and tranylcypromine irreversible: 3-week washout often recommended in practice

Why the asymmetry? Fluoxetine's extremely long active metabolite half-life means it can still be present 5 weeks after the last dose, still capable of causing SS if combined with MAOI.

Practical scenario: Patient stable on SSRI, needs to switch to MAOI-class antidepressant.

1. Stop SSRI (use 5-week washout for fluoxetine, 2 weeks for others)
2. During washout: bridge with psychotherapy, sleep hygiene, PRN benzodiazepines for anxiety
3. Monitor for withdrawal syndrome (reinstate briefly if severe)
4. Begin MAOI at minimum dose after washout period

Emergency situation (patient critically unwell): Hospitalise, use ECT as bridge. Do NOT overlap serotoninergic agents.

ANSWER 10

What is neuroleptic malignant syndrome? Discuss its pathophysiology, clinical features, management, and guidelines for antipsychotic re-challenge. (10 marks)

Introduction

Neuroleptic malignant syndrome (NMS) is a rare, life-threatening idiosyncratic reaction to dopamine-blocking agents, characterised by the tetrad of hyperthermia, rigidity, altered consciousness, and autonomic instability. Before the introduction of active management protocols, mortality was 25–30%. With current management, mortality is approximately 5–10%.

Pathophysiology

NMS results from abrupt or excessive dopamine D2 receptor blockade across three anatomical domains:

1. Striatum: D2 blockade → loss of dopaminergic modulation of extrapyramidal motor system → lead-pipe rigidity
2. Hypothalamus: Dopamine normally inhibits the heat-dissipating mechanisms; D2 block → thermoregulatory failure → hyperthermia
3. Mesocortical/mesolimbic pathways: D2 blockade → altered consciousness, confusion, stupor

Precipitating factors:

• High-potency typical antipsychotics (haloperidol most implicated)
• Rapid dose escalation
• IM depot injections
• Dehydration
• Agitation (metabolic demand increases muscle heat production)
• Physical restraint
• Ambient heat
• Prior NMS episode (strongest predictor, 10–15x increased risk)
• Young male patients
• Underlying brain pathology

Clinical Features

Cardinal tetrad:

1. Hyperthermia: Temperature >38°C (often >40°C, sometimes >42°C)
2. Muscle rigidity: Lead-pipe rigidity (unlike clonus in SS), generalised, severe, can cause rhabdomyolysis from sustained contraction
3. Altered consciousness: Confusion → obtundation → stupor → coma
4. Autonomic instability: Tachycardia, labile blood pressure (oscillates, hyper and hypotensive episodes), tachypnoea, diaphoresis, sialorrhea, incontinence

Laboratory findings:

• CK: Very elevated, often >1000 U/L, can reach >50,000 U/L
• Leukocytosis: 10,000–40,000/mm³
• Metabolic acidosis
• Elevated LFTs
• Myoglobinuria → risk of acute kidney injury
• Low serum iron (<12 μmol/L), specific marker for NMS, useful diagnostically
• Elevated ESR, CRP

Onset: Hours to days after drug initiation or dose change (unlike SS which develops within hours)

Duration: 1–2 weeks without treatment; shorter with dantrolene/bromocriptine

DSM-5 Diagnostic Criteria

Development of severe muscle rigidity and elevated temperature following antipsychotic exposure, PLUS ≥2 of: diaphoresis, dysphagia, tremor, incontinence, altered consciousness, mutism, tachycardia, elevated/labile BP, leukocytosis, elevated CK, in the absence of an alternative medical/neurological explanation.

Management

Immediate steps:

1. Stop antipsychotic (and all other dopaminergic agents including metoclopramide)
2. ICU admission
3. IV fluid resuscitation (prevent renal failure from myoglobinuria)
4. Cooling measures (cooling blankets, ice packs to axillae/groin, NOT antipyretics which are ineffective)
5. Monitor: temperature, vitals, CK, renal function, urine myoglobin

Pharmacological:

ECT: For refractory NMS or when malignant catatonia cannot be excluded. ECT has both diagnostic and therapeutic utility in this context.

Antipsychotic Re-challenge

When indicated: Patient has psychotic illness with no alternative to antipsychotic treatment, NMS has fully resolved.

Contraindications to re-challenge:

• NMS within the past 2 weeks
• Persistent fever, rigidity, or elevated CK
• Patient's refusal with informed consent
• Malignant catatonia (alternative diagnosis, ECT is first-line)

Protocol:

1. Wait minimum 2 weeks after NMS resolution (ANC and CK normalised; some sources recommend 4–6 weeks)
2. Choose lowest-potency atypical antipsychotic (clozapine, quetiapine, or olanzapine)
3. Start at very low dose with slow titration
4. Avoid precipitating factors: ensure adequate hydration, avoid IM depots initially
5. Close monitoring: daily temperature and vitals for first 2 weeks
6. Written informed consent documenting recurrence risk (~10–15%)

Best evidence for re-challenge without recurrence:

• Clozapine: multiple case reports of successful re-challenge
• Quetiapine: low D2 affinity, low recurrence risk

ANSWER 11

Discuss the pharmacology, monitoring, and practical prescribing of long-acting injectable antipsychotics. What are the clinical advantages and disadvantages compared to oral formulations? (8 marks)

Introduction

Long-acting injectable antipsychotics (LAIs) address the single most important modifiable factor in schizophrenia outcomes, medication non-adherence. Non-adherence affects 50–70% of patients with schizophrenia within the first year of treatment. LAIs eliminate covert non-adherence, reduce the daily decision burden, and provide pharmacokinetic stability.

Available LAI Formulations

Pharmacological Principles of LAIs

Mechanism of prolonged action:

• Decanoate esters (haloperidol, fluphenazine): esterified drug dissolved in sesame oil → released slowly from injection site → cleaved by esterases → active drug
• Microspheres (risperidone): drug encapsulated in biodegradable polymer → gradual release
• Nanocrystal suspension (paliperidone palmitate): water-insoluble nanocrystals → very slow dissolution

Pharmacokinetic advantages of LAIs:

• Eliminate first-pass metabolism (higher relative bioavailability for some drugs)
• Stable plasma levels without peaks (oral) or troughs (missed doses)
• Plasma level predicts dose adjustment, clinician can titrate based on measured levels

PP3M (Paliperidone Palmitate 3-Monthly), Key Exam Focus

Prerequisites for switching from PP1M to PP3M:

1. Adequately treated with PP1M for ≥4 months
2. Last two PP1M doses must be at the same dose level
3. Dose conversion: PP3M = 3.5 × PP1M dose

PP3M doses available: 175 mg, 263 mg, 350 mg, 525 mg (corresponding to PP1M 39, 78, 117, 156 mg)

Clinical Advantages of LAIs

Meta-analytic evidence: Kishimoto et al. (2014), 25 RCTs, LAIs significantly reduced all-cause discontinuation and relapse vs oral.

