Mednotes

L5 Clinical Pharmacology Antidepressants

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tagsclinicalpharmacology, lecture
aliasesAntidepressant drugs

19 min read

Overview

This lecture covers antidepressant drugs: how their efficacy is measured, what Major Depressive Disorder (MDD) is and how common it is, the proposed biological causes of depression (with a focus on the monoamine hypothesis and its limitations), the physiology of serotonin and noradrenaline, how monoamines are normally recycled, and the general mechanism by which antidepressants raise monoamine levels. It then works through the five drug classes in order of typical use — SSRIs, SNRIs, TCAs, and MAOIs (all monoamine-based), plus ketamine/esketamine (glutamate-based, for treatment-resistant depression) — covering mechanism, place in therapy, and adverse effects/interactions for each, before closing on real-world outcome data (STAR-D) and a summary.

Measuring Antidepressant Efficacy

  • Efficacy (pharmacological definition): the extent to which a drug can produce a desired therapeutic effect under ideal, controlled conditions such as clinical trials.
  • Clinical efficacy measures: years of life added, remission, odds ratio (OR), rate ratio, standardized mean difference (SMD), Hedges g.
  • SMD (standardized mean difference) is an attempt to normalise the many different efficacy measures into one number.
  • Approximate conversions given (guideline only, “take with a grain of salt”):
    • SMD 0.2 ≈ OR 1.44 ≈ remission rate 39% (if placebo remission is 30%)
    • SMD 0.5 ≈ OR 2.48 ≈ remission rate 52% (if placebo remission is 30%)
    • SMD 0.8 ≈ OR 4.27 ≈ remission rate 69% (if placebo remission is 30%)
  • Equation relating OR and SMD shown:

Major Depressive Disorder (MDD)

Major Depressive Disorder is defined as presenting at least 5 of the following symptoms over a 2-week period:

  • Depressed mood
  • Substantially reduced interest or pleasure in all, or almost all, activities
  • Considerable weight loss when not dieting, weight gain, or decrease/increase in appetite
  • Insomnia or hypersomnia
  • Psychomotor agitation or retardation
  • Fatigue or loss of energy
  • Feelings of worthlessness or excessive/inappropriate guilt
  • Reduced ability to think or concentrate, or indecisiveness
  • Recurrent thoughts of death, suicidal ideation (with or without a plan), or a suicide attempt

People diagnosed with depression are:

  • 2x as likely to suffer from 1+ chronic disease
  • 3x as likely to suffer from a pain-related disorder
  • 7x as likely to suffer from an alcohol or substance use disorder
  • This burden can lead to a loss of nearly 10 years of healthy life

Prevalence

  • Twice as high in females as males
  • Lifetime prevalence: 10%
  • 12-month prevalence: 4–5%
  • More than 70% of depressive episodes subside within 12 months
  • Global prevalence trends (1990–2019/2020): high-income countries have the highest prevalence (rising from ~2.8 to a peak of ~3.2 around 2005–2010, settling ~3.1); upper-middle-income countries show a rising trend (~2.0 to ~2.3–2.4); low-income and lower-middle-income countries show lower, fluctuating prevalence (~2.1–2.6).

Causes of Depression

Causes are described as complex, with a low-to-moderate genetic correlation for MDD. Four contributing categories are given:

  1. Genetic — genes correlated with MDD include:
    • DRD2 (encodes the dopamine D2 receptor subtype)
    • CELF4 (coordinates synaptic function in excitatory neurons)
    • ELAVL2 (encodes a protein regulating gene expression pathways in neurodevelopment)
    • Twin concordance rates (identical vs fraternal) support a genetic contribution: any mood disorder ~63% vs ~20%, severe depression ~59% vs ~30%, depression ~35% vs ~17%, bipolar disorder ~80% vs ~15%.
  2. Environmental — poverty, recent negative life events, childhood trauma.
  3. Psychological (cognitive patterns) — CBT can show effect sizes of 0.4–0.6 SMD.
  4. Biological (emphasised) — monoamine levels and inflammation.

