Unipolar depression: the monoamine hypothesis (biological)

The hypothesis

The monoamine hypothesis says depression is caused by a deficiency of monoamine neurotransmitters, mainly serotonin (5-HT) and noradrenaline (NA), in the synapse.

It grew out of chance findings in the 1950s: drugs that stopped the breakdown of monoamines (iproniazid) or blocked their reuptake (imipramine) relieved depression. It guided antidepressant development for decades.

Evidence for

• Antidepressants work on monoamines: SSRIs block the reuptake of serotonin; tricyclics raise serotonin and noradrenaline. Most available antidepressants act on monoamine transporters or receptors.
• Many people with moderate or severe depression benefit from them (NHS).

Evidence against

• Delayed onset: SSRIs raise serotonin within hours, but usually take 2 weeks or more to work (the NHS says up to 8 weeks to work fully). If low serotonin were the direct cause, improvement should be quicker.
• Tryptophan depletion: lowering brain serotonin did not cause depression in healthy people (Ruhé et al., 2007).
• Not everyone responds: people may need to try two or more antidepressants.
• Stahl (2013) wrote that there is no clear and convincing evidence that monoamine deficiency accounts for depression.

Evaluation

• Reductionist (9.3.3): explains depression by one chemical system and ignores thinking styles and life events (Beck's triad).
• Cause or effect? Even if serotonin activity is altered, it may be a result of depression.
• Application: still useful because it led to drug treatments that help many people.
• Nature and nurture (9.3.7): biology may interact with stressful life events (diathesis-stress).

Worked example

Explain why the delay in SSRIs' effects is a problem for the monoamine hypothesis.

1. SSRIs block serotonin reuptake, raising synaptic serotonin quickly.
2. But mood usually takes 2 weeks or more to improve.
3. If low serotonin directly caused depression, mood should lift as soon as serotonin rose.
4. So the drugs may work through slower changes, and serotonin deficiency may not be the direct cause.

Answer: The mismatch between fast chemical change and slow recovery undermines a direct deficiency explanation.

Check yourself

1. Which two neurotransmitters are central to the monoamine hypothesis?
   • Dopamine and glutamate
   • Serotonin and noradrenaline
   • GABA and acetylcholine
   • Cortisol and testosterone
   Show answer

   Serotonin and noradrenaline. Serotonin (5-HT) and noradrenaline.

2. How do SSRIs act?
   • They block dopamine receptors
   • They destroy serotonin
   • They block NMDA receptors
   • They block the reuptake of serotonin so more stays in the synapse
   Show answer

   They block the reuptake of serotonin so more stays in the synapse. Selective serotonin reuptake inhibitors.

3. Which finding most challenges the monoamine hypothesis?
   • Most antidepressants act on monoamines
   • Antidepressants raise serotonin quickly but mood improves only after weeks
   • Iproniazid relieved depression
   • SSRIs are the usual first choice
   Show answer

   Antidepressants raise serotonin quickly but mood improves only after weeks. The time lag suggests a less direct mechanism.

4. The NHS says antidepressants can take up to 8 weeks to work fully. How many days is that?
   Show answer

   56 days. 8 x 7 = 56 days.

5. Explain how tryptophan depletion research challenges the monoamine hypothesis.
   Show answer

   Lowering brain serotonin by depleting tryptophan did not cause depression in healthy people, so low serotonin alone cannot be the cause of depression.. If lowering serotonin does not cause depression, deficiency is not sufficient.

6. Explain one strength of the monoamine hypothesis.
   Show answer

   It has practical application because it led to antidepressants such as SSRIs, which help many people with moderate or severe depression.. Practical application through drug treatment.

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Sources

• Pearson Edexcel International Advanced Subsidiary/Advanced Level in Psychology specification (issue January 2026)
• Pearson IAL Psychology component guide: WPS04 (Issue 2, November 2024)
• Liu et al. (2017), Review of the monoamine hypothesis and its limitations, Frontiers in Cellular Neuroscience
• NHS: Depression in adults, treatment
• NHS: Antidepressants, side effects

Last updated 8 November 2026. Spotted a mistake? Tell us.