Antidepressants & Recreational

Question 1

What is the monoamine hypothesis of depression?

Answer 1

• Depression is associated with reduced serotonin, noradrenaline, and dopamine in the brain.
• Leads to underactivity at monoaminergic synapses, particularly serotonergic and noradrenergic.

Question 2

What are the main affective disorders and their prevalence?

Answer 2

• Affective disorders involve mood disturbances, not cognition or perception.
• Unipolar depression (MDD): ~9–15% incidence, higher in women, average onset 35–45.
• Bipolar disorder: affects men and women equally, onset ~30 years.
• Up to 20% of the population affected by some form of affective disorder.

Question 3

What is the genetic and environmental basis of affective disorders?

Answer 3

• ~25% of MDD cases have a family history.
• Twin studies show 30–90% concordance in bipolar disorder.
• Environmental factors likely include stress, illness, and early life experiences.

Question 4

What are the symptoms of major depressive disorder (MDD)?

Answer 4

• Physical: weight change, sleep disturbance, fatigue.
• Emotional: depressed mood, reduced interest, guilt, psychomotor changes.
• Cognitive: diminished ability to concentrate, suicidal thoughts.
• Diagnosis requires ≥5 symptoms over ≥2 weeks (DSM-5 criteria).

Question 5

What are the typical features and risks of mania?

Answer 5

• Elevated mood, overactivity, decreased need for sleep, irritability.
• May include delusions/hallucinations (psychosis) in ~10% of patients.
• Treated separately from depressive episodes; often with mood stabilisers.

Question 6

How do monoamine oxidase inhibitors (MAOIs) work?

Answer 6

• Inhibit monoamine oxidase enzymes localised in the outer membrane of presynaptic mitochondria that degrade 5HT, NA, and DA.
• Increase synaptic levels of monoamines, enhancing receptor activation.
• Examples: Tranylcypromine (irreversible, non-selective); Moclobemide (reversible, MAO-A selective).
• MAO-A mainly degrades 5HT and NA; inhibition is the therapeutic target.
• MAO-B preferentially metabolises DA and phenylethylamine.

Question 7

What are tricyclic antidepressants (TCAs) and how do they act?

Answer 7

• Inhibit reuptake of NA and 5HT, prolonging monoamine signalling.
• Examples: Imipramine (non-selective), Desipramine (NA-selective), Amitriptyline.
• Older drugs, effective but non-specific.

Question 8

What are the major side effects of TCAs?

Answer 8

• Anticholinergic effects: dry mouth, sedation, hypotension.
• Cardiotoxicity in overdose (dysrhythmias).
• Sedation due to H1 receptor blockade.

Question 9

What are SSRIs, SNRIs, and NRIs?

Answer 9

• SSRIs (e.g. fluoxetine, sertraline): block serotonin reuptake.
• SNRIs (e.g. venlafaxine): inhibit reuptake of both serotonin and noradrenaline.
• NRIs: selective for noradrenaline transporters.
• All enhance monoamine signalling.

Question 10

What are NaSSAs and how do they differ from other antidepressants?

Answer 10

• Noradrenergic and Specific Serotonergic Antidepressants.
• Example: Mirtazapine.
• Antagonises α2-adrenergic autoreceptors and 5HT2/5HT3 receptors.
• Increases NA and 5HT release indirectly i.e. puts brakes on the brakes by preventing negative feedback loops that return serotonin and noradrenaline levels to normal.
• This action prevents the negative feedback effect of synaptic noradrenaline on 5-HT and noradrenaline neurotransmission, sustaining neurotransmission.
• NaSSAs also block 5-HT2 and 5-HT3 receptors on the post-synaptic membrane, which causes enhanced 5-HT1 mediated neurotransmission.
• Fewer anticholinergic or sodium channel effects.

Question 11

What is the clinical evidence for St John’s Wort in depression?

Answer 11

• Herbal antidepressant; mechanism unclear (hypericin content).
• May induce CYP450 enzymes → drug interactions.
• Some meta-analyses show efficacy ≈ standard antidepressants with fewer side effects.
  Variability between studies; not widely adopted outside Germany.

Question 12

How is mania treated pharmacologically?

Answer 12

• Lithium carbonate: effective mood stabiliser with unclear mechanism (possibly inhibits Phosphatidylinositol metabolism).
• Narrow therapeutic window; risk of toxicity.
• Antipsychotics or anticonvulsants (e.g. valproate, gabapentin) may be used as alternatives.

Question 13

What are the main problems with current antidepressants?

Answer 13

• Delayed onset (3–6 weeks).
• Side effects: nausea, weight gain, sedation, anticholinergic effects.
• Not all patients respond: ~50% show full response, 67% with multiple steps (STAR*D trial).
• Risk of suicide remains high in young adults.

Question 14

What were the findings of the STAR*D clinical trial?

