GC168 I Heard Those Newer Drugs Are Better Than My Current Psychiatric Medications
A clinical education session addressing patient concerns about switching established psychiatric medications to newer agents, emphasizing that newer psychotropic drugs are not inherently superior and that treatment decisions should be individualized based on efficacy, side-effect profiles, and patient response.
This lecture (GC 168, Dr. Albert Chung) tackles a deceptively simple patient question — "I heard those newer drugs are better than my current psychiatric medications" — and uses it as a vehicle to teach the neuropharmacology, side-effect profiles, and evidence base for antidepressants (ADs) and antipsychotics (APs). The central message is that "newer" does not automatically mean "better." The choice of psychotropic medication should be guided by understanding of receptor pharmacology, individual side-effect profiles, and evidence from large-scale meta-analyses, not by marketing or recency bias.
Learning Objectives [1]:
- Describe the neuropharmacology of antidepressants and antipsychotics
- List the common side-effects of antidepressants and antipsychotics
- Distinguish the neuropharmacological differences between traditional and newer types of antidepressants, and their side-effect profiles
- Distinguish the neuropharmacological differences between 1st and 2nd generation antipsychotics, and their side-effect profiles
Exam Relevance
AOS contributors note that medication questions on the psych paper commonly fail — particularly around antidepressants, antipsychotics, mood stabilizers, and the principle that "sleeping pills and BZD will NOT be used in long-term management" [2]. This lecture is the primary source for these pharmacology MCQs.
Part 1: Antidepressants
1.1 The Monoamine Deficiency Hypothesis
The Monoamine Deficiency Hypothesis of Depression formed the earlier basis for antidepressants. [1]
The hypothesis states that depression arises from a deficiency in one or more monoamine neurotransmitters — serotonin (5-HT), noradrenaline (NA), and dopamine (DA) — in the synaptic cleft. All traditional antidepressants work by increasing the availability of these monoamines.
Why does this matter? Understanding this hypothesis is essential because it directly explains the mechanism of action of every major antidepressant class. It also explains why drugs with very different chemical structures can all treat depression — they all converge on increasing monoamine transmission.
The lecture specifically highlights evidence at two levels:
"Manufacturer" level (presynaptic):
- Inhibition of tyrosine hydroxylase (rate-limiting enzyme for catecholamine synthesis) or depletion of dietary tryptophan (precursor for serotonin)
- Increased frequency of a mutation in brain-specific tryptophan hydroxylase (TPH-2) — the enzyme that converts tryptophan to 5-hydroxytryptophan (a serotonin precursor)
- Increased specific ligand binding to MAO-A — more MAO-A means faster breakdown of monoamines
"Customer" level (postsynaptic/signaling):
- Sub-sensitive 5-HT1A receptors
- Malfunctioning 5-HT1B receptors and/or decreased levels of p11
- Polymorphisms of the serotonin-reuptake transporter (SERT) — genetic variants affect how much serotonin is cleared from the synapse
- Inadequate G-protein response to neurotransmitter signals
- Reduced levels of cAMP, inositol, and CREB
High Yield
The "manufacturer vs customer" framing is the lecturer's own way of explaining presynaptic vs postsynaptic/signal-transduction deficits. If an exam question asks "what molecular evidence supports the monoamine hypothesis," recall these two levels.
Monoamine-related targets: Monoamine Oxidase (MAO); Serotonin system (serotonin, 5-HT1A, 5-HT2A, 5-HT2C); Noradrenaline system (α1, α2); Dopamine system. Complex interaction of 5-HT, NA, and DA systems exist in patients with depression.
This tells you that antidepressants don't just increase serotonin — they can act on any combination of these targets. The specific receptor profile of each drug determines its therapeutic and side-effect profile.
7 subtypes of serotonin receptors (5-HT1 to 5-HT7); some subtypes are further subdivided and mediate different functions. [1]
Key subtypes for this lecture:
- 5-HT1A: Autoreceptor on raphe neurons. When blocked or desensitized → ↑serotonin release. Also involved in anxiolysis.
- 5-HT2A: Blockade → helps negative symptoms, sleep, reduces EPSE when combined with D2 blockade (critical for understanding SGAs)
- 5-HT2C: Blockade → ↑NA and DA release → can improve cognition and mood but also contributes to weight gain
In addition to increasing serotonin availability at the synaptic cleft, targeting specific subtypes of 5-HT receptors also help depression via NA and DA systems. [1]
This is a subtle but important point: blocking 5-HT2C receptors removes the tonic inhibition on NA and DA pathways, effectively "disinhibiting" them. This is why some drugs that act primarily on serotonin can also improve dopaminergic and noradrenergic function.
Increased cortisol level in depression is associated with reduced hippocampal volume, reduced brain-derived neurotrophic factor (BDNF) and neurogenesis. Antidepressants targeted on monoamine systems help stabilize and/or improve depression via stabilizing the cAMP/CREB/BDNF system. [1]
The pathway: Activation of cAMP cascade → enhanced induction of CREB → enhanced BDNF → neurogenesis
Why does this matter? This hypothesis explains:
- Why depression is associated with cognitive and memory impairment (hippocampal atrophy)
- Why antidepressants take 2-4 weeks to work — you need time for BDNF-mediated neuroplasticity
- Why chronic stress (via cortisol) is a risk factor for depression
"Cognitive Neuropsychological Model" — negative emotional processing bias is corrected early, but subjective mood improvement takes 2-4 weeks. [1]
Two explanations from the lecture:
-
Cognitive Neuropsychological Model: Antidepressants rapidly correct the negative bias in emotional processing (within days), but the patient doesn't feel better until this translates into changed emotional experiences over 2-4 weeks.