Disadvantages and Practical Challenges

Monitoring Protocol for LAIs

1. Document last oral antipsychotic dose and timing
2. Weight, metabolic panel at baseline and 3-monthly
3. EPS assessment at each visit
4. Prolactin if symptoms (risperidone/paliperidone: cause significant prolactin elevation)
5. Document injection site, lot number, expiry
6. Ensure patient is aware of washout and carry-over effects before stopping

ANSWER 12

Discuss psilocybin-assisted therapy: mechanism of action, clinical evidence, and current regulatory status in psychiatry. (8 marks)

Introduction

Psilocybin is a classic serotonergic psychedelic compound derived from Psilocybe mushroom species. After decades of prohibition following the Controlled Substances Act of 1970, it has re-emerged as a genuinely promising treatment for several psychiatric conditions. Its mechanism differs fundamentally from all currently approved psychiatric medications.

Mechanism of Action

Primary: Psilocybin is dephosphorylated to psilocin by alkaline phosphatase (liver, small intestine, blood). Psilocin is the active compound.

Receptor actions:

• 5-HT2A agonist (primary): binding in prefrontal cortex, thalamus, anterior cingulate cortex, and limbic system
• 5-HT2C agonist: contributes to subjective effects
• 5-HT1A: some affinity

Neural mechanisms:

1. Default Mode Network (DMN) disruption: The DMN (medial PFC, posterior cingulate, angular gyrus) is hyper-connected in depression, OCD, addiction. Psilocin disrupts DMN connectivity → ego dissolution → reduced self-referential rumination.

1. Global brain connectivity increase: Psilocin causes a transient hyperconnected brain state, regions that do not normally communicate become temporarily linked. This "breaking of habits" may be the substrate for lasting psychological change.

1. Neuroplasticity: 5-HT2A agonism → BDNF release → TrkB-mTOR activation → synaptic plasticity. New dendritic spines form within 24 hours and persist for weeks.

1. Psychological "reset": The mystical/peak experience reliably produced at therapeutic doses correlates strongly with therapeutic outcomes, suggesting the subjective experience itself is therapeutic, not just the pharmacology.

Clinical Evidence

Adverse effects:

• Transient: headache, nausea, dizziness, anxiety during session
• Challenging experiences ("bad trips"): managed by therapist presence
• HPPD (Hallucinogen Persisting Perception Disorder): rare (<1%)
• No withdrawal syndrome, no physical dependence

Contraindications:

• Personal or first-degree family history of schizophrenia or bipolar I (manic episodes)
• Acute psychosis
• Unstable cardiac disease
• Pregnancy
• Concurrent lithium (seizure risk reported)

Therapeutic Model

Psilocybin is NOT a standalone drug, it is psilocybin-assisted psychotherapy:

1. Preparation sessions (2–3): Build therapeutic alliance, set intentions, reduce anticipatory anxiety
2. Drug session (1–3 sessions): Supervised in a comfortable environment; music, eye shades; therapist present throughout
3. Integration sessions (2–4): Processing the experience; applying insights to life; CBT-like work

The set (psychological state), setting (physical environment), and therapeutic relationship are considered pharmacologically relevant.

Regulatory Status (2026)

Outlook: Phase III trial results expected 2025–2026; FDA decision likely by 2027–2028.

ANSWER 13

Discuss the clinical pharmacology of brexanolone and zuranolone for postpartum depression. What is the mechanism of action and how do they differ from conventional antidepressants? (8 marks)

Introduction

Postpartum depression (PPD) affects 10–15% of postpartum women. Until 2019, it was treated with the same antidepressants used for MDD, which take 4–8 weeks to act, cross into breast milk, and do not address the peripartum-specific neurobiological mechanism. Brexanolone (2019) and zuranolone (2023) are the first drugs targeting the specific pathophysiology of PPD.

The Peripartum Neurobiological Hypothesis

During pregnancy:

• Progesterone levels rise massively (×100 above baseline)
• Progesterone is metabolised to allopregnanolone (3α-hydroxy-5α-pregnan-20-one)
• Allopregnanolone is a potent positive allosteric modulator of GABA-A receptors
• Chronically elevated allopregnanolone → GABA-A receptor adaptations (downregulation, subunit changes)

At delivery:

• Progesterone and allopregnanolone fall precipitously within 24–48 hours
• GABA-A receptors, adapted to high allopregnanolone, are suddenly deprived
• Neuronal excitability surges → PPD in vulnerable individuals

The vulnerability model: Women with PPD may have GABA-A receptors that respond abnormally to allopregnanolone fluctuations, a trait rather than purely a state phenomenon.

Brexanolone (Zulresso)

Class: Synthetic allopregnanolone (neuroactive steroid)

Approval: FDA 2019, first drug specifically approved for PPD

Mechanism: Positive allosteric modulation of both:

• Synaptic GABA-A receptors (γ2-subunit containing): phasic inhibition
• Extrasynaptic GABA-A receptors (δ-subunit containing): tonic inhibition

The extrasynaptic GABA-A modulation is particularly important, these receptors, largely concentrated in limbic and corticolimbic regions, mediate sustained inhibitory tone. Allopregnanolone (and brexanolone) are among the only endogenous/exogenous substances that modulate extrasynaptic GABA-A at physiological concentrations.

Administration:

• IV infusion over 60 hours (2.5 days), continuous
• Hospital admission required
• Doses: 30 mcg/kg/hour for 4 hours → 60 mcg/kg/hour for 20 hours → 90 mcg/kg/hour for 28 hours → taper down

REMS requirements:

• Administered only in certified healthcare facilities
• Risk: excessive sedation and sudden loss of consciousness
• Continuous oxygen saturation monitoring
• Patient must be accompanied when discharged

Clinical evidence:

• HUMMINGBIRD trial: 73.7% Hamilton Depression Rating Scale response at 60 hours (vs 47.8% placebo)
• 94 hours post-infusion: 83.3% response rate vs 64.5% placebo
• Effect sustained at 30 days

Limitations: IV only, 60-hour infusion, cost ~USD 34,000, requires hospitalisation, limited global availability.

Zuranolone (Zurzuvae)

Class: Same mechanism as brexanolone (neuroactive steroid, GABA-A PAM), but oral

Approval: FDA August 2023, first oral neuroactive steroid for both MDD and PPD

Pharmacokinetics:

• Oral bioavailability: moderate-high (better with fatty meal)
• Half-life: ~16–19 hours
• CYP3A4 metabolism
• Dose: 30 mg or 50 mg once daily at bedtime for 14 days

Clinical evidence:

• ROBIN trial (PPD): 50 mg zuranolone → significant reduction in HAMD-17 at Day 15
• LANDSCAPE/SHORELINE (MDD): Both trials positive
• Onset: significant separation from placebo within 3 days

No REMS required, can be prescribed from pharmacy for home use

Comparison with Conventional Antidepressants

ANSWER 14

Discuss discontinuation syndromes in psychiatry: focusing on SSRI discontinuation, benzodiazepine withdrawal, and antipsychotic supersensitivity psychosis. How do you manage each? (10 marks)

Introduction

Discontinuation syndromes arise when drugs that alter receptor density, signalling cascades, or neurotransmitter homeostasis are stopped. They differ from drug withdrawal in mechanism (not mediated by physical dependence per se) but share clinical urgency. In psychiatry, three syndromes are clinically most important: SSRI discontinuation, benzodiazepine withdrawal, and antipsychotic supersensitivity psychosis.