The Monoamine Hypothesis

  • The exact mechanism of depression remains unknown; biological mechanisms are described as very complex.
  • Predominant theory: a reduction in monoamine neurotransmitters — noradrenaline, serotonin, and dopamine — causes depression.
  • Diagrammatically, a “depressed” synapse is shown releasing fewer monoamine molecules across the synaptic cleft to postsynaptic receptors than a “normal” synapse, with reuptake transporters present on the presynaptic membrane in both cases.

Limitations of the monoamine hypothesis

  • No difference in serotonin transporter expression between depressed and non-depressed people.
  • Serotonin deprivation does not cause depression in non-depressed people or those with a familial history of depression.
  • No difference in serotonin receptor amount between depressed and non-depressed people.
  • No difference in serotonin levels measured in cerebrospinal fluid between depressed and non-depressed people.
  • Antidepressants give a statistically significant improvement in depression scores, but often not a clinically significant one:
    • Many meta-analyses find antidepressants decrease depression scores by 2 points over placebo.
    • Clinically significant improvement is defined as a decrease of 3 points.

Support for the monoamine hypothesis

  • A large analysis (522 studies, 116,477 patients) of monoamine antidepressant drug studies showed modest but significant improvement over placebo (SMD 0.18–0.42).
  • 82% of trials showed moderate-to-high risk of bias; studies are often run by pharmaceutical companies with a profit motive.
  • A forest plot (Cipriani et al. 2018) of 21 antidepressants ranked by odds ratio (95% credible interval) vs placebo, all significantly favouring the active drug, from highest to lowest OR:
DrugOR (95% CrI)
Amitriptyline2.13 (1.89–2.41)
Mirtazapine1.89 (1.64–2.20)
Duloxetine1.85 (1.66–2.07)
Venlafaxine1.78 (1.61–1.96)
Paroxetine1.75 (1.61–1.90)
Milnacipran1.74 (1.37–2.23)
Fluvoxamine1.69 (1.41–2.02)
Escitalopram1.68 (1.50–1.87)
Nefazodone1.67 (1.32–2.12)
Sertraline1.67 (1.49–1.87)
Vortioxetine1.66 (1.45–1.92)
Agomelatine1.65 (1.44–1.88)
Vilazodone1.60 (1.28–2.00)
Levomilnacipran1.59 (1.24–2.05)
Bupropion1.58 (1.35–1.86)
Fluoxetine1.58 (1.40–1.66)
Citalopram1.52 (1.33–1.74)
Trazodone1.51 (1.25–1.83)
Clomipramine1.49 (1.21–1.85)
Desvenlafaxine1.49 (1.24–1.79)
Reboxetine1.37 (1.16–1.63)
  • Classic antidepressants “work” in about 15% of patients with depression.
  • Antidepressants account for ~3–4% of all drugs prescribed in New Zealand.
  • Response-to-treatment data (71,393 patients, 1979–2016), percentage improving by ten points or more on the Hamilton depression score (drug vs placebo):
    • Mild depression (score 13–17): 34.6% vs 27.2%
    • Moderate depression (score 18–22): 48.0% vs 36.7%
    • Severe depression (score ≥23): 54.9% vs 42.3%

Serotonin and Noradrenaline Physiology

Serotonin (5-hydroxytryptamine, 5-HT) is synthesised from tryptophan. Only 10% is in the central nervous system, where it is involved in:

  • Mood and behaviour
  • Sleep
  • Reality perception — LSD and psilocin are serotonin receptor agonists, approved for treatment-resistant depression in NZ in 2025; also implicated in the default mode network (sense of self)

Outside the CNS, serotonin is involved in blood clotting (vasoconstriction and platelet aggregation) and mediates GI function (increases GI motility, vasodilation, and mediates appetite).

Serotonergic projections arise from the raphe nuclei (pons/medulla) and radiate widely through the thalamus, cerebral cortex, corpus callosum, cerebellum, and spinal cord. Serotonin receptor subtypes (5-HTT, 5-HT1AR, 5-HT1BR, 5-HT2AR, 5-HT4R) are distributed at varying densities across cortical and subcortical brain regions, with 5-HT2AR density notably highest in cortical regions [slide shows region-by-region density data without a single summary figure — not reproduced in full].