Answer 14

• The Sequenced Treatment Alternatives to Relieve Depression
• Largest trial assessing effectiveness of sequential antidepressant strategies, completed in 2006
• Stepwise treatment of ~4,000 MDD patients over multiple drug stages.
• Remission rates: 36.8%, 30.6%, 13.7%, 13.0% across 4 drug steps.
• Cumulative remission: 67%.
• Highlights need for personalised treatment; more steps = lower success and higher relapse risk.

Question 15

How do all antidepressants ultimately increase monoamine levels?

Answer 15

• Reuptake inhibition (SSRIs, SNRIs, TCAs, NRIs).
• MAO inhibition (MAOIs).
• Receptor antagonism to disinhibit monoamine release (NaSSAs).
• All aim to raise synaptic 5HT and NA levels to restore normal mood regulation.

Question 16

What are the mechanisms and effects of caffeine?

Answer 16

• Competitive antagonist at adenosine A1 and A2A GPCRs.
• Stimulates CNS activity; may protect dopaminergic neurons (Parkinson’s link).
• Also acts as ryanodine receptor agonist.

Question 17

What is nicotine’s mechanism of action?

Answer 17

• Agonist at nicotinic acetylcholine receptors (nAChRs), especially α4β2 subtype.
• Enhances dopamine release via reward pathway.
• Chronic use increases receptor expression but decreases sensitivity.
• Common in schizophrenia patients (self-medication hypothesis).

Question 18

How does ethanol (alcohol) affect the CNS?

Answer 18

• CNS depressant; acts at GABA A receptors, inhibits NMDA and 5HT3 receptors.
• Activates dopaminergic reward pathway.
• Naltrexone (opioid antagonist) reduces craving and consumption.
• Effects: sedation, motor impairment, reduced inhibition.

Question 19

What is the mechanism of psychostimulants like cocaine and amphetamine?

Answer 19

• Act on dopamine reward pathway.
• Cocaine blocks reuptake of DA, 5HT, and NA.
• Amphetamine promotes release of these neurotransmitters from ventral tegmental area and blocks reuptake and breakdown in nucleus accumbens.
• Euphoria primarily due to increased dopamine in nucleus accumbens.
• Can induce psychosis-like symptoms (dopamine hypothesis of schizophrenia).

Question 20

How do hallucinogens like LSD and ketamine act?

Answer 20

• LSD and mescaline: partial 5HT2A receptor agonists (alter memory/perception).
• Ketamine and PCP: NMDA receptor channel blockers.
• Low-dose ketamine shows promise as fast-acting antidepressant (off-label use).
• Associated with dissociation and hallucinations.

Question 21

How does cannabis affect the CNS and mental health?

Answer 21

• Δ9-THC is an agonist at CB1 receptors (GPCRs in cortex, hippocampus).
• Endocannabinoids include anandamide and 2-AG.
• CB1 activation inhibits Ca2+ entry, enhances K+ outflow, modulates gene expression.
• Acute effects: relaxation, altered perception, impaired memory.
• Linked to increased risk of psychosis/schizophrenia in vulnerable individuals.

Question 22

What is the dopamine reward pathway and its role in addiction?

Answer 22

• VTA neurons release dopamine to nucleus accumbens (mesolimbic pathway).
• All drugs of abuse enhance this pathway.
• Opioids inhibit GABAergic inhibition (disinhibition).
• Cocaine/amphetamines block reuptake or increase dopamine release.

Question 23

What are the risks and side effects associated with MAOIs?

Answer 23

• The ‘cheese reaction’: MAO-A inhibition prevents tyramine breakdown, leading to hypertensive crisis.
• Can interact with SSRIs or other sympathomimetics — risk of serotonin syndrome.
• Adverse effects: anticholinergic symptoms, postural hypotension, weight gain.
• Significant drug and dietary restrictions limit clinical use.

Question 24

How do tricyclic antidepressants (TCAs) act, and what makes them non-specific?

Answer 24

• Inhibit reuptake of both 5HT and NA by blocking SERT and NET.
• Also block mACh, H1, and α1-adrenergic receptors — contributing to sedation, hypotension, and anticholinergic side effects.
• Common TCAs: imipramine, amitriptyline, desipramine.
• Efficacious but high toxicity in overdose — especially cardiac arrhythmias.

Question 25

What distinguishes SSRIs from earlier antidepressants?

Answer 25

* Selectively block serotonin reuptake (SERT) with minimal affinity for other receptors. * Examples: fluoxetine, sertraline, citalopram, escitalopram. * Fewer side effects: less sedation, no anticholinergic burden. * Delayed onset: effects take ~3–6 weeks despite rapid pharmacokinetics.

Question 26

How do newer agents like SNRIs, NRIs, and NaSSAs differ mechanistically?

