NEW ENGLAND JOURNAL OF MEDICINE January 3, 2008, Volume 358:55-68, Number 1

1. NEW ENGLAND JOURNAL OF MEDICINEJanuary 3, 2008, Volume 358:55-68, Number 1 Major Depressive Disorder R.H. Belmaker, M.D., and GalilaAgam, Ph.D.

2. MAJOR DEPRESSIVE DISORDERS • Depression is related to the normal emotions of sadness andbereavement, but it does not remit when the external cause ofthese emotions dissipates, and it is disproportionate to theircause. • Classic severe states of depression often have no externalprecipitating cause. It is difficult, however, to draw cleardistinctions between depressions with and those without psychosocialprecipitating events.

3. MAJOR DEPRESSIVE DISORDERS • The diagnosis of major depressive disorderrequires: • distinct change of mood, characterized bysadnessor irritabilityand accompanied by at least several psychophysiologicalchanges, such as disturbances in sleep, appetite, or sexualdesire; constipation; loss of the ability to experience pleasurein work or with friends; crying; suicidal thoughts; and slowingof speech and action. • must last a minimum of 2weeks and interfere considerably with work and family relations.

4. THE MONOAMINE DEFICIENCY HYPOTHESIS • Postulates a deficiency in serotonin or norepinephrine neurotransmission in the brain. • Monoaminergicneurotransmission is mediated by serotonin (5-hydroxytryptamine 1A [5-HT1A] and 5-hydroxytryptamine 1B [5-HT1B]) or norepinephrine (noradrenaline) released from presynaptic neurons • Serotonin is synthesized from tryptophan, with the first step in the synthetic pathway catalyzed by tryptophan hydroxylase; norepinephrine is synthesized from tyrosine, with the first step catalyzed by tyrosine hydroxylase. • Both transmitters are stored in vesicles in the presynaptic neuronand released into the synaptic cleft, thereby affecting both presynaptic and postsynaptic neurons. • Cessation of the synaptic action of the neurotransmitters occurs by means of both reuptake through the specific serotonin and norepinephrine transporters and feedback control of release through the presynapticreceptors (5-HT1A and 5-HT1B regulatory autoreceptors for serotonin and the 2-noradrenergic autoreceptors for norepinephrine).

5. THE MONOAMINE DEFICIENCY HYPOTHESIS • Numerousstudies of norepinephrine and serotonin metabolites in plasma,urine, and cerebrospinal fluid, as well as postmortem studiesof the brains of patients with depression, have yet to identifythe purported deficiency reliably. • However, a newly discoveredform of the enzyme tryptophan hydroxylase, designated TPH-2,is specific to the brain and could explain why previous postmortemstudies of total enzyme activity did not show differences intryptophan hydroxylase activity between patients with depressionand controls. • A recent positron-emission tomographic studyusing a ligand for brain monoamine oxidase showed a 30% increaseof the enzyme in a subgroup of patients with depression. Astudy measuring differences in monoamine metabolites betweenthe internal jugular vein and the brachial artery showed lowerproduction by the brain of norepinephrine metabolites in patientswith depression than in controls. • The monoamine-deficiencyhypothesis continues to stimulate research whenever a new technicalwindow into the brain is opened.

6. THE MONOAMINE DEFICIENCY HYPOTHESIS • Numerousstudies of norepinephrine and serotonin metabolites in plasma,urine, and cerebrospinal fluid, as well as postmortem studiesof the brains of patients with depression, have yet to identifythe purported deficiency reliably. • However, a newly discoveredform of the enzyme tryptophan hydroxylase, designated TPH-2,is specific to the brain and could explain why previous postmortemstudies of total enzyme activity did not show differences intryptophan hydroxylase activity between patients with depressionand controls. • A recent positron-emission tomographic studyusing a ligand for brain monoamine oxidase showed a 30% increaseof the enzyme in a subgroup of patients with depression. Astudy measuring differences in monoamine metabolites betweenthe internal jugular vein and the brachial artery showed lowerproduction by the brain of norepinephrine metabolites in patientswith depression than in controls. • The monoamine-deficiencyhypothesis continues to stimulate research whenever a new technicalwindow into the brain is opened.

7. THE MONOAMINE DEFICIENCY HYPOTHESIS • Serotonin and norepinephrine can be depleted experimentallyin humans by oral treatments. • A drink containing all aminoacids except tryptophan stimulates the liver to synthesize proteinsand rapidly depletes the plasma (and therefore the brain) oftryptophan (Tryptophan is rate-limiting for serotonin synthesisin the brain). • Such oral tryptophan depletion does not inducedepression in healthy subjects but will cause a relapse of depressionin patients who have been successfully treated with a serotonin-reuptakeinhibitor.

8. THE MONOAMINE DEFICIENCY HYPOTHESIS • Similarly, alpha-methyl paratyrosine inhibits tyrosinehydroxylase, the rate-limiting step in catecholamine synthesis. • Treatment with alpha-methyl paratyrosine does not induce depressionin normal subjects but will induce a relapse in patients whohave been treated successfully with a norepinephrine-reuptakeinhibitor.

10. PHARMACOPHYSIOLOGY

11. ANTI-DEPRESSANTS • Tricyclic antidepressants • MAOIs • SSRIs • Dopamine-norepinephrine reuptake inhibitors • Serotonin-norepinephrine reuptake inhibitors • Serotonin modulators • Norepinephrine-serotonin modulator • Selective noradrenaline reuptake inhibitor

12. THE MONOAMINE DEFICIENCY HYPOTHESIS • The early antidepressants blocked the reuptakeof norepinephrine and serotonin by the presynaptic neuron. Theimmediate effects of this pharmacologic action are to increasethe availability of norepinephrine and serotoninin the synapseand to increase stimulation of the postsynaptic neuron.

13. THE MONOAMINE DEFICIENCY HYPOTHESIS • Inhibitorsof the enzyme monoamine oxidase were also discovered to haveantidepressant properties. This enzyme catabolizesnorepinephrineand serotonin in their respective presynaptic neurons, and suchinhibition could be expected to increase the availability ofneurotransmitters.

14. ACTIONS OF ANTIDEPRESSANTS ON AMINE NEUROTRANSMITTERS • Tricyclicsblock the norepinephrine and serotonin transporters, terminating amine neurotransmission which permits a longer sojourn of neurotransmitter in the intrasynaptic spaceat the receptor site.

15. ACTIONS OF ANTIDEPRESSANTS ON AMINE NEUROTRANSMITTERS • MAO inhibitors block a major intraneuronaldegradative pathway for the amine neurotransmitters, which permits more amines to accumulate in presynaptic stores and more to be released. • Countering this increased synaptic activity is increasing evidence of alterations in presynaptic regulation of neurotransmitter release. • Presynapticautoreceptors respond to increased synaptic transmitter by down-regulating transmitter synthesis and release

16. ACTIONS OF ANTIDEPRESSANTS ON AMINE NEUROTRANSMITTERS • Some of the second-generation antidepressants have similar strong effects on amine transporters, whereas others have only moderate or minimal effects on reuptake or metabolism. • SSRIs • Dopamine-norepinephrine reuptake inhibitors • Serotonin-norepinephrine reuptake inhibitors • Serotonin modulators • Norepinephrine-serotonin modulator • Selective noradrenaline reuptake inhibitor