-
Neuroadaptive delay: Presynaptic autoreceptors (e.g., 5-HT1A) initially counteract the increased serotonin. Over 2-4 weeks, these autoreceptors desensitize/downregulate, allowing the full antidepressant effect. Additionally, downstream changes (BDNF, neurogenesis) take time.
Clinical Pearl
A common exam trap: students say antidepressants "don't work" after 1 week. The correct counselling is to tell patients it takes at least 2-4 weeks for therapeutic effects. Side effects, however, often appear earlier. This is critical for compliance counselling.
1.5 Classification of Antidepressants — By Mechanism
The lecture explicitly classifies antidepressants by their mechanism of action rather than by chemical structure [1]:
| Class | Key Mechanism | Examples | Key Features |
|---|---|---|---|
| TCAs (Non-selective monoamine RI + antagonists) | SRI + NRI + H1, α1, M1, 5-HT2C blockade | Amitriptyline, Imipramine, Clomipramine, Nortriptyline | Effective but "dirty" — multiple receptor actions cause many side effects |
| MAOIs | Inhibit MAO → ↑5-HT, NA, DA | Phenelzine, Tranylcypromine, Moclobemide (RIMA) | Dietary restrictions (tyramine crisis); drug interactions |
| SSRIs | Selective serotonin reuptake inhibition | Fluoxetine, Sertraline, Paroxetine, Citalopram, Escitalopram, Fluvoxamine | First-line; best tolerability profile |
| SNRIs | Serotonin + noradrenaline reuptake inhibition | Venlafaxine, Duloxetine, Desvenlafaxine | "Dual action"; also used for pain, anxiety |
| NaSSA | α2 antagonist + 5-HT2A/2C/3 antagonist + H1 | Mirtazapine | ↑NA & 5-HT release; sedating, weight gain |
| NDRI | NA + DA reuptake inhibition | Bupropion | Activating; used for smoking cessation; weight neutral |
| Multimodal/SPaARI | 5-HT partial agonist/antagonist + SRI | Vortioxetine | Pro-cognitive effects |
| Glutamatergic | NMDA receptor antagonism | Esketamine (Spravato) | For treatment-resistant depression |
TCAs possess: H1 (histaminergic-1 receptor antagonist), α1 (adrenergic-1 receptor antagonist), M1 (muscarinic/ACh receptor antagonist), 5-HT2C/2A (serotonin receptor antagonist), SRI (serotonin reuptake inhibitor), NRI (noradrenaline reuptake inhibitor). [1]
TCAs are "non-selective" because they hit many receptors. Their therapeutic effect comes from SRI + NRI, but their side-effect profile comes from the additional blockade:
| Receptor Blocked | Side Effect |
|---|---|
| H1 (histamine) | Sedation, weight gain |
| α1 (adrenergic) | Postural hypotension, sedation |
| M1 (muscarinic) | Dry mouth, constipation, urinary retention, blurred vision, glaucoma |
| Cardiac Na channels | QT prolongation, arrhythmias → dangerous in overdose |
Why are TCAs still used? They remain useful for neuropathic pain (amitriptyline), OCD (clomipramine), and treatment-resistant depression. But they are not first-line due to side effects and lethality in overdose.
Some SSRIs possess additional, though weaker, monoamine antagonistic/RI properties. [1]
| SSRI | Additional Properties |
|---|---|
| Fluoxetine | NRI, 5-HT2C antagonist |
| Sertraline | Dopamine RI |
| Paroxetine | M1, NRI |
| Citalopram | H1 |
| Escitalopram | S-isomer of citalopram; "cleanest" SSRI |
Why does this matter? These additional properties explain subtle clinical differences:
- Fluoxetine is more activating (NRI + 5-HT2C → ↑NA, DA); long half-life (good for compliance, less discontinuation syndrome)
- Sertraline has mild DA effect — may help anhedonia
- Paroxetine has muscarinic blockade → more sedating, more weight gain, more discontinuation symptoms (short half-life)
- Escitalopram is the "purest" SSRI with fewest off-target effects
Venlafaxine and duloxetine are SNRIs — dual serotonin and noradrenaline reuptake inhibition. [1]
At low doses, venlafaxine is essentially an SSRI; the NRI effect kicks in at higher doses. Duloxetine has more balanced SRI/NRI from the start. SNRIs are useful for:
- Depression with prominent fatigue/pain
- Generalized anxiety disorder
- Neuropathic pain (duloxetine)
The lecture specifically covers these "newer" agents:
Mirtazapine (NaSSA) [1]:
- Blocks α2 autoreceptors → ↑NA and 5-HT release
- Blocks 5-HT2A, 5-HT2C, 5-HT3 → fewer sexual side effects, less nausea
- Blocks H1 → very sedating, causes weight gain
- Clinical pearl: Useful in patients who need sleep and appetite improvement. "California rocket fuel" = mirtazapine + venlafaxine (combination for refractory depression)
Bupropion (NDRI) [1]:
- Noradrenaline + dopamine reuptake inhibitor
- Activating; no sexual side effects; weight neutral
- Also used for smoking cessation
- Caution: Lowers seizure threshold
Vortioxetine (SPaARI — "Multimodal") [1]:
- SRI + 5-HT1A partial agonist + 5-HT3, 5-HT1D, 5-HT7 antagonist
- Pro-cognitive effects — beneficial for depressed patients with cognitive complaints
- The "multimodal" mechanism simultaneously modulates multiple 5-HT receptor subtypes
Esketamine (Spravato) [1]:
FDA approved treatment as augmentation medication in treatment-resistant depression.