1. SSRI Discontinuation Syndrome

Pathophysiology:

Chronic SSRI use → adaptive changes in serotonin receptors (down-regulation of 5-HT1A, up-regulation of post-synaptic receptors) + serotonin transporter upregulation. Abrupt withdrawal → sudden reduction in synaptic serotonin → transient serotonergic deficit.

FINISH mnemonic:

• Flu-like symptoms: malaise, myalgia, lethargy
• Insomnia, vivid dreams/nightmares
• Nausea, vomiting, diarrhoea
• Imbalance: dizziness, ataxia, vertigo
• Sensory: electric shock sensations (paraesthesias, "brain zaps"), pathognomonic
• Hyperarousal: anxiety, irritability, agitation

Onset and duration:

• Short half-life drugs (paroxetine, venlafaxine): within 24–48 hours of stopping; duration 1–2 weeks
• Longer half-life (sertraline, escitalopram): 2–4 days; usually milder
• Fluoxetine: rarely causes syndrome due to ~4-6 day half-life + norfluoxetine active metabolite

Risk by drug:

Paroxetine > Venlafaxine > Sertraline > Escitalopram > Fluoxetine (lowest risk)

Management:

1. Gradual taper: Reduce by 25% every 1–2 weeks minimum. For long-term use (>2 years): taper over months.
2. If syndrome has started: reinstate at half the previous dose, stabilise for 2–4 weeks, then taper more slowly
3. Switch to fluoxetine 20 mg (self-tapering due to long half-life), taper fluoxetine over 2–4 weeks
4. Liquid formulations (sertraline oral solution): enable micro-taper protocols (the Horowitz/Taylor method: hyperbolic taper)
5. Inform patient: distinguish from relapse of depression (SSRI discontinuation ≠ return of depression, but can be confused)

2. Benzodiazepine Withdrawal Syndrome

Pathophysiology:

Chronic BZD → GABA-A receptor downregulation + subunit composition changes (from γ2 to δ subunits) + compensatory NMDA upregulation. Withdrawal → generalised CNS excitability.

Clinical features:

• Mild: anxiety, insomnia, tremor, sweating, irritability, hypersensitivity to sensory stimuli
• Moderate: tachycardia, hypertension, perceptual disturbances (visual/auditory)
• Severe: grand mal seizures, delirium (benzodiazepine withdrawal delirium)

Life-threatening: Benzodiazepine withdrawal (like alcohol withdrawal) can cause death. This is NOT the case with most other psychotropic drugs.

Timeline:

• Short-acting (lorazepam, oxazepam, alprazolam): onset 12–24 hours; peak 36–72 hours
• Long-acting (diazepam, clonazepam): onset 3–4 days; peak 5–7 days; prolonged course

Protracted withdrawal syndrome: Anxiety, insomnia, cognitive fog persisting for months, true or psychological?; evidence supports neurobiological basis in some patients.

Management:

1. Substitution: Convert all short-acting BZDs to equivalent diazepam dose (or chlordiazepoxide)
2. Example: Lorazepam 4 mg/day = diazepam ~40 mg/day
3. Gradual taper: 10% reduction every 1–2 weeks (Ashton Protocol)
4. For high-dose long-term users: may take 6–18 months
5. Adjuncts:
6. Carbamazepine or valproate: reduce seizure risk, improve completion rates
7. Propranolol: autonomic symptoms
8. Hydroxyzine, pregabalin: adjunct anxiolytics
9. Flumazenil infusion: specialist use only for protracted withdrawal
10. Inpatient if: high dose, history of seizures, concurrent alcohol dependence, medical comorbidity

3. Antipsychotic Discontinuation, Supersensitivity Psychosis

Pathophysiology:

Chronic D2 receptor blockade → compensatory D2 receptor upregulation (increase in number and sensitivity). Abrupt discontinuation → dopaminergic rebound → florid psychosis even in patients who may not have had psychosis as primary presentation.

Features:

• Rapid onset: hours to days after discontinuation (distinguishes from relapse of underlying illness)
• Severity: often more severe and atypical than original episode
• Features: hallucinations, agitation, excitement, often more florid than original illness
• Can occur even after gradual taper if years of AP exposure

Distinguishing from relapse:

• Supersensitivity: onset within days; very rapid; may be atypical symptoms
• Relapse: onset over weeks to months; similar to original presentation

Cholinergic rebound:

• Stopping low-potency APs (clozapine, quetiapine) with high anticholinergic properties
• Features: nausea, vomiting, diarrhoea, headache, insomnia within 24–48 hours

Management:

1. Prevention: Gradual taper is mandatory, never abrupt for long-term AP users
2. Minimum taper: 3–6 months for decade-long use; some sources recommend hyperbolic taper
3. Clozapine: even slower, 6–12 months taper
4. If supersensitivity has occurred: Reinstate AP promptly (do not wait)
5. If AP reinstatement fails: different AP class; consider clozapine
6. Manage cholinergic rebound: antiemetics, symptomatic treatment for 1–2 weeks

ANSWER 15

Write a critical note on rational prescribing and deprescribing in psychiatric practice. What constitutes irrational polypharmacy? (8 marks)

Introduction

Polypharmacy in psychiatry is a double-edged reality. Evidence-based combinations exist and save lives (lithium augmentation, clozapine + lamotrigine). Irrational polypharmacy, adding drugs reflexively, defensively, or due to inertia, harms patients through adverse effects, drug interactions, reduced adherence, and increased cost.

Rational Polypharmacy, Evidence-Based Combinations

Irrational Polypharmacy, Definitions and Examples

Irrational polypharmacy is defined as the concurrent use of multiple drugs without adequate clinical justification, where:

• The evidence does not support the combination
• The combination adds risk without proportionate benefit
• The combination resulted from sequential addition without review ("prescribing cascade")
• The combination creates dangerous interactions

Examples:

1. Two antipsychotics simultaneously (excluding specific combinations): Meta-analyses show no benefit over optimised monotherapy for most combinations. Exception: clozapine augmentation with amisulpride/aripiprazole, some RCT evidence.

1. Two drugs from the same class: Two SSRIs, two SNRIs, no clinical rationale; additive adverse effects and serotonin toxicity risk.

