GC168 I Heard Those Newer Drugs Are Better Than My Current Psychiatric Medications

7 receptor families (5-HT1 to 5-HT7); several contain further subtypes and mediate different functions. ^[1]

The slide's membrane cartoons add an easy structural discriminator: most 5-HT receptors are seven-transmembrane G-protein-coupled receptors, whereas 5-HT3 is a ligand-gated ion channel.

Key subtypes for this lecture:

• 5-HT1A: Somatodendritic autoreceptor on raphe neurons; its activation initially restrains firing, and later adaptation/desensitisation is one proposed contributor to delayed SSRI effects. Postsynaptic 5-HT1A signalling also differs by circuit.
• 5-HT2A: Antagonism is common in many SGAs and may modulate nigrostriatal dopamine/EPS; it does not guarantee efficacy for primary negative symptoms
• 5-HT2C: Antagonism can disinhibit NA/DA in some circuits but is also linked to appetite and 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.

The slide proposes links among HPA-axis activation, cortisol, hippocampal structure, BDNF/neurogenesis and antidepressant-related cAMP/CREB signalling. ^[1]

How to read the HPA diagram: cortex/cingulate/amygdala influence hypothalamic CRH release → pituitary ACTH → adrenal cortisol, with feedback inhibition to brain and pituitary. The arrows labelled “depression” show group-level associations (more CRH/cortisol, altered pituitary/adrenal size, lower hippocampal volume/BDNF/neurogenesis), not a settled one-way causal chain or a diagnostic cortisol test.

Why does this matter? This hypothesis explains:

1. Why depression is associated with cognitive and memory impairment (hippocampal atrophy)
2. Why benefit may lag behind immediate transporter blockade — downstream adaptation and new emotional learning take time
3. Why chronic stress (via cortisol) is a risk factor for depression

“Cognitive Neuropsychological Model” — the slide proposes that negative emotional-processing bias changes early, while subjective mood improvement emerges later. ^[1]

Two explanations from the lecture:

1. Cognitive Neuropsychological Model: early changes in emotional processing may need repeated real-world experience before translating into subjective mood improvement; timing varies.

2. Neuroadaptive model shown across slides 15–19: acute SERT blockade increases 5-HT around somatodendritic and axon-terminal synapses; inhibitory autoreceptors initially restrain firing; later autoreceptor adaptation permits more terminal release, while postsynaptic adaptation may reduce early adverse effects. This is a teaching model, not a complete or proven account of response.

The slide lists depressive disorders, anxiety disorders, PTSD, OCD, sexual disorders and eating disorders (AN/BN). ^[1]

This is a class-level teaching list, not a prescribing licence: indication and evidence depend on the specific drug, diagnosis, age and jurisdiction. For example, evidence for one SSRI in bulimia nervosa does not make every antidepressant a treatment for every eating disorder.

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]

Drug-Specific Adverse Effects [1]

SSRI discontinuation syndrome: sensory abnormality (electric shock-like sensation), dizziness, headache, lethargy, GI upsets, insomnia, mood change (depressed/anxious feelings). ^[1]

The biology of withdrawal is not completely established; do not describe it as a proven “sudden serotonin deficiency”. It can follow missed doses, abrupt cessation or dose reduction and may be prolonged or severe. Paroxetine and venlafaxine are more commonly implicated, while fluoxetine's long half-life often makes withdrawal less abrupt. NICE recommends an agreed, stepwise taper—sometimes over weeks or months—with smaller reductions at low doses and monitoring for both withdrawal and relapse ^[13].

FDA warnings on prescribing antidepressants in child and adolescence group of patients due to potential increased risk of suicidality. ^[1]

The slide reproduces pooled short-term FDA risk differences for suicidal thoughts or behaviours, not completed suicide ^[1]:

Do not infer a proven “energy before mood” mechanism from this table. Depression itself carries suicide risk. Ask directly about ideation, intent and access to means; do not withhold effective depression treatment solely because risk is present. For people aged 18–25 or at increased risk, NICE recommends assessment before prescribing, review for suicidality after 1 week, and further review as often as needed (no later than 4 weeks); also consider overdose toxicity and limit quantities when appropriate ^[13].