This is a landmark drug — the first truly novel mechanism in decades:
Pharmacodynamics: (1) Disinhibition Hypothesis: NMDA blockade on GABA-interneurons → ↑glutamate release → activation of AMPA receptors → ↑BDNF → dendritic sprouting and synaptogenesis in corticolimbic brain regions. (2) Direct Inhibition of NMDA receptors with GluN2B subunits → eEF2 dephosphorylation → ↑BDNF translation. [1]
Pharmacokinetics: extensive hepatic metabolism by CYP450 3A4 & 2B6. [1]
Why is esketamine revolutionary? It produces rapid antidepressant effects (hours to days, not weeks) by acting on glutamate rather than monoamines. It is given as a nasal spray under clinical supervision due to risks of dissociation, sedation, and abuse potential.
Clinical uses include: Depressive Disorders, Anxiety Disorders, PTSD, OCD, Sexual Disorders, Eating Disorders (AN/BN). [1]
Actions: Increase 5-HT, DA and NA. "Unwanted" actions can sometimes be therapeutically useful: Anti-histaminergic → promotes sleep, weight gain; 5-HT effects → weight gain, delayed ejaculation useful for premature ejaculation. [1]
This is a key exam concept: side effects can become therapeutic effects in the right context. For example:
- Mirtazapine's sedation and appetite stimulation → useful in depressed elderly patients with insomnia and poor appetite
- SSRI-induced delayed ejaculation → used off-label for premature ejaculation
Side effects depend on receptor profiles. [1]
| Receptor Profile | Adverse Effects |
|---|---|
| 5-HT | Serotonin Syndrome (delirium, autonomic instability, pyrexia, diaphoresis, GI symptoms, restlessness, hyperreflexia, rigidity, convulsion, coma) — especially with MAOIs + SSRIs/TCAs; SSRI discontinuation syndrome (electric shock-like sensations, dizziness, headache, lethargy, GI upset, insomnia, mood changes); Weight gain; Sexual side effects (delayed ejaculation, ED, retrograde ejaculation, anorgasmia, ↓libido) |
| Anti-muscarinic (M1) | Dry mouth, constipation, urinary retention, blurred vision, visual accommodation problems, glaucoma |
| Anti-adrenergic (α1) | Postural hypotension, sedation |
| Anti-histaminergic (H1) | Weight gain, sedation |
Serotonin Syndrome — Medical Emergency
Serotonin Syndrome occurs especially with MAO-I in combination with SSRIs/TCAs.* [1] The classic triad is: mental status changes + autonomic instability + neuromuscular abnormality (hyperreflexia, clonus, rigidity). Treatment: stop offending agents, supportive care, cyproheptadine (5-HT2A antagonist). This is distinct from NMS (which involves D2 blockade, not serotonin excess).
SSRI discontinuation syndrome: sensory abnormality (electric shock-like sensation), dizziness, headache, lethargy, GI upsets, insomnia, mood change (depressed/anxious feelings). [1]
Why does discontinuation syndrome occur? Abrupt withdrawal of SSRIs causes sudden serotonin deficiency at desensitized postsynaptic receptors. It is worst with short half-life agents (paroxetine, venlafaxine) and rare with fluoxetine (long half-life, self-tapering).
FDA warnings on prescribing antidepressants in child and adolescence group of patients due to potential increased risk of suicidality. [1]
This is the black box warning. The mechanism is thought to be that antidepressants may initially increase energy/motivation before lifting mood, creating a window where a suicidal patient now has the drive to act on suicidal thoughts. Close monitoring is essential in the first weeks.
"Is there any efficacious difference amongst ADs clinically?" — the latest evidence from 522 double-blind RCTs [1]
The lecture references the landmark Cipriani et al. (2018) Lancet network meta-analysis. Key findings from the slide:
Agomelatine, Escitalopram, Mirtazapine, Sertraline, and Venlafaxine were among the most efficacious and acceptable antidepressants. All were superior to placebo. [1]
The bottom line: All antidepressants are roughly similar in efficacy. The choice between them should be guided by side-effect profile, patient preference, comorbidities, and drug interactions — not by the assumption that newer is better.
High Yield for Exams
All antidepressants have broadly comparable efficacy. The key differentiator is their side-effect profile, which is determined by their receptor-binding profile. "Newer" does not necessarily mean "better." This is the central take-home message of the lecture.
Gut-Brain Hypothesis [1]:
Research on gut microbiota and their relation to depression in animals and human beings is an evolving area. The gut-brain axis communicates via the vagus nerve, immune signaling, and microbial metabolites (e.g., short-chain fatty acids, tryptophan metabolites). This is still largely preclinical.