1. Unnecessary anticholinergic drugs: Procyclidine or trihexyphenidyl prescribed for EPS that has resolved, patient continues on it for years. Results in cognitive impairment, constipation, urinary retention in elderly.

1. Benzodiazepine + Z-drug: Additive CNS depression without additive efficacy; both work on GABA-A.

1. Prescribing cascade: Drug A causes side effect → Drug B added to treat side effect → Drug B causes new side effect → Drug C added...

1. The "defensive add-on": A drug is added "just in case" without evidence-based indication. Example: standing lorazepam added indefinitely after acute agitation episode.

Principles of Deprescribing

Deprescribing is the planned, supervised reduction or discontinuation of medications that are no longer needed, causing harm, or where benefit-risk ratio has shifted.

STOPP/START criteria (Ireland): Widely used tool, STOPP identifies potentially inappropriate prescriptions; START identifies omissions.

Five-step deprescribing process:

1. Reconcile: Comprehensive medication review, list ALL drugs, doses, durations, indications
2. Identify targets: Highest risk/lowest benefit first (anticholinergics in elderly, long-term BZDs, redundant antipsychotics)
3. Assess feasibility: Can this drug be stopped? What is the taper plan?
4. Patient engagement: Shared decision-making, patient must agree and understand withdrawal risk
5. Monitor: Explicit review date after each deprescription

Specific deprescribing in psychiatry:

Monitoring After Deprescription

• Explicit withdrawal monitoring schedule
• Patient and family education on discontinuation syndrome features vs relapse features
• Clear re-entry plan if needed
• Documentation of reason for deprescription (legal protection)

Mnemonics & Memory Tricks

15+ Mnemonics

MNEMONIC 01

FINISH: SSRI Discontinuation Syndrome

How to use it: Any question about SSRI discontinuation asks for this triad. The sensory "brain zaps" are the only truly pathognomonic feature, nothing else causes them.

Risk order (high to low): Paroxetine > Venlafaxine > Sertraline > Escitalopram > Fluoxetine

Memory hook: "Parrots Vomit Suddenly; Eventually Fine"

MNEMONIC 02

FEVER: NMS Core Features

Companion memory: NMS = "Never Move Suddenly" (Neuroleptic / Malignant / Syndrome)

CK elevation + lead-pipe rigidity = NMS

Clonus + hyperreflexia = Serotonin Syndrome

MNEMONIC 03

CLONUS: Serotonin Syndrome vs NMS Differentiator

The single most important differentiating sign:

Full Hunter Criteria trigger: "Spontaneous Inducible Ocular Tremor Hypertonia"

SIOTHS, each needs clonus or hyperreflexia present

• Spontaneous clonus → SS
• Inducible clonus + agitation/diaphoresis → SS
• Ocular clonus + agitation/diaphoresis → SS
• Tremor + hyperreflexia → SS
• Hypertonia + temp >38 + clonus → SS

MNEMONIC 04

VORTEX: Vortioxetine Receptor Profile

Exam shortcut: "Vortioxetine = the one with 5 different receptor actions, not just SERT"

The 3 antagonist (5-HT3) is why nausea is less and cognition improves.

The 7 antagonist (5-HT7) is why circadian rhythm and sleep improve.

MNEMONIC 05

CLOZAPINE MONITORING: "Every Week, Every Two, Monthly"

Memory: "1st half year = weekly watch; 2nd half = fortnight; after that = monthly forever"

ANC thresholds, "Green / Amber / Red / STOP"

• ≥1500 = Green (continue)
• 1000–1499 = Amber (more frequent monitoring)
• 500–999 = Red (interrupt + daily)
• <500 = STOP, PERMANENT contraindication

MNEMONIC 06

NMS MANAGEMENT: "STOP, DRIP, DAN-BRO"

Add-on: Lorazepam for agitation/muscle relaxation

ECT for refractory NMS or when malignant catatonia cannot be excluded

Dantrolene dose: 0.25–2 mg/kg IV every 6–12 hours

Bromocriptine dose: 2.5–10 mg TID

MNEMONIC 07

LITHIUM TOXICITY LEVELS: "Fine to Seizing"

Memory hook: "One-Five Fine; Two-Zero Drowsy; Two-Five Dying"

Haemodialysis triggers:

• Level >4.0 mmol/L (any symptoms)
• Level >2.5 mmol/L + severe symptoms
• Anuric renal failure + any toxic level

MNEMONIC 08

CYP2D6 PHENOTYPES: "PURE UM"

PURE UM, the two extremes are the clinical problems

Key CYP2D6 substrates to memorise: "Risky Antidepressants Halt Perfectly"

• Risperidone
• Aripiprazole
• Haloperidol
• Paroxetine, nortriptyline (TCAs)

Paroxetine + fluoxetine = substrate AND inhibitor (phenoconversion from EM to functional PM)

MNEMONIC 09

HLA-B*1502: "Asians Before Carbamazepine"

Memory sentence: "Before Carbamazepine, Check Blood in Asians"

• HLA-B*1502: East/South Asian → SJS/TEN with carbamazepine
• HLA-A*3101: European/Japanese → DRESS + milder reactions
• If positive: use valproate or lamotrigine instead

MNEMONIC 10

ESKETAMINE REMS: "CASH In Hand"

Esketamine schedule: Induction → 2x/week × 4 weeks; Maintenance 1 → weekly × 4 weeks; Maintenance 2 → weekly or every 2 weeks

REMS reason: Abuse potential + dissociation + BP spikes + no safe self-administration

MNEMONIC 11

OREXIN ANTAGONIST COMPARISON: "SLD: Short Long Daytime"

Memory: "Sleeping pills get better with time, Suvorexant, then Lemborexant, then Daridorexant"

Key distinguisher: Daridorexant was the first DORA with daytime functioning as a co-primary endpoint in trials. Use it when next-day performance matters most.

MNEMONIC 12

CARIPRAZINE D3 SELECTIVITY: "D3 = Dopamine for Drive and Desire"

Why cariprazine is unique: 20× selectivity for D3 over D2 → targets negative symptoms

Evidence: RGH-MD-16 trial: cariprazine superior to risperidone on PANSS negative symptoms

Dosing by indication:

• Negative symptoms / schizophrenia: 3–6 mg
• Bipolar depression: 1.5–3 mg (LOWER than schizophrenia)
• Bipolar mania: 3–6 mg

MNEMONIC 13

LUMATEPERONE: "D1 Activator, Not Just Blocker"

Every other antipsychotic = D1 neutral or blocker

Lumateperone = D1 AGONIST in PFC (the key novelty)

Memory: "Luma Turns D1 ON"

Plus: Lumateperone is the only AP approved for Bipolar I AND Bipolar II depression (most only approved for Bipolar I).

