3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.3.2 The Biogenic Amine Hypothesis

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Written by Resident Doctor Committee · Published

Origins

The biogenic amine hypothesis links mood disorder to serotonin, noradrenaline and dopamine. It arose from drug observations, not from direct evidence of a chemical imbalance.

  • Reserpine depleted monoamines and was reported, inconsistently, to cause depression.

  • Iproniazid, a tuberculosis drug, inhibited monoamine oxidase (MAO) and affected mood.

  • Imipramine improved depression and was later shown to inhibit reuptake.

  • Schildkraut's 1965 model emphasised noradrenaline; later versions added serotonin and framed mania as catecholamine excess.

Benefit from raising monoamine signalling does not prove that deficiency caused the illness.

Pharmacological evidence

Drug

Acute action

Implication

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin transporter blockade

Serotonin is a target

Serotonin and noradrenaline reuptake inhibitors, tricyclics

Serotonin and noradrenaline transporter blockade

Both pathways matter

MAO inhibitors

Less monoamine breakdown

Several amines contribute

Mirtazapine

Alpha-2 and serotonin 5-HT2 and 5-HT3 blockade

Release and receptor effects matter

Reuptake inhibitors such as SSRIs and tricyclics block the transporter (1) that returns transmitter to the terminal, while MAO inhibitors block the mitochondrial MAO (3) that breaks down dopamine, noradrenaline and serotonin, so both classes leave more monoamine available. Drawn for MRCPsychiatrist

  • Tryptophan depletion lowers serotonin synthesis and can briefly provoke symptoms in remitted or susceptible people, including some SSRI responders, but acts inconsistently in healthy volunteers.

  • Catecholamine depletion can provoke symptoms after response to noradrenergic treatment.

Depletion findings support pathway dependence in some people, not a universal deficiency.

Transmitter systems

Transmitter

Functions and symptoms

Serotonin (raphe nuclei)

Mood, anxiety, impulsivity, threat, sleep

Noradrenaline (locus coeruleus)

Energy, concentration, arousal, vigilance

Dopamine

Reward, motivation, anhedonia, psychomotor activity

Catecholamine excess

Mania

  • SSRIs can reduce negative emotional bias before mood improves, and reduced negative bias is not the same as increased positive mood.

  • Moderate noradrenaline activity supports focus, while excess can increase anxiety.

Delayed response

  • Reuptake inhibition begins rapidly but benefit takes weeks, so a refilled-reservoir model cannot explain the time course.

  • Proposed adaptations include receptor and autoreceptor changes, altered second messengers, cyclic AMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and sleep, stress and learning changes.

  • Ketamine improves depression within hours, so a long delay is not inherent to recovery.

  • Antidepressants may increase plasticity, letting experience and psychological treatment reshape networks, though this mechanism is not established.

Limits

  • No universal monoamine deficiency has been established, and cerebrospinal fluid, receptor and transporter findings are inconsistent.

  • Similar symptoms arise with adversity, medical illness, substance use and chronic pain, so group-level drug effects do not identify an individual's cause.

  • Mania involves more than catecholamine excess, including sleep and circadian disruption.

  • Purely biochemical explanations can make patients pessimistic about recovery; depression usually reflects interacting biological, personal and environmental factors.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.