"Are these 'antidepressants'???" [1] — The lecture ends the AD section by questioning whether interventions like exercise, psychotherapy, and lifestyle modification should also be considered "antidepressants" given their evidence base.
Part 2: Antipsychotics
4 important dopamine pathways: Mesolimbic, Mesocortical, Nigrostriatal, Tuberoinfundibular. [1]
| Pathway | Normal Function | Effect of ↑DA | Effect of D2 Blockade |
|---|---|---|---|
| Mesolimbic | Reward, motivation | Positive symptoms (hallucinations, delusions) | ✅ Therapeutic — reduces positive symptoms |
| Mesocortical | Cognition, executive function | — | ❌ Worsens negative symptoms (anhedonia, avolition, alogia) and cognition |
| Nigrostriatal | Motor control | Dyskinesia | ❌ Causes EPSE (parkinsonism, dystonia, akathisia, tardive dyskinesia) |
| Tuberoinfundibular | Inhibits prolactin release | — | ❌ Causes hyperprolactinaemia → galactorrhoea, amenorrhoea, sexual dysfunction, osteoporosis |
The core problem with FGAs: They block D2 in ALL four pathways, so while they treat positive symptoms (mesolimbic), they cause EPSE (nigrostriatal), worsen negative symptoms (mesocortical), and raise prolactin (tuberoinfundibular).
"D1-like" family: D1 and D5 → increases intracellular cAMP. "D2-like" family: D2, D3, D4 → decreases intracellular cAMP. [1]
Antipsychotics primarily target the D2-like family. The D2 receptor is the main target for antipsychotic efficacy.
FGAs are classified by chemical class: [1]
| Chemical Class | Examples |
|---|---|
| Phenothiazine — Aliphatic | Chlorpromazine |
| Phenothiazine — Piperidine | Thioridazine, Perphenazine |
| Phenothiazine — Piperazine | Trifluoperazine, Fluphenazine |
| Thioxanthene | Thiothixene, Flupentixol, Zuclopenthixol |
| Butyrophenone | Haloperidol |
| Diphenylbutylpiperidine | Pimozide |
| Substituted Benzamide | Sulpiride |
FGAs have additional receptor blockade: H1, α1/2, M1, D2. Side-effect profiles depend on these receptor blockades. [1]
High-potency FGAs (e.g., haloperidol, fluphenazine): Strong D2 blockade → more EPSE, less sedation/hypotension Low-potency FGAs (e.g., chlorpromazine, thioridazine): Weaker D2 but strong H1/α1/M1 → less EPSE but more sedation, hypotension, anticholinergic effects
FGAs are potent D2 blockers. [1]
"Antipsychotic threshold" vs Extra-pyramidal Side-effect (EPSE) [1]
The therapeutic window for FGAs is narrow. You need ~65-70% D2 occupancy for antipsychotic effect, but >80% occupancy causes EPSE. FGAs bind tightly and for long durations, making it hard to stay in the therapeutic window.
Types of EPSE (acute and chronic):
| EPSE | Onset | Mechanism | Features | Treatment |
|---|---|---|---|---|
| Acute dystonia | Hours to days | D2 blockade in nigrostriatal pathway | Sustained muscle contractions (torticollis, oculogyric crisis, laryngospasm) | Anticholinergics (benztropine, trihexyphenidyl), IM |
| Parkinsonism | Days to weeks | D2 blockade → ↓DA in nigrostriatal pathway | Tremor, rigidity, bradykinesia, mask-like facies | Reduce dose, switch drug, anticholinergics |
| Akathisia | Days to weeks | Unclear; possibly mesocortical D2 blockade | Subjective restlessness, inability to sit still | Beta-blockers (propranolol), benzodiazepines, reduce dose |
| Tardive dyskinesia | Months to years | D2 receptor supersensitivity from chronic blockade | Involuntary choreoathetoid movements (lip smacking, tongue protrusion) | Prevention best; reduce/stop offending drug; valbenazine, deutetrabenazine, clozapine |
Tardive Dyskinesia is delayed in onset. DSM-5-TR requires at least 3-month exposure to neuroleptics ( >1 month if age ≥60). Reported incidence ~5% adults with FGAs with persistence up to 68% in 25 years. ~0.8% adults for SGAs. [1]
High Yield — Tardive Dyskinesia
TD has a much lower incidence with SGAs (~0.8%) than FGAs (~5%). This is one of the strongest arguments for preferring SGAs. TD is often irreversible, which makes prevention (using lowest effective dose, preferring SGAs, monitoring with AIMS scale) critical.
NMS is a MEDICAL EMERGENCY in psychiatry with incidence ~0.01-3%; potentially fatal. Treatment: discontinuation of antipsychotics + supportive treatment. [1]
| Feature | Details |
|---|---|
| Mechanism | Sudden, severe D2 blockade (especially in nigrostriatal and hypothalamic pathways) |
| Classic tetrad | Hyperthermia, muscle rigidity ("lead-pipe"), altered mental status, autonomic instability |
| Labs | Markedly elevated CK, leukocytosis, elevated LFTs, metabolic acidosis |
| Risk factors | High-potency FGAs, rapid dose escalation, dehydration, IM injection |
| Treatment | Stop offending drug, supportive care (cooling, hydration), dantrolene (muscle relaxant), bromocriptine (DA agonist) |
NMS vs Serotonin Syndrome
Both cause altered mental status + autonomic instability + rigidity. Key discriminator: NMS has "lead-pipe" rigidity + very high CK + slow onset (days); Serotonin syndrome has clonus/hyperreflexia + rapid onset (hours) + associated with serotonergic drugs. NMS = D2 blockade; SS = 5-HT excess.