Side effect advantage: "LAMP"

• Low EPS
• Anti-metabolic (weight-neutral)
• Minimal prolactin rise
• Preserved cognition (D1 agonism)

MNEMONIC 14

LITHIUM DRUG INTERACTIONS: "NADS Raise Lithium Levels"

Aspirin (low dose): Minimal effect, safe to use

Loop diuretics (frusemide): Less effect than thiazides, still caution

Reverse direction (REDUCE lithium levels): Theophylline, sodium loading, osmotic diuretics

MNEMONIC 15

CLOZAPINE CONTRAINDICATIONS: "BONE MARROW PROBLEMS"

The ONE absolute combination to never do: Clozapine + Carbamazepine

Reason: DOUBLE agranulocytosis risk + carbamazepine induces CYP1A2 → reduces clozapine levels to sub-therapeutic

MNEMONIC 16

PSILOCYBIN CONTRAINDICATIONS: "SPAS"

Plus: Pregnancy, Lithium concurrent use (seizure risk combination)

Memory addition: "SET and SETTING matter, bad set = bad outcome"

Set = psychological preparation

Setting = physical environment + therapist relationship

MNEMONIC 17

BREXANOLONE vs ZURANOLONE: "IV vs PO, Both GABA"

Memory: "Brex needs the DRIP; Zuran takes a TRIP home"

Both: GABA-A PAM (positive allosteric modulator)

Both: approved for PPD

Zuranolone: ALSO approved for MDD (broader indication)

Mechanism unique point: extrasynaptic δ-GABA-A receptors, different from benzodiazepines which act on synaptic γ-GABA-A receptors

MNEMONIC 18

PHARMACOGENOMICS QUICK RECALL: "Poor UltraRapid EATS"

CYP2D6 clinically important phenotypes:

High-yield exam fact: CYP2C19 PMs in Asians → high escitalopram/citalopram levels → QTc risk → dose reduction to 20 mg max

MNEMONIC 19

DISCONTINUATION WASHOUT: "5 WEEKS FOR FLUOX"

Memory: "Fluoxetine takes FIVE, the rest take TWO"

Why 5 weeks for fluoxetine: norfluoxetine active metabolite has ~14-day half-life → fully eliminated at 5 half-lives = ~70 days → practically 5 weeks is the clinical minimum

MNEMONIC 20 (BONUS)

AUVELITY (DXM-BUP): "DXM Needs BUP to Survive"

Without bupropion: DXM metabolised too fast by CYP2D6 → no therapeutic levels

With bupropion: CYP2D6 inhibited → DXM levels ↑8-fold → NMDA antagonism achieved

Memory: "Bupropion saves Dextromethorphan from being eaten by CYP2D6"

Result: Antidepressant effect via:

1. NMDA antagonism (ketamine-like pathway)
2. NDRI effect (bupropion)
3. Sigma-1 agonism (DXM)

First oral NMDA-targeting antidepressant approved (FDA 2022)

QUICK MNEMONIC REFERENCE TABLE

Swipe to compare →

High-Yield Comparisons

10 Comparison Tables

TABLE 01

Serotonin Syndrome vs NMS vs Malignant Catatonia vs Malignant Hyperthermia

Swipe to compare →

TABLE 02

Newer Antidepressant Mechanisms: Side-by-Side

TABLE 03

Long-Acting Injectable Antipsychotics: Comprehensive Comparison

TABLE 04

Orexin Receptor Antagonists (DORAs): Full Comparison

TABLE 05

CYP450 Drug Interaction Matrix: Psychiatry High-Yield

Key rule: Substrates are victims; inhibitors/inducers are perpetrators. Most psychiatric drugs are substrates, they are affected by co-prescribed inhibitors/inducers.

TABLE 06

Ketamine vs Esketamine: Clinical Comparison

TABLE 07

Newer Antipsychotics: Mechanism and Side Effect Profile

TABLE 08

Lithium Monitoring: Baseline, Ongoing, Specific Situations

Special monitoring situations:

• Patient starting NSAID: recheck level in 3–5 days
• Patient febrile/vomiting: advise holding lithium + recheck level on recovery
• Surgery: discuss with surgeon; hold morning dose; restart when eating/drinking
• Stopping smoking: recheck clozapine level (not lithium, this is for CYP1A2)

TABLE 09

Antidepressant Augmentation: Evidence and Practical Guide

TABLE 10

High-Risk Drug Combinations: Summary Reference

PYQ Frequency Analysis

Previous Year Question Analysis

SECTION A: HIGH-FREQUENCY TOPIC MAP

The following topics have appeared repeatedly across Indian PG psychiatry exit examinations (PG exams, Exam pattern). Frequency ratings are based on pattern analysis across 17+ years of available question data.

Swipe to compare →

SECTION B: RECONSTRUCTED PYQ BANK

Category 1: Long Essays (15 marks): Most Likely Patterns

Q1.1

Discuss the pharmacology, indications, adverse effects, and monitoring of clozapine. How would you manage a patient who develops agranulocytosis while on clozapine?

Q1.2

What is treatment-resistant depression? Discuss the various pharmacological augmentation strategies with evidence for each. Which strategy has the strongest evidence base?

Q1.3

Describe the pharmacology, therapeutic drug monitoring, long-term effects, and use in pregnancy of lithium. How would you manage lithium toxicity?

Category 2: Short Notes (8–10 marks): High-Frequency

Q2.1

Write a short note on serotonin syndrome. How does it differ from NMS?

Q2.2

Discuss the pharmacology and clinical uses of newer antipsychotics, cariprazine, lumateperone, and brexpiprazole.

Q2.3

Write a note on pharmacogenomics in psychiatry. What is the significance of CYP2D6 polymorphisms?

Q2.4

Discuss the management of NMS. How does it differ from malignant catatonia?

Q2.5

Write a short note on long-acting injectable antipsychotics. What are their advantages and disadvantages?

Q2.6

Discuss esketamine nasal spray, mechanism of action, indications, REMS requirements, and place in therapy.

Q2.7

Write a short note on benzodiazepine withdrawal syndrome, pathophysiology, clinical features, and management.

Q2.8

Discuss drug interactions in psychiatry. Which combinations are potentially fatal?

Category 3: Short Notes (5 marks): Lower Frequency but Emerging

Q3.1

Write a brief note on psilocybin-assisted therapy.

Q3.2

Write a note on brexanolone for postpartum depression.

Q3.3

Write a note on orexin antagonists in the management of insomnia.

Q3.4

Write a note on rational polypharmacy in psychiatry.