Noradrenaline has several roles in the brain:

  • Wakefulness
  • Attention
  • Cognitive function
  • Implicated in some types of depression
  • Primarily binds α2- and β1-adrenergic receptors in the brain

Noradrenergic projections arise from the locus coeruleus and project through the cerebral cortex, thalamus, corpus callosum, pons, medulla, cerebellum, and spinal cord. Adrenaline differs structurally from noradrenaline by an added methyl group on the amine nitrogen.

Neurotransmitter Recycling

  • Monoamine oxidase (MAO) metabolises monoamines (noradrenaline, dopamine, serotonin) by oxidising the monoamine to remove the amine group. It is widely distributed throughout the nervous system, with two isoforms:
    • MAOA — metabolises noradrenaline, adrenaline, and serotonin
    • MAOB — metabolises dopamine and noradrenaline
  • Transporters move monoamines from the synapse back into the presynaptic neuron:
    • SERT — moves serotonin into the presynaptic neuron
    • NET — moves noradrenaline into the presynaptic neuron (recycles NA)

General Mechanism of Antidepressants

Antidepressants act to increase monoamine concentrations to counteract low monoamine levels in depressed patients, via two main routes:

  1. Inhibit transporters (e.g. SERT, NET) → increases monoamines at the synaptic cleft.
  2. Inhibit monoamine oxidase → reduces breakdown of monoamines.

Drug Classes

Selective serotonin reuptake inhibitors (SSRIs)

  • Selectively increase serotonin (5-HT). Core drug: escitalopram.
  • First-line treatment for unipolar depression: comparable benefits to other classes, but a lower side-effect profile and lower overdose risk.
  • Can take 3–4 weeks to see positive effects.

Proposed mechanism (stepwise)

  1. Transporter inhibition increases 5-HT at the synapse.
  2. 5-HT1A activation on raphe nuclei autoreceptors decreases serotonin release.
  3. Decreased serotonin release downregulates 5-HT1A receptors.
  4. This causes greater serotonin release throughout the brain, activating receptors and stabilising mood.
  5. 5-HT2A receptor activation or glutamate release may release BDNF (brain-derived neurotrophic factor), enhancing synaptic plasticity (long-term potentiation).

The molecular basis of mood and emotion is not understood well enough to fully extrapolate SERT inhibition to antidepressant efficacy.

Two phases of SSRI effects (hypothesis)

  • Acute phase: (1) the reuptake transporter is blocked, acutely raising synaptic 5-HT; (2) autoreceptors activated by the increased synaptic 5-HT reduce 5-HT synthesis and release; (3) these two acute effects cancel out, causing little net change in 5-HT action.
  • Later phase: (1) the reuptake transporter continues to be blocked; (2) autoreceptors become down-regulated, resulting in increased 5-HT release; (3) more 5-HT produces significantly greater postsynaptic effects.

SSRI adverse effects

  • Increased risk of suicidal ideation in adolescents (some studies)
  • Acute increased anxiety
  • Sleep disruption
  • Sexual dysfunction
  • Emotional blunting
  • Cognitive impairment
  • Withdrawal symptoms (SSRI discontinuation syndrome)

SSRI drug interactions

  • Monoamine oxidase inhibitors — serious toxicity via serotonin syndrome, from combined inhibition of serotonin reuptake and metabolism.
  • NSAIDs — SSRIs block serotonin uptake in platelets, reducing platelet aggregation → increased bleeding (haemorrhage) risk, including interaction with low-dose aspirin.
  • Codeine — SSRIs can inhibit CYP450 enzymes, inhibiting the conversion of codeine to morphine → decreased pain relief.

Serotonin and noradrenaline reuptake inhibitors (SNRIs)

  • Second-line treatment (e.g. venlafaxine), with slightly higher efficacy than SSRIs.
  • Inhibit NAT and SERT → increases serotonin and noradrenaline effects.
  • Higher overdose risk than SSRIs.
  • Similar side effects to SSRIs.
  • Increased blood pressure at higher doses, due to enhanced noradrenergic effects.

Tricyclic antidepressants (TCAs)

  • Second-to-third-line treatment (e.g. amitriptyline, nortriptyline), with slightly higher efficacy than SNRIs.
  • Inhibit NAT and SERT → increases serotonin and noradrenaline effects, with more selectivity for NAT than SNRIs.
  • Dangerous in overdose — block voltage-gated sodium channels (VGSCs).
  • More side effects than SSRIs and SNRIs; considered a “dirty drug” due to non-selective (promiscuous) binding.