2.6 Second-Generation Antipsychotics (SGAs / "Atypical")
SGAs possess both 5-HT2A and D2 receptor blockade for core efficacy. [1]
| Chemical Class | Drug |
|---|---|
| Di-benzodiazepines | Clozapine |
| Thieno-benzodiazepine | Olanzapine |
| Di-benzo-thiazepine | Quetiapine |
| Benzisoxazoles | Risperidone |
| Imidazolidinone | Sertindole |
| Dibenzo-oxepino | Asenapine |
| Benzo-iso-thiazol | Lurasidone |
| Benzo-thiazolyl-piperazine | Ziprasidone |
Three reasons from the lecture:
- More limbic selective [1] — SGAs preferentially block D2 in the mesolimbic pathway rather than the nigrostriatal pathway
- Lower D2 affinity / "Fast-Off Theory" [1] — SGAs bind more loosely to D2 receptors and dissociate quickly, allowing endogenous dopamine to compete. This means transient D2 blockade sufficient for antipsychotic effect without sustained blockade that causes EPSE
- 5-HT2A antagonism — Blocking 5-HT2A receptors in the nigrostriatal pathway disinhibits DA release there, partially counteracting the D2 blockade and reducing EPSE
SGAs, in general, have lower affinity to D2 receptor than FGAs. D2 antagonism for SGAs is more limbic selective. [1]
Less "tight" in binding to D2 receptors — "Fast-Off Theory" / "Insurmountability" [1]
Different SGAs have different additional receptor blockade properties. [1]
| SGA | Key Additional Properties | Notable Side Effects |
|---|---|---|
| Clozapine | D1, D4, 5-HT2A, H1, α1, M1 | Agranulocytosis, seizures, weight gain, metabolic syndrome, myocarditis, constipation → intestinal obstruction |
| Olanzapine | 5-HT2A, H1, M1, M2 | Significant weight gain, metabolic syndrome |
| Quetiapine | 5-HT2A, H1, α1 | Sedation, weight gain, postural hypotension |
| Risperidone | 5-HT2A, α1, D2 | Hyperprolactinaemia (most prolactin-raising SGA), EPSE at higher doses |
| Aripiprazole | D2 partial agonist, 5-HT1A partial agonist, 5-HT2A antagonist | Akathisia, insomnia; weight neutral, low prolactin |
| Amisulpride | D2, D3 only | Hyperprolactinaemia (high at low doses) |
| Lurasidone | 5-HT2A, 5-HT7, D2 | Weight neutral; useful in bipolar depression |
| Ziprasidone | 5-HT2A, SRI, NRI | Weight neutral; QTc prolongation concern |
| Brexpiprazole | D2 partial agonist, 5-HT1A partial agonist, 5-HT2A antagonist | Similar to aripiprazole but less akathisia |
The SGA with dopamine D2 partial agonist — Aripiprazole — is termed a Dopamine System Stabilizer (DSS). [1]
What does "partial agonist" mean? Unlike full antagonists (which completely block D2), aripiprazole has intrinsic activity at the D2 receptor. In states of high dopamine (mesolimbic pathway in psychosis), it acts as a functional antagonist (competing with excess dopamine). In states of low dopamine (mesocortical pathway, nigrostriatal pathway), it provides some agonist activity — preventing the deficits caused by pure blockade.
What DSS can do [1]:
- Reduce positive symptoms (blocks excess DA in mesolimbic)
- Less worsening of negative/cognitive symptoms (maintains some DA in mesocortical)
- Less EPSE (partial agonism in nigrostriatal)
- Less hyperprolactinaemia (partial agonism in tuberoinfundibular)
- Weight neutral
The latest class: Serotonin-Dopamine Activity Modulator (SDAM), e.g., Brexpiprazole. [1]
Why do we need to get serotonin system involved? [1]
Brexpiprazole is a next-generation partial agonist (after aripiprazole). It has:
- D2 partial agonism (like aripiprazole)
- 5-HT1A partial agonism (stronger than aripiprazole → more anxiolysis)
- 5-HT2A antagonism (stronger than aripiprazole → further reduces EPSE)
The involvement of the serotonin system helps modulate dopaminergic activity more finely across all four pathways, with potentially fewer activating side effects (less akathisia than aripiprazole).