SECTION C: EXAMINER FOCUS AREAS BY YEAR PATTERN

What Examiners Test More in Each Sub-topic

Clozapine questions, examiner preferences:

• Almost always include: monitoring protocol (exact ANC thresholds and frequencies)
• Frequently asked: management of agranulocytosis (G-CSF now standard, mention it)
• Occasionally asked: re-challenge protocol; clozapine in suicidality; clozapine vs other APs in TRS
• Rarely asked: pharmacogenomics of clozapine (CYP1A2, smoking interaction)

Serotonin syndrome, examiner preferences:

• Hunter criteria are more likely to be asked than Sternbach criteria (Hunter has better sensitivity/specificity)
• Comparison with NMS is asked almost every time SS appears
• Management: cyproheptadine dose (12 mg loading, 2 mg q2h) is a specific detail that scores marks
• The MAOI washout periods (5 weeks for fluoxetine, 2 weeks for others) appear regularly

Lithium, examiner preferences:

• Pregnancy section almost always included (Ebstein anomaly risk, use updated 2017 NEJM figures)
• Renal effects (NDI, CKD) are frequently asked in the adverse effects section
• Drug interactions (NSAIDs, ACEi, thiazides) always expected
• Haemodialysis indications are specific and examinable

Newer drugs, examiner preferences:

• Mechanism of action questions dominate: "Explain the multimodal mechanism of vortioxetine"
• Esketamine REMS is a high-yield specific topic (few candidates know the monitoring requirements)
• Cariprazine D3 selectivity and clinical significance is a favourite newer topic
• Psilocybin has started appearing as a 5-mark short note since 2022–2023

SECTION D: PREDICTED HIGH-PROBABILITY QUESTIONS FOR 2026

Based on topic frequency trends and emerging areas:

Tier 1: Almost Certain (>80% probability)

1. Clozapine: monitoring, adverse effects, management of agranulocytosis (long essay or 10-mark short note)
2. Serotonin syndrome vs NMS: pathophysiology, clinical features, management, differentiation (10 marks)
3. Lithium: comprehensive pharmacology, TDM, toxicity management (long essay or 10 marks)
4. TRD augmentation strategies (10 marks)

Tier 2: Very Likely (60–80% probability)

1. Drug interactions in psychiatry, high-risk combinations (8–10 marks)
2. LAI antipsychotics, advantages, types, monitoring (8 marks)
3. Newer antipsychotics, cariprazine, lumateperone, brexpiprazole (8 marks)
4. Esketamine, mechanism, REMS, place in therapy (8 marks)
5. Benzodiazepine withdrawal, management (5–8 marks)
6. Antipsychotic discontinuation and supersensitivity psychosis (5 marks)

Tier 3: Likely (40–60% probability)

1. Psilocybin-assisted therapy (5 marks)
2. Brexanolone / postpartum depression pharmacology (5 marks)
3. Orexin antagonists for insomnia (5 marks)
4. Pharmacogenomics: CYP2D6, CYP2C19, HLA-B1502 (5–8 marks)*
5. Rational polypharmacy and deprescribing (5 marks)

Tier 4: Watch List (Emerging, 20–40% probability)

1. MDMA-assisted therapy for PTSD (5 marks)
2. Auvelity (dextromethorphan-bupropion) mechanism (5 marks)
3. Zuranolone for MDD/PPD (5 marks)
4. Precision psychiatry and biomarker-guided treatment (5 marks)
5. Cannabis-based medicines in psychiatry (5 marks)

SECTION E: MARK ALLOCATION STRATEGY

For a 15-mark long essay:

For a 10-mark short note:

For a 5-mark short note:

SECTION F: COMMON EXAM MISTAKES: AVOID THESE

SECTION G: INTEGRATIVE QUESTION FORMATS

These are multi-part questions that test integration across topics. Increasingly common in PG exams-pattern papers.

Integrative Q1:

A 35-year-old male with treatment-resistant schizophrenia is started on clozapine 300 mg/day. Six weeks later he develops fever, chest pain, and elevated troponin. His ANC is 2,800/mm³.

(a) What is the most likely diagnosis? (2 marks)

(b) What is your immediate management? (4 marks)

(c) Can this patient be re-challenged with clozapine in future? Discuss. (4 marks)

Integrative Q2:

A 28-year-old woman with bipolar II disorder is stable on lithium 800 mg/day (level 0.7 mmol/L). She plans to get pregnant.

(a) What are the teratogenic risks of lithium? (3 marks)

(b) How would you manage her medication during pregnancy and post-partum? (4 marks)

(c) What monitoring is required if lithium is continued? (3 marks)

Integrative Q3:

A 45-year-old man with schizophrenia on haloperidol 20 mg/day develops fever (40.2°C), generalised rigidity, altered consciousness, and CK of 18,000 U/L. Simultaneously, his SSRI was increased two weeks ago.

(a) What are the two most important differential diagnoses? (2 marks)

(b) How would you differentiate them clinically and on investigations? (4 marks)

(c) Outline management for each. (4 marks)

Quick Review

30 Rapid-Fire Q&A

Format: Question → Answer → Examiner tip where relevant

Q01

What is the mechanism of action of vortioxetine that makes it a "multimodal" antidepressant?

Vortioxetine acts at 6 targets simultaneously: SERT inhibitor + 5-HT1A partial agonist + 5-HT1B partial agonist + 5-HT3 antagonist + 5-HT7 antagonist + 5-HT1D antagonist. The 5-HT3 antagonism increases acetylcholine in the prefrontal cortex, explaining its cognitive benefits. The 5-HT7 antagonism modulates circadian rhythm and sleep architecture.

Q02

What are the Hunter Serotonin Toxicity Criteria? Give any two diagnostic patterns.

Hunter criteria require a serotonergic agent PLUS one of five patterns, all involving clonus or hyperreflexia:

1. Spontaneous clonus alone
2. Inducible clonus + agitation or diaphoresis
3. Ocular clonus + agitation or diaphoresis
4. Tremor + hyperreflexia
5. Hypertonia + temperature >38°C + ocular or inducible clonus

Sensitivity 84%, specificity 97%, superior to Sternbach criteria.

Q03

What is the REMS programme for esketamine, and why is it required?

REMS = Risk Evaluation and Mitigation Strategy. For esketamine (Spravato): drug dispensed only in certified healthcare settings (not pharmacy); patient monitored for 2 hours post-dose for dissociation, sedation, and blood pressure elevation; patient cannot drive on dosing day; healthcare setting must enrol in REMS programme.

Required because of: abuse potential (Schedule III), high rates of dissociation (>50%), significant BP elevation, and the impossibility of safe unsupervised self-administration.

Q04

What is the key difference between NMS and serotonin syndrome on neurological examination?

NMS: lead-pipe rigidity + normal or reduced reflexes + NO clonus.

Serotonin syndrome: clonus (spontaneous, inducible, ocular) + hyperreflexia + mild-to-moderate rigidity.

Clonus is present in SS and absent in NMS. This single finding is the most reliable bedside differentiator.

Q05

Name the three approved dual orexin receptor antagonists (DORAs) and their half-lives.

1. Suvorexant (Belsomra), ~12 hours, FDA 2014
2. Lemborexant (Dayvigo), ~17–27 hours, FDA 2019
3. Daridorexant (Quviviq), ~8 hours, FDA 2022

Daridorexant has the shortest half-life and the best next-day performance profile. Lemborexant has the longest half-life and is preferred for sleep maintenance in elderly patients.