TCA "promiscuous binding" — non-selective effects

  • α1 antagonism → prevents vasoconstriction → hypotension → dizziness
  • H1 antagonism → prevents histamine regulation of the sleep-wake cycle (sedation, drowsiness) and of appetite (weight gain)
  • mAChR antagonism (anticholinergic effects) → reduced parasympathetic modulation → pupil dilation, reduced secretions (xerostomia), reduced GI motility, cardiotoxicity

Clinical picture from these effects: drowsiness/lightheadedness, dry mouth, blurred vision, excessive sweating, constipation and appetite/weight changes, urine retention, sexual dysfunction, tremors.

Monoamine oxidase inhibitors (MAOIs)

  • Used for neurological disorders.
  • MAOB inhibitors — increase dopamine and noradrenaline; used in combination treatment of Parkinson’s disease.
  • MAOA inhibitors — increase noradrenaline and serotonin; used as antidepressants.
  • More side effects than TCAs.
  • Risk of serotonin syndrome if given with SSRIs, TCAs, or SNRIs.

Serotonin syndrome

  • The serotonin system generally has a high therapeutic index.
  • Combining serotonin receptor (specifically 5-HT2A) modulators can cause synergistic toxicity — e.g. MAOIs combined with SSRIs or MDMA.
  • Delirium can last for days; muscle weakness can last for months.

Serotonin syndrome — symptoms

Anxiety, confusion, diarrhoea and vomiting, sweating, tremor, muscle stiffness (especially in the legs), difficulty with balance.

Real-World Outcomes and Clinical Consensus

  • There are 20 antidepressants available in NZ, modulating serotonin, dopamine, and/or noradrenaline levels.
  • STAR-D clinical trial: regardless of which antidepressant is used, after 4 different drug treatments, 67% of patients will respond and 33% will still be depressed (considered treatment-resistant).
  • Clinical consensus (Cowen, 2023, quoted): SSRIs are a “welcome though modest advance.” Their availability and tolerability have let many more patients benefit from antidepressant medication, but antidepressants may be over-prescribed for milder depressive states/problems in living where psychosocial approaches are more appropriate. In more severely unwell patients, SSRIs may have somewhat less utility than TCAs, and both seem relatively ineffective for anhedonia, a key symptom domain of severe and treatment-resistant depression.

Treatment-Resistant Depression: Ketamine and Esketamine

A newer theory of the biological mechanism of depression proposes it is caused by glutamate disruption (NMDA and GABA receptors), rather than solely monoamine deficiency.

Ketamine mechanism (stepwise)

  1. Ketamine disinhibits GABAergic interneurons (via NMDAR).
  2. This leads to net excitation.
  3. Increased release of glutamate follows.
  4. This produces increased synaptic plasticity and increased BDNF.
    Diagram detail: ketamine binds NMDAR on a GABAergic interneuron, inhibiting it and reducing GABA release; this drives evoked glutamate release from a presynaptic glutamatergic neuron acting on AMPAR and NMDAR (also a ketamine target) on the postsynaptic neuron, with an astrocyte (EAAT2 transporter) adjacent to the synapse.
  • Acute depression improvement is seen after one dose (moderate–high effect size, 0.48–0.73).
  • Peak effects occur one day after treatment; effects last for 2 weeks.
  • Used in clinics in America and for treatment-resistant depression in New Zealand.

Efficacy

  • Ketamine shows significant response rates for depression, though controls are problematic with psychoactive drugs.
  • Ketamine generally shows higher response rates than traditional antidepressants.
  • A forest plot of odds ratios [95% CI] for response rate vs placebo across treatment types: Mood Stabilizers 1.09 [0.63; 1.88]; Antipsychotics 1.36 [1.04; 1.78]; Other Pharmacological Mechanisms 1.44 [0.86; 2.39]; Serotonergic Psychedelics 2.26 [0.91; 5.61]; NMDAR-targets 2.94 [2.03; 4.27] (highlighted); Neuromodulatory Treatments 3.35 [2.09; 5.35].
  • Ketamine has also shown improvements in cognition in patients with major depressive disorder.