This is a critical exam table directly from the lecture slides: [1]
| Feature | FGAs | SGAs (excluding clozapine) |
|---|---|---|
| Receptor profiles | Various | Various (5-HT2A and/or D2 antagonism in common) |
| Site of action | All dopamine pathways | More limbic selective |
| D2 receptor occupancy | Higher affinity | Lower affinity, "Fast-off" theory, D2 partial agonism for aripiprazole/brexpiprazole |
| EPSEs | Higher incidence | Lower incidence |
| Hyperprolactinaemia | Higher incidence | Lower incidence (except amisulpride, risperidone & paliperidone) |
| Efficacy in negative symptoms | Lacking | Better (5-HT2A antagonism, D2 partial agonism, reduced EPSEs) |
| Efficacy in affective symptoms | Lacking (except flupenthixol) | All have indication for mania and/or depressive disorders (except amisulpride, paliperidone & sertindole) |
| Metabolic syndrome | Various | Increased risks, especially olanzapine (aripiprazole, lurasidone & ziprasidone → weight neutral) |
| QTc prolongation | Various (thioridazine & pimozide → highest risk) | Sertindole → significant increased risk; Aripiprazole → significant lowered risk |
High Yield — Exceptions to SGA Advantages
Risperidone, amisulpride, and paliperidone STILL cause significant hyperprolactinaemia despite being SGAs. Olanzapine has the highest metabolic risk among SGAs. Know these exceptions — examiners love testing them.
Prevalence of metabolic syndrome varies between different drugs. [1]
From the Korean study cited in the lecture:
| Drug | Metabolic Syndrome Prevalence |
|---|---|
| Quetiapine | 18.8% |
| Aripiprazole | 22.0% |
| Amisulpride | 33.3% |
| Paliperidone | 33.3% |
| Olanzapine | 34.0% |
| Risperidone | 35% |
| Haloperidol | 39.4% |
| Clozapine | 44.7% |
Can metabolic syndrome be related to receptor-binding profile of APs? [1]
Yes. The lecture references evidence that:
- H1 blockade → weight gain (appetite stimulation, sedation → less activity)
- 5-HT2C blockade → weight gain (removed satiety signal)
- M3 blockade → impaired insulin secretion → glucose dysregulation
- Direct effects on lipid metabolism via unknown mechanisms
Clinical implication: All patients on antipsychotics (especially olanzapine and clozapine) need regular metabolic monitoring: weight, waist circumference, fasting glucose, HbA1c, lipid panel.
Statistically significant lowered risk for aripiprazole on QTc prolongation has been demonstrated. [1]
However, a recently published meta-analysis showed that SGAs either caused non-significant reduction in QTc, or caused a statistically significant prolongation in QTc even for some recently launched new drugs. [1]
Clinical implication: Baseline ECG and monitoring are important, especially with:
- High-risk FGAs: thioridazine, pimozide
- High-risk SGAs: sertindole, ziprasidone
- Combination with other QTc-prolonging drugs
- Safest: aripiprazole
Specific Issues on Clozapine: [1]
| Issue | Details |
|---|---|
| Agranulocytosis/neutropenia | Worldwide consensus for regular CBP with ANC — weekly for first 18 weeks, then at least monthly. Stop if ANC < 1.5 × 10⁹/L |
| Seizures | Dose-dependent increased risk — higher doses → higher risk |
| Common side effects | Over-sedation, weight gain, hypotension, hyper-salivation, nocturnal enuresis, constipation |
| Rarer but important | Intestinal obstruction (from severe constipation) and cardiotoxicity (myocarditis) |
| Indications | Effective for treatment-resistant schizophrenia and tardive syndrome |
High Yield — Clozapine
Clozapine is the gold standard for treatment-resistant schizophrenia (failed ≥2 adequate trials of different antipsychotics). It is the only antipsychotic with proven superiority for this indication. The trade-off is its unique and dangerous side-effect profile, necessitating mandatory blood monitoring.
"Is there any efficacious difference between FGAs and SGAs clinically? Is there any efficacious difference amongst SGAs clinically?" [1]
SGAs vs FGAs (Leucht et al. 2009 Lancet) [1]:
- Only 4 SGAs were statistically superior to FGAs in overall efficacy: amisulpride, clozapine, olanzapine, risperidone
- The remaining SGAs showed no significant efficacy advantage over FGAs
- Take-home: The class effect of "SGAs are better than FGAs" is oversimplified. Some SGAs are better; many are equivalent.
SGAs vs SGAs (Kishimoto et al. 2019) [1]:
- Long-term head-to-head comparisons show olanzapine and clozapine tend to have the best efficacy outcomes
- But their side-effect burden (metabolic syndrome for olanzapine, agranulocytosis for clozapine) limits their use as universal first-line agents
The bottom line (mirroring the antidepressant conclusion): "Newer" does not automatically mean "better." The choice of antipsychotic should be individualized based on side-effect profile, patient comorbidities, and the specific clinical situation.
The last point… a particular problem in polypharmacy. [1]
The lecture ends with a reminder about drug-drug interactions, which are especially important in psychiatry where patients often receive multiple psychotropics. Key interactions to know:
| Interaction | Mechanism | Clinical Consequence |
|---|---|---|
| SSRI/SNRI + MAOI | ↑↑serotonin | Serotonin syndrome (potentially fatal) |
| Antipsychotics + anticholinergics | Additive M1 blockade | Cognitive impairment, delirium, urinary retention |
| Antipsychotics + QTc-prolonging drugs | Additive K+ channel blockade | Torsades de pointes |
| Carbamazepine (CYP3A4 inducer) + antipsychotics | ↓antipsychotic levels | Treatment failure |
| Fluvoxamine (CYP1A2 inhibitor) + clozapine | ↑clozapine levels | Toxicity (seizures, sedation) |
| SSRIs + warfarin | Altered platelet function + possible CYP interaction | Increased bleeding risk |
The AGS Beers Criteria [3] and STOPP-START criteria emphasize avoiding combinations of ≥3 CNS-active drugs in older adults, and specifically caution against anticholinergic burden from psychiatric medications.