Before treating apparent unipolar depression: ask about past periods of overactivity, disinhibition, reduced need for sleep and other manic/hypomanic symptoms. NICE advises specialist assessment when overactivity or disinhibited behaviour lasted 4 days or more; if mania/hypomania emerges during antidepressant monotherapy, consider stopping the antidepressant and offer antimanic treatment ^[14].

"Is there any efficacious difference amongst ADs clinically?" — the slide presents the 2018 network meta-analysis of 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]

How to read the plots: in the network diagram, node size reflects participant count and line width reflects the number of direct comparisons—not effectiveness. The forest plots show that all 21 studied drugs outperformed placebo on acute response, but estimated efficacy and all-cause discontinuation varied with overlapping uncertainty. The two-dimensional head-to-head plot does not identify a universal winner. Choice should therefore combine likely benefit, adverse effects, previous response, patient preference, comorbidities and interactions—not recency alone.

Gut-Brain Hypothesis ^[1]:

Research on gut microbiota and their relation to depression in animals and human beings is an evolving area. The slide maps bidirectional neural, metabolic, endocrine and immune routes between gut and brain. This is a mechanistic research framework, not a stool-test diagnosis or a routine indication for probiotics.

"Are these 'antidepressants'???" ^[1] — The photographed products are omega-3, probiotics, N-acetylcysteine and inositol. The question marks are the teaching point: supplements are not interchangeable with licensed antidepressants, product quality and interactions vary, and none should replace evidence-based assessment or treatment. Ask specifically about over-the-counter and “natural” products during medicines reconciliation.

4 important dopamine pathways: Mesolimbic, Mesocortical, Nigrostriatal, Tuberoinfundibular. ^[1]

The core pathway trade-off: systemic D2 blockade cannot be confined to the mesolimbic target. Depending on dose, exposure and drug, it can also produce EPS (nigrostriatal), prolactin elevation (tuberoinfundibular), and secondary negative/cognitive effects.

The subsequent aberrant-salience diagram is broader than a “too much dopamine” slogan: genes, stress, drugs and frontotemporal dysfunction are shown converging on striatal dopamine dysregulation, causing neutral stimuli to acquire inappropriate significance. Antipsychotics act downstream to dampen salience; they do not reverse every upstream cause or reliably treat all cognitive/negative symptoms.

"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]

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 → lower average EPS at usual doses but more sedation, hypotension and anticholinergic effects

FGAs are potent D2 blockers. ^[1]

"Antipsychotic threshold" vs Extra-pyramidal Side-effect (EPSE) ^[1]

The occupancy curve depicts a population-level relationship: clinical response often appears as striatal D2 occupancy approaches roughly 60%, while EPS risk rises as occupancy approaches/exceeds roughly 80% ^[1]. It is not a bedside target measured in routine care, and exceptions vary by drug and patient.

Types of EPSE (acute and chronic):

The slide describes TD as delayed and quotes the diagnostic exposure convention of at least 3 months (over 1 month in older adults), plus historical FGA/SGA incidence estimates. ^[1]

NMS is a MEDICAL EMERGENCY in psychiatry with incidence ~0.01-3%; potentially fatal. Treatment: discontinuation of antipsychotics + supportive treatment. ^[1]

The SGA with dopamine D2 partial agonist — Aripiprazole — is termed a Dopamine System Stabilizer (DSS). ^[1]

What does “partial agonist” mean? Aripiprazole has lower intrinsic D2 activity than dopamine. In the slide's conceptual diagram it competes with dopamine and lowers net signalling in a high-dopamine synapse, while providing some receptor stimulation in a low-dopamine synapse. “Dopamine system stabiliser” is useful shorthand, not evidence that it normalises each pathway in an individual patient.