Esketamine (Spravato)

  • FDA-approved in 2019 for use alongside oral antidepressants for treatment-resistant depression.
  • Must be administered in clinic; a healthcare provider must stay with the patient for 2 hours post-administration.

Ketamine side effects

  • Drug abuse potential
  • Acute hypertension
  • Heavy chronic use can cause bladder inflammation, nocturia, and cystitis

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Summary

  • There are 5 main classes of antidepressants: SSRIs, SNRIs, TCAs, MAOIs, and NMDA antagonists (ketamine).
  • The efficacy of serotonergic antidepressants is statistically significant, and often clinically significant, but this does not likely justify the side effects in many patients.
  • Odds ratios and effect size are critical metrics for determining treatment efficacy.
  • The pathology and pharmacology of depression is complex; BDNF and neuroplasticity may underlie effective treatment of depression.

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Self-test

  1. Define efficacy as used in pharmacology, and list at least three ways it can be measured clinically.
  2. What SMD, OR, and remission rate roughly correspond to each other according to the lecture’s guideline conversions (state one of the three tiers)?
  3. List the diagnostic threshold and symptom domains required to diagnose Major Depressive Disorder.
  4. Describe the comorbidity and life-expectancy burden associated with a diagnosis of depression.
  5. State the lifetime and 12-month prevalence of depression, and what proportion of episodes subside within 12 months.
  6. List the four categories of causes of depression described in the lecture, with one example from each.
  7. What do twin concordance rates suggest about the causes of mood disorders, and how does this evidence support that category of cause?
  8. State the predominant (monoamine) theory of the pharmacological mechanism of depression.
  9. List four pieces of evidence that limit or challenge the monoamine hypothesis.
  10. Why might a statistically significant improvement in depression score from an antidepressant not be clinically significant? Use the point thresholds given.
  11. Describe the two isoforms of monoamine oxidase and their respective substrates.
  12. Distinguish the roles of SERT and NET in monoamine recycling.
  13. Describe the two main mechanisms by which antidepressants increase monoamine concentrations.
  14. Describe the five-step proposed mechanism by which SSRIs are thought to stabilise mood, from transporter inhibition to BDNF release.
  15. Explain why SSRIs might have little net effect on serotonin acutely, but a much greater effect after continued use (use the two-phase hypothesis).
  16. List the major adverse effects of SSRIs.
  17. A patient on an SSRI is prescribed low-dose aspirin for cardiovascular prophylaxis. Explain the mechanism behind the interaction risk this raises.
  18. A patient on an SSRI is also taking codeine for pain. Explain why their pain relief might be reduced.
  19. Distinguish SNRIs from SSRIs in terms of mechanism, efficacy, and side-effect/overdose risk.
  20. Explain why TCAs are described as a “dirty drug,” and list the three non-selective (promiscuous) binding effects with their clinical consequences.
  21. A patient taking amitriptyline in overdose develops cardiac toxicity. What is the underlying pharmacological mechanism?
  22. Distinguish the therapeutic uses of MAOB inhibitors from MAOA inhibitors.
  23. A patient stabilised on an MAOI is prescribed an SSRI for breakthrough symptoms. Explain the risk this combination poses and name the resulting syndrome.
  24. List the symptoms of serotonin syndrome, and describe how its time course can differ for delirium versus muscle weakness.
  25. According to the STAR-D trial, what proportion of patients will respond after four different antidepressant drug treatments, and what happens to those who do not?
  26. Explain, using the lecture’s quoted clinical consensus, why the increased use of SSRIs is regarded as having both benefits and drawbacks.
  27. Describe the newer, glutamate-based theory of the mechanism of depression and how it differs from the monoamine hypothesis.
  28. Describe the step-by-step mechanism by which ketamine is thought to produce an antidepressant effect.
  29. Compare the time course of ketamine’s antidepressant effect (onset, peak, duration) with the 3-4 week onset described for SSRIs.
  30. What administration requirements apply to esketamine (Spravato), and why might these be in place?
  31. List the side effects of chronic heavy ketamine use.
  32. Integrative: A patient with severe, treatment-resistant major depressive disorder has failed multiple monoamine-based antidepressants. Using the lecture’s material on the monoamine hypothesis’s limitations and the glutamate-based theory, explain why a clinician might consider ketamine or esketamine for this patient.

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