Q06

What is the TRS definition required before initiating clozapine (TRRIP consensus)?

Inadequate response (CGI-S ≥4, persistent positive symptoms) despite:

• ≥2 adequate antipsychotic trials
• At least one must be a second-generation antipsychotic
• Each trial at adequate dose (≥600 mg chlorpromazine equivalents)
• Each trial for adequate duration (≥6 weeks)
• With documented adherence

Q07

What is the clozapine ANC monitoring schedule?

• Weeks 1–26: Weekly ANC
• Weeks 27–52: Every 2 weeks
• After 52 weeks: Monthly

Thresholds: ≥1500 = continue; 1000–1499 = continue with increased monitoring; 500–999 = interrupt and monitor daily; <500 = STOP permanently (agranulocytosis, never re-challenge).

Q08

What is the mechanism of brexanolone and how does it differ from benzodiazepines?

Brexanolone is synthetic allopregnanolone, a positive allosteric modulator (PAM) of GABA-A receptors. Unlike benzodiazepines which modulate only synaptic γ2-subunit-containing GABA-A receptors, brexanolone modulates BOTH synaptic (γ2-containing) AND extrasynaptic (δ-subunit-containing) GABA-A receptors. Extrasynaptic GABA-A receptors mediate tonic inhibition in limbic regions, this is the proposed mechanism for the rapid antidepressant effect specific to postpartum depression.

Q09

What is the washout period required between fluoxetine and an MAOI, and why is it different from other SSRIs?

5 weeks, because fluoxetine has an active metabolite, norfluoxetine, with a half-life of approximately 4–16 days. At 5 half-lives of norfluoxetine, the drug is substantially cleared. All other SSRIs and SNRIs require only 2 weeks washout before starting an MAOI.

Going from MAOI to any serotonergic drug: always 2 weeks minimum (3 weeks for irreversible MAOIs like phenelzine and tranylcypromine in clinical practice).

Q10

What is the mechanism by which smoking reduces clozapine levels, and what is the clinical implication?

Cigarette smoke contains polycyclic aromatic hydrocarbons (PAHs) that strongly induce CYP1A2. Clozapine is metabolised primarily by CYP1A2. Heavy smokers (>10 cigarettes/day) may require 50–100% higher clozapine doses to achieve therapeutic levels.

Clinical implication: if a patient stops smoking (e.g., admitted to hospital), CYP1A2 induction is lost → clozapine levels rise → toxicity risk. Monitor clozapine levels with any change in smoking status.

Q11

What is the clinical significance of D3 receptor selectivity in cariprazine?

D3 receptors are concentrated in mesolimbic areas, prefrontal cortex, and hippocampus, circuits governing motivation, reward, and cognition. Cariprazine has 20× selectivity for D3 over D2. High-affinity D3 partial agonism is proposed to improve negative symptoms of schizophrenia (avolition, anhedonia) by restoring reward salience and motivational drive. The RGH-MD-16 trial demonstrated statistically significant superiority of cariprazine over risperidone on PANSS negative symptom scores, the first such finding in a head-to-head trial.

Q12

Name four drugs that raise lithium levels and explain one mechanism.

1. NSAIDs, reduce renal prostaglandins → ↓renal blood flow → ↓lithium clearance
2. ACE inhibitors/ARBs, reduce glomerular filtration rate → lithium retention
3. Thiazide diuretics, sodium depletion → compensatory lithium retention in proximal tubule
4. Dehydration/low-sodium diet, same mechanism as thiazides (proximal tubule Na/Li competition)

NSAIDs raise lithium levels by 50–100%. Activated charcoal does NOT help in lithium toxicity.

Q13

What are the indications for haemodialysis in lithium toxicity?

1. Lithium level >4.0 mmol/L (regardless of symptoms)
2. Lithium level >2.5 mmol/L with severe symptoms (seizures, coma, cardiovascular instability)
3. Anuric renal failure with any toxic level (cannot excrete lithium renally)
4. Rapidly rising lithium level despite IV saline

Q14

What is lumateperone's novel mechanism compared to all other antipsychotics?

Lumateperone is the only antipsychotic that acts as a D1 receptor agonist/partial agonist in the prefrontal cortex. All other antipsychotics either block D1 or have no D1 activity. Prefrontal D1 stimulation is predicted to improve cognition and negative symptoms. Additionally, lumateperone has dual D2 activity (pre-synaptic agonist + post-synaptic antagonist) and SERT inhibition, explaining its approval for both schizophrenia and bipolar I + II depression.

Q15

What distinguishes pimavanserin from all other antipsychotics, and what is its approved indication?

Pimavanserin has NO dopamine receptor binding, it is a 5-HT2A and 5-HT2C inverse agonist only. This makes it the only antipsychotic that does not worsen motor symptoms in Parkinson's disease. It is FDA-approved specifically for Parkinson's disease psychosis (PDP), the only drug with this indication. Because it avoids D2 blockade, it does not cause EPS, worsening of tremor/rigidity, or prolactin elevation.

Q16

What is the mechanism of Auvelity (dextromethorphan-bupropion) and why are the two drugs combined?

Dextromethorphan (DXM) is an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist with ketamine-like antidepressant mechanisms. However, DXM is rapidly metabolised by CYP2D6 in extensive metabolisers. Bupropion is a potent CYP2D6 inhibitor, when co-administered, it raises DXM levels 8-fold to therapeutic concentrations. Bupropion also contributes NDRI antidepressant activity independently. The combination achieves NMDA antagonism via an oral route without requiring IV administration or REMS.

Q17

What are the four cardinal features of NMS?

1. Hyperthermia (>38°C, often >40°C)
2. Lead-pipe muscle rigidity (generalised, severe)
3. Altered consciousness (confusion → stupor → coma)
4. Autonomic instability (tachycardia, labile BP, diaphoresis, tachypnoea)

Supporting findings: very elevated CK (>1000 U/L), leukocytosis, low serum iron, metabolic acidosis, myoglobinuria.

Q18

What is supersensitivity psychosis and how do you prevent it?

Supersensitivity psychosis occurs after abrupt antipsychotic discontinuation. Chronic D2 blockade → compensatory upregulation of D2 receptors. Abrupt withdrawal → dopaminergic rebound → florid psychosis within days, often more severe and atypical than the original illness.

Prevention: gradual taper, minimum 3–6 months for long-term use; for clozapine: 6–12 months taper. Never abruptly stop antipsychotics in chronic schizophrenia.

Q19

What is the CYP2D6 ultrarapid metaboliser phenotype and its clinical significance in psychiatry?

Ultrarapid metabolisers (UM) carry duplicated or amplified CYP2D6 genes, they metabolise CYP2D6 substrates very rapidly, resulting in sub-therapeutic drug levels. Clinical consequence: patients on tricyclic antidepressants, risperidone, aripiprazole, or haloperidol may show treatment failure at standard doses. Prevalence: ~1–2% Caucasians; up to 29% in Ethiopian populations.