When a Patient Asks "Are the Newer Drugs Better?"
- Acknowledge the question — it shows the patient is engaged in their care
- Explain that "newer ≠ better" — evidence shows broadly comparable efficacy within and across classes
- Explain why their current medication was chosen — based on their specific symptoms, comorbidities, and response
- Discuss side-effect profile — this is the main differentiator between drugs
- Reassure about monitoring — metabolic, ECG, blood counts as appropriate
- Only switch if clinically indicated — inadequate response, intolerable side effects, drug interactions
Exam Intelligence
| Trap | Correct Understanding |
|---|---|
| "SSRIs have no side effects" | They cause sexual dysfunction, GI upset, discontinuation syndrome, and rare but serious serotonin syndrome |
| "SGAs don't cause EPSE" | They cause less EPSE, but it can still occur, especially with risperidone at high doses |
| "All SGAs cause less hyperprolactinaemia" | Risperidone, amisulpride, paliperidone are exceptions — they significantly raise prolactin |
| "Clozapine is first-line for schizophrenia" | It is reserved for treatment-resistant schizophrenia (failed ≥2 adequate trials) |
| "Newer antidepressants are more efficacious" | Network meta-analysis shows all ADs have broadly similar efficacy; choice is by side-effect profile |
| "Tardive dyskinesia is an acute side effect" | It is a chronic/delayed side effect requiring ≥3 months exposure (≥1 month if age ≥60) |
| "NMS and serotonin syndrome are the same" | NMS = D2 blockade, lead-pipe rigidity, slow onset; SS = serotonin excess, clonus, rapid onset |
| "Aripiprazole is a D2 antagonist" | It is a D2 partial agonist — a "Dopamine System Stabilizer" |
| "Metabolic syndrome is only from SGAs" | FGAs can also cause it (haloperidol 39.4% in Korean study), but highest risk is with clozapine and olanzapine |
- Weight-neutral antipsychotics: aripiprazole, lurasidone, ziprasidone
- Weight-neutral antidepressant: bupropion
- Most sedating antidepressant: mirtazapine (H1 blockade)
- SSRI with longest half-life: fluoxetine (least discontinuation syndrome)
- SSRI with most anticholinergic effects: paroxetine
- SGA most likely to cause hyperprolactinaemia: risperidone/paliperidone
- Safest antipsychotic for QTc: aripiprazole
- Only antipsychotic proven superior in treatment-resistant schizophrenia: clozapine
- Esketamine mechanism: NMDA antagonism → ↑glutamate → AMPA activation → ↑BDNF
Past Paper Questions
Stem: "A 45-year-old woman presents at a follow-up at the General Outpatient Clinic (GOPC) for low mood and fatigue for the past 6 months. During the same time, she has had difficulty falling asleep because she is worried about her health. She has muscle tension, weight gain of 5 kg, and loss of concentration. She denies suicidal ideation. She lives alone and has few friends. Which of the following symptoms would be MOST SUGGESTIVE of depression over general anxiety disorder?"
Options: A. Difficulty falling asleep | B. Loss of concentration | C. Muscle tension | D. Weight gain
Answer: D. Weight gain
Rationale: Difficulty falling asleep (initial insomnia) and muscle tension are more characteristic of GAD. Loss of concentration occurs in both. Weight change (gain or loss) and early morning waking are more specific to MDD. Among the options, weight gain best discriminates depression from GAD.
Stem: "A 36-year-old clerk consulted a general practitioner for hypnotics to relieve his sleep problem. He complained of unhappy events that occurred recently. What is the MOST IMPORTANT area that needs to be covered in the consultation?"
Options: A. The dosage of hypnotics he wants | B. The family history of primary insomnia problem | C. The symptoms of psychiatric comorbidity should be explored | D. The type of hypnotics he wants
Answer: C. The symptoms of psychiatric comorbidity should be explored
Rationale: A patient presenting with sleep problems after "unhappy events" needs screening for depression, anxiety, and suicidal ideation — psychiatric comorbidity is the most important area. Hypnotics are not first-line for insomnia related to mood disorders; antidepressants are preferred for long-term management [2].
Stem: "Bipolar affective disorder (BAD) is a common and serious mood disorder. Which of the following is the diagnostic criterion listed in the DSM-V for bipolar I disorder?"
Options: A. Irritability must be present | B. Manic symptoms that have lasted for at least 1 week | C. Past or current depressive episodes should be present | D. Patients notice the mood change
Answer: B. Manic symptoms that have lasted for at least 1 week
Rationale: Bipolar I requires at least one manic episode ≥7 days (or any duration if requiring hospitalization). Depressive episodes are common but NOT required for diagnosis. Irritability can be present but is not mandatory. Patients often lack insight.
These EMQs test psychiatric diagnosis matching. Relevant to this lecture: understanding which disorders antidepressants treat (depression, GAD, panic disorder, OCD, PTSD) helps identify correct diagnoses.