Answer 26

* SNRIs (e.g., venlafaxine) block reuptake of both 5HT and NA — more potent dual action than TCAs. * NRIs selectively inhibit NA reuptake (e.g., reboxetine). * NaSSAs (e.g., mirtazapine) block presynaptic α2-adrenergic receptors, disinhibiting NA/5HT release. * Also antagonise 5HT2/5HT3 — reducing anxiety, nausea.

Question 27

How does serotonin influence mood and antidepressant response?

Answer 27

* Serotonin (5HT) regulates mood, anxiety, sleep, and appetite. * Low 5HT is associated with depressive and anxious symptoms. * SSRIs block the SERT transporter, increasing 5HT availability. * Postsynaptic 5HT1A activation is key for mood improvement. * Delayed response may reflect time for receptor desensitisation and BDNF-mediated neuroplasticity.

Question 28

What is ketamine’s mechanism in rapid antidepressant action?

Answer 28

* NMDA receptor antagonist that reduces inhibitory GABAergic tone on excitatory neurons. * Enhances AMPA receptor signalling → rapid synaptic strengthening. * Effective in treatment-resistant depression within hours. * Limited by short duration of effect and potential for addiction/dissociation.

Question 29

How does nicotine affect neurotransmission and addiction risk?

Answer 29

* Nicotine is an agonist at nicotinic acetylcholine receptors (nAChRs), especially α4β2 in the CNS. * Activates dopaminergic neurons in the VTA → nucleus accumbens (reward circuit). * Improves attention and mood in the short term. * Long-term use leads to receptor upregulation but reduced sensitivity → dependence. * High prevalence of smoking in schizophrenia may reflect self-medication.

Question 30

What is the mesolimbic dopamine pathway and its role in addiction?

Answer 30

* Originates in the ventral tegmental area (VTA), projecting to the nucleus accumbens and prefrontal cortex via medial forebrain bundle. * All drugs of abuse increase dopamine in the nucleus accumbens. * This dopamine release is associated with reward, motivation, and reinforcement. * Repeated exposure sensitises the pathway → craving and compulsive drug seeking. * Opponent process theory: initial pleasure is replaced by drug use to avoid withdrawal.

Question 31

What is the difference between tolerance, dependence, and addiction?

Answer 31

* Tolerance: reduced effect with repeated use, due to receptor desensitisation or compensatory changes. * Dependence: physiological adaptation to drug; withdrawal symptoms on cessation. * Addiction: compulsive drug-seeking despite harm; involves long-term changes in reward, learning, and stress circuits. * All involve neuroadaptive changes such as altered gene expression, receptor trafficking, and synaptic plasticity.

Question 32

How do tricyclic antidepressants (TCAs) work and what are their characteristics?

Answer 32

* Block reuptake of both noradrenaline and serotonin, prolonging their action at the synapse. * Examples: imipramine (non-selective), desipramine (NA-selective), amitriptyline. * Also antagonise histamine (H1), α1-adrenergic, and muscarinic (mACh) receptors. * Side effects: sedation (H1), postural hypotension (α1), and anticholinergic symptoms (dry mouth, blurred vision, urinary retention). * Risk of cardiac arrhythmias and death in overdose. * Effective but now less preferred due to side effect profile and toxicity.

Question 33

How do selective serotonin reuptake inhibitors (SSRIs) work and what are their properties?

Answer 33

* Block serotonin reuptake transporter (SERT), increasing synaptic 5HT levels. * Do not significantly affect NA or DA reuptake. * Common first-line antidepressants. * Examples mentioned: none explicitly in PDF, but the class is discussed generally. * Side effects: nausea, sexual dysfunction, insomnia, weight gain, emotional blunting. * Delayed onset of therapeutic effects (2–6 weeks). * Risk of serotonin syndrome when combined with other serotonergic agents. * Discontinuation syndrome possible with abrupt cessation.

Question 34

How do reuptake inhibitor classes differ (SNRIs, NRIs)?

Answer 34

* SNRIs inhibit reuptake of both serotonin and noradrenaline. * NRIs selectively inhibit noradrenaline reuptake. * These increase monoamine transmission, similar to TCAs but with different side effect profiles. * Specific examples are not listed in the PDF, but the mechanisms are described. * Clinical differences and side effects vary depending on receptor affinities. * Offer alternatives to patients who do not respond to SSRIs.

Question 35

What are NaSSAs and how do they function as antidepressants?

Answer 35

* Noradrenergic and specific serotonergic antidepressants. * Example: mirtazapine. * Antagonise presynaptic α2-adrenergic receptors → increases NA and 5HT release. * Also block postsynaptic 5HT2 and 5HT3 receptors. * Enhance serotonergic signalling indirectly without inhibiting reuptake. * Fewer anticholinergic and sodium channel effects compared to TCAs. * Different side effect profile; may cause sedation or weight gain.