What DSS can do ^[1]:

• Reduce positive symptoms (blocks excess DA in mesolimbic)
• It may reduce some D2-blockade effects, but primary negative/cognitive symptoms are not reliably normalised
• Lower average parkinsonism/prolactin burden than many D2 antagonists, but akathisia and other EPS can still occur
• Less hyperprolactinaemia (partial agonism in tuberoinfundibular)
• Lower average metabolic burden than high-risk agents, not metabolically “neutral” in every patient

The 2023 slide calls brexpiprazole a Serotonin-Dopamine Activity Modulator (SDAM). ^[1]

Why do we need to get serotonin system involved? ^[1]

“Latest class” and “SDAM” are historical/marketing language rather than a durable therapeutic hierarchy. Brexpiprazole has:

• D2 partial agonism (like aripiprazole)
• 5-HT1A partial agonism
• 5-HT2A antagonism

The receptor profile may alter tolerability relative to aripiprazole, but it does not guarantee lower akathisia or superior efficacy for an individual.

This is the lecture's historical comparison table; read it as tendencies with important exceptions. ^[1]

Prevalence of metabolic syndrome varies between different drugs. ^[1]

From the Korean study cited in the lecture:

These are cross-sectional prevalences from one Korean cohort, not randomised drug-attributable rates or a prescribing rank. Patient selection, duration, illness and prior treatment confound the comparison; the unexpectedly high haloperidol value is a useful warning against reading it as intrinsic weight-gain propensity.

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

How to read the two metabolic diagrams: appetite and energy expenditure are only the top-left balance. Receptor effects can also alter satiety/hunger centres, reward, autonomic output, gut nutrient absorption, pancreatic insulin secretion and β-cell survival, hepatic/muscle/adipose insulin sensitivity, glucose uptake and lipogenesis. H1, 5-HT2C and muscarinic signalling are prominent, but no single receptor predicts the whole clinical phenotype.

Current monitoring anchor: before starting an antipsychotic, NICE records weight, waist, pulse/BP, fasting glucose or HbA1c, lipids, prolactin, movement disorder status, nutrition/diet and activity. During treatment: weight weekly for 6 weeks, then at 12 weeks, 1 year and annually; waist annually; pulse/BP, glucose/HbA1c and lipids at 12 weeks, 1 year and annually, alongside response, adverse effects, movements and adherence ^[15]. Follow drug-specific/local schedules when more intensive monitoring is required.

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]

How to read the forest plot: mean QTc change and confidence intervals differ markedly by drug; a mean close to zero does not make torsades risk zero, and a statistically significant mean change is not itself an arrhythmia. Baseline ECG is indicated when the product information requires it, cardiovascular disease/risk is present, or the patient is admitted as an inpatient; repeat according to risk, dose, symptoms and co-prescribed QT-prolonging drugs ^[15]. Particular slide concerns include:

• High-risk FGAs: thioridazine, pimozide
• High-risk SGAs: sertindole, ziprasidone
• Combination with other QTc-prolonging drugs
• Relatively small mean QT effect in the plotted evidence: aripiprazole; still review patient-specific risk rather than calling any antipsychotic “QT-safe”

Specific Issues on Clozapine: ^[1]

"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 slide) ^[1]: some individual SGAs—especially clozapine in its appropriate treatment-resistant population—showed advantages in some symptom domains, while many comparisons crossed no-effect. Comparator choice, dose and study population matter; this is not evidence that an entire generation is superior.

SGAs vs SGAs (Kishimoto et al. 2019 slides) ^[1]: the two-page forest plot is sparse—many pairs are supported by only one or a few trials and many confidence intervals cross zero. A few significant pairwise results do not establish a stable universal rank; balance symptom response against each drug's adverse-effect burden.

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.

• Lower average weight-gain antipsychotics: aripiprazole, lurasidone, ziprasidone (not risk-free)
• Lower average weight/sexual adverse-effect antidepressant: bupropion (not risk-free)
• Prominently sedating antidepressant: mirtazapine (H1 blockade; compare the individual drug/dose)
• SSRI with longest half-life: fluoxetine (least discontinuation syndrome)
• SSRI with most anticholinergic effects: paroxetine
• SGA most likely to cause hyperprolactinaemia: risperidone/paliperidone
• Relatively small mean QTc effect: aripiprazole; still assess patient factors and interacting drugs
• Key evidence-based antipsychotic for treatment-resistant schizophrenia: clozapine
• Esketamine mechanism: NMDA antagonism → ↑glutamate → AMPA activation → ↑BDNF