Codeine (a prodrug activated by CYP2D6 to morphine): UMs may produce excessive morphine → toxicity risk. PMs get no analgesia.

Q20

What is HLA-B*1502 and when must it be tested?

HLA-B*1502 is a genetic variant of the Human Leukocyte Antigen complex found predominantly in individuals of East and Southeast Asian descent (Han Chinese ~10%, Thai ~8%, South Asian ~2–4%). Carriers who receive carbamazepine face dramatically elevated risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), life-threatening mucocutaneous reactions.

Must be tested: before initiating carbamazepine (or oxcarbazepine) in any patient of Asian ancestry. FDA label mandates this testing. If positive → do not prescribe carbamazepine; use valproate or lamotrigine instead.

Q21

Enumerate the evidence-based FDA-approved augmentation strategies for treatment-resistant depression.

1. Aripiprazole + antidepressant (SSRI/SNRI), FDA approved
2. Quetiapine XR + antidepressant, FDA approved
3. Brexpiprazole + antidepressant, FDA approved
4. Olanzapine + fluoxetine (OFC), FDA approved (bipolar depression + TRD)
5. Esketamine nasal spray + oral antidepressant, FDA approved (TRD 2019; MDSI 2020)

Non-FDA approved but Level I evidence: lithium augmentation of antidepressants.

Q22

What is the peripartum mechanism hypothesis for postpartum depression and how does brexanolone target it?

During pregnancy, progesterone is metabolised to allopregnanolone → GABA-A receptor adaptations to chronically elevated allopregnanolone (downregulation of surface receptors, subunit changes). At delivery, allopregnanolone falls precipitously → GABA-A receptor excitability surge → PPD in vulnerable women.

Brexanolone = synthetic allopregnanolone. IV administration replaces the lost allopregnanolone signal, restoring GABA-A function → rapid antidepressant effect within 24–48 hours. This is pharmacologically distinct from SSRIs, which act on monoamine systems and take 4–8 weeks.

Q23

What are the prerequisites for switching from paliperidone palmitate 1-monthly (PP1M) to 3-monthly (PP3M)?

1. Patient must have been adequately treated with PP1M for at least 4 months
2. Last two consecutive PP1M doses must be at the same dose level (dose must be stable)
3. PP3M dose = 3.5 × PP1M dose
4. PP3M can be administered at deltoid or gluteal sites (unlike PP1M which requires deltoid for first two doses)

Q24

What is the Ashton Protocol and when is it used?

The Ashton Protocol is a benzodiazepine tapering method developed by Prof. Heather Ashton. Key principles:

• Convert all short-acting benzodiazepines to equivalent diazepam dose
• Reduce diazepam dose by approximately 10% every 1–2 weeks
• Taper can take months to years for long-term high-dose users
• Adjuncts: carbamazepine or valproate to reduce seizure risk during taper

Used for: benzodiazepine dependence management. Prevents withdrawal seizures and delirium while minimising protracted withdrawal syndrome.

Q25

What is pimavanserin's key safety concern and the FDA black box warning?

QTc prolongation, pimavanserin carries moderate QTc prolongation risk. Avoid with other QTc-prolonging drugs (antiarrhythmics, some antipsychotics, azithromycin).

FDA black box warning: increased risk of death in elderly patients with dementia-related psychosis (class warning shared by all antipsychotics). Despite its Parkinson's Disease Psychosis approval, this warning applies and pimavanserin should not be used for dementia-related psychosis outside of PDP.

Q26

What is the mechanism of action of psilocybin in depression and what neural network does it disrupt?

Psilocybin is dephosphorylated to psilocin → 5-HT2A agonist in prefrontal cortex, anterior cingulate, thalamus, and limbic areas.

Key neural network disrupted: Default Mode Network (DMN), the medial prefrontal cortex, posterior cingulate cortex, and angular gyrus network. The DMN is hyperconnected in depression and mediates self-referential rumination. Psilocin disrupts DMN connectivity → ego dissolution + reduced rumination. Simultaneously increases global brain connectivity (hyperconnected state) and promotes neuroplasticity via BDNF-mTOR-synaptogenesis cascade.

Q27

What is the clinical significance of valproate inhibiting UGT enzymes?

Valproate inhibits UDP-glucuronosyltransferase (UGT) enzymes, specifically UGT1A4 and UGT2B7. Clinical consequence: lamotrigine is primarily metabolised by UGT. When valproate is added to lamotrigine, lamotrigine levels double.

Practical rule: When adding valproate to a patient already on lamotrigine → halve the lamotrigine dose immediately. When starting lamotrigine in a patient already on valproate → use half the usual lamotrigine titration schedule. Failure to follow this → lamotrigine toxicity and potentially Stevens-Johnson syndrome.

Q28

What distinguishes brexpiprazole from aripiprazole pharmacologically?

Both are dopamine partial agonists. Key differences:

• Brexpiprazole has LOWER intrinsic activity at D2 than aripiprazole (more antagonist-like behaviour)
• Brexpiprazole has MORE potent 5-HT1A partial agonism
• Brexpiprazole has MORE potent α1B and α2C adrenergic antagonism
• Clinical result: brexpiprazole causes LESS akathisia than aripiprazole
• Brexpiprazole is FDA-approved for Alzheimer's disease agitation (2023), aripiprazole is not approved for this

Q29

What are the three phases of psilocybin-assisted psychotherapy?

1. Preparation sessions (2–3 sessions): Build therapeutic alliance; set intentions; psychoeducation about the experience; reduce anticipatory anxiety; establish safety protocols
2. Drug session(s) (1–3 sessions): Supervised in a carefully designed environment (comfortable room, curated music, eye shades); therapist present throughout 6–8 hours; non-directive supportive presence
3. Integration sessions (2–4 sessions): Process the experience; translate insights into behaviour change; CBT-like work; address challenging content from the drug session

The set (psychological state/intention), setting (physical and relational environment), and therapeutic relationship are considered pharmacologically relevant to outcomes, not just the drug.

Q30

What is the dose conversion rule for PP3M and what does PDSS mean in the context of LAI antipsychotics?

PP3M dose conversion: PP3M dose (mg) = PP1M monthly dose (mg) × 3.5

Example: Patient on PP1M 78 mg monthly → PP3M 273 mg every 3 months (nearest available dose: 263 mg)

PDSS = Post-Injection Delirium/Sedation Syndrome, a rare but serious adverse effect unique to olanzapine pamoate (Zypadhera). It occurs when olanzapine pamoate crystals enter the bloodstream during injection, releasing a bolus of olanzapine rapidly → sudden sedation, delirium, or cardiovascular collapse. Incidence: ~0.07% per injection. Management: 3-hour mandatory monitoring in a healthcare setting after every injection. This is why olanzapine pamoate requires on-site monitoring unlike other LAIs.

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