- Q23: Constant worrying even when no specific threat → D. Generalised anxiety disorder
- Q24: Waking too early → E. Major depressive disorder (early morning waking is a biological symptom of depression)
- Q25: Recurrent episodes of SOB → G. Panic disorder
- Q26: Loss of pleasure → E. Major depressive disorder (anhedonia)
- Q27: Constant need to check → F. OCD
Stem: "Alzheimer's disease is the most common underlying cause of dementia. What is the MOST COMMON gene contributing to the risk of developing Alzheimer's disease?"
Options: A. APOE gene | B. COMT gene | C. SERT gene | D. TRIO gene
Answer: A. APOE gene
Rationale: APOE ε4 is the most common genetic risk factor for late-onset AD. COMT and SERT are relevant to psychiatric pharmacology (catechol-O-methyltransferase for dopamine metabolism, serotonin transporter polymorphisms for SSRI response) but not AD risk.
- GC 164 (Depression) and GC 167 (Anxiety) provide the clinical contexts in which these antidepressants are prescribed [7][8]
- GC 163 (Bipolar Disorder) covers mood stabilizers (lithium, valproate, lamotrigine) which are distinct from antidepressants and are the focus of different exam questions [9]
- GC 079 (Prescribing in Older People) and AGS Beers Criteria [3] highlight that anticholinergic antidepressants (TCAs, paroxetine) and antipsychotics with high anticholinergic burden should be avoided in elderly patients
- GC 169 (Dementia) — Antipsychotics in dementia carry a black box warning for increased mortality. Only use when non-pharmacological measures fail and psychosis is distressing/dangerous. Quetiapine and clozapine preferred in DLB due to lower D2 affinity [10]
- GC 070 (Is this the best drug for me) and GC 029 (Am I prescribing the right drug) cover pharmacogenomics (CYP2D6 poor metabolizers may have altered antidepressant/antipsychotic metabolism) and general principles of rational prescribing [11]
- Ryan Ho Psychiatry Notes [12] provide additional detail on schizophrenia management algorithms, refractory depression strategies (augmentation with lithium, T3, low-dose antipsychotic, ECT), and the neurodevelopmental hypothesis of schizophrenia
High Yield Summary
Antidepressants:
- All based on the Monoamine Deficiency Hypothesis (↑5-HT, NA, DA)
- Classifications: TCAs (non-selective), SSRIs, SNRIs, NaSSA (mirtazapine), NDRI (bupropion), Multimodal (vortioxetine), Glutamatergic (esketamine)
- Side effects determined by receptor profile: 5-HT → serotonin syndrome, sexual dysfunction; M1 → anticholinergic; H1 → sedation/weight gain; α1 → hypotension
- 2-4 week delay in therapeutic effect (neuroadaptive changes, BDNF/CREB pathway)
- All ADs have broadly similar efficacy — choice is by side-effect profile, not by "newer = better"
- FDA black box warning for suicidality in children/adolescents
Antipsychotics:
- Based on the Dopamine Hypothesis; 4 DA pathways explain both therapeutic and side effects
- FGAs: potent D2 blockade in all pathways → effective for positive symptoms but cause EPSE, hyperprolactinaemia
- SGAs: 5-HT2A + D2 blockade, more limbic selective, fast-off D2 binding → less EPSE but more metabolic side effects
- Aripiprazole (DSS) = D2 partial agonist → weight neutral, low EPSE, low prolactin
- Clozapine: gold standard for treatment-resistant schizophrenia; requires mandatory blood monitoring for agranulocytosis
- NMS is a medical emergency: stop antipsychotic, supportive care, dantrolene/bromocriptine
- "Newer ≠ better" — SGAs not uniformly superior to FGAs; only clozapine, olanzapine, risperidone, amisulpride shown superior in meta-analyses
- Drug-drug interactions critical in polypharmacy
Active Recall - Lecture Notes
[1] Lecture slides: GC 168. I heard those newer drugs are better than my current psychiatric medications.pdf [2] AOS material: AOS - Psych.md [3] GC lecture slides: GC 079 (supp-3)AGS Beers Criteria for potentially inappropriate med use_2023.pdf [4] Past papers: 2023 Fourth Summative MCQ.pdf [5] Past papers: 2025 Fourth Summative MCQ.pdf [6] Past papers: 2020 Fourth Summative Assessment MCQ paper.pdf [7] Lecture slides: GC 164. I am depressed Mood disorders.pdf [8] Lecture slides: GC 167. I feel very nervous Anxiety disorders.pdf [9] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf [10] Reference: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf [11] Lecture slides: GC 070. Is this the best drug for me.pdf; GC 029. Am I prescribing the right drug.pdf [12] Senior notes: Ryan Ho Psychiatry.pdf
GC167 I Feel Very Nervous Anxiety Disorders
Anxiety disorders are a group of mental health conditions characterized by excessive, persistent fear, worry, or nervousness that causes significant distress and impairment in daily functioning.
GC169 My Grandmother Keeps Forgetting Things Geriatric Psychiatry, Dementia
Dementia is a chronic, progressive neurodegenerative syndrome characterized by decline in memory, cognition, and functional ability sufficient to impair independent daily living, most commonly caused by Alzheimer's disease in the elderly.