The Role of Neurobiologic Processes in Treating Depression
Michael E. Thase, MD
Departments of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia Veterans Affairs Medical Center, and the University of Pittsburgh Medical Center, Philadelphia and Pittsburgh
Many antidepressants are currently available for the treatment of depression. However, although depression is a heterogeneous condition, all approved antidepressants have relatively similar mechanisms of action, ie, they directly affect the neurotransmission of the monoamines serotonin (5-HT) and/or norepinephrine (NE). These neurotransmitters mainly originate from major nuclei in the brain stem: 5-HT from the raphe nuclei and NE from the locus coeruleus. Both 5-HT and NE have ascending pathways to the cerebral cortex, which is involved with executive function, and to the limbic system, which includes structures such as the hippocampus, anterior cingulate cortex, and amygdala, all of which are associated with behavior, motivation, and emotion.1
Mechanisms of Action
Monoaminergic neurotransmitters originally became the focus of MDD treatment about 50 years ago, when drugs that inhibited either the reuptake or the catabolism of 5-HT or NE were serendipitously discovered to work as antidepressants. The exact role these neurotransmitters play in the treatment of depression is not known, but 5-HT and NE have large modulating effects on regions of the brain involved in depression, and, when effective, antidepressants normalize disturbances in neurocircuitry in these same regions. For example, overactivation of the amygdala, as seen in patients with depression, is normalized with antidepressant treatment.2
Antidepressants have noticeable differences in side effects and in drug-drug interactions, but, owing to their relative commonness of mechanism, have only small and inconsistent differences in overall efficacy in studies of depressed outpatients. Studies have also failed to demonstrate large and consistent differences in the effects of serotonergic versus noradrenergic antidepressants on particular symptoms. However, one specific efficacy finding related to the mechanisms of action of antidepressants can be seen in depletion studies in which the neurotransmitters thought to initiate the antidepressant activity of these medications are pharmacologically reduced in subjects with depression. A meta-analysis3,4 of studies examining the depletion of either tryptophan (the precursor of 5-HT) or catecholamine (the precursor of NE) found that depletion of either amino acid led to increases in the HDRS scores of patients in the trials. The symptoms evoked by each type of depletion were similar, suggesting that 5-HT and NE neuromodulation overlaps in many areas. Some differences, however, were seen in the effects of tryptophan and catecholamine depletion on symptoms such as somatic anxiety and cognition (AV 1).4 These results suggest that drugs with serotonergic selectivity may improve anxiety more than drugs with more noradrenergic activity, and noradrenergically selective drugs may improve cognition and energy more than a serotonergically selective drug would.
Studies have also shown that patients who have responded to SSRIs are at greater risk of experiencing a relapse of depressive symptoms when tryptophan is depleted, while patients who have responded to a noradrenergically active medication are more likely to relapse when catecholamines have been depleted.5 In healthy volunteers with no history of depression, depletion of either monoamine had no clinical effect.3 Monoamine depletion was also found to have no effect in patients with depression who were not receiving antidepressant treatment, suggesting that, while the role of monoamine deficiency in the pathophysiology of depression is unclear, the therapeutic effect of current antidepressants requires a monoamine system with no deficiencies.
The homology of response to antidepressants that initiate effects through different neurotransmitters may be due in part to crosstalk between neurons. That is, noradrenergic neurons also have 5-HT receptors (called heteroreceptors), and 5-HT neurons also have noradrenergic receptors.6 Antidepressants that primarily affect either 5-HT or NE may nevertheless have indirect effects on the other neurotransmitter through these heteroreceptors.
Antidepressant Effect on Gene Expression
The antidepressant effects of current medications do not happen in a time course that is explained by increasing monoamines in the synapse or by changes in receptor sensitivity. The delay in antidepressant effect is suggestive of either downregulation or upregulation of the activity of certain genes. For example, use of antidepressants has been shown to upregulate the expression of BDNF, a neurotrophin that enhances neuroplasticity and neurogenesis.7,8
Animal models have demonstrated that antidepressant use provides resiliency against stress-induced decreases in neurogenesis.9 In 1 study,10 disrupting antidepressant-induced neurogenesis through either genetic means (eg, mice bred with a genetic impairment in the 5-HT1A receptor) or radiologic methods (x-irradiation of the hippocampus) also blocked antidepressant behavioral effects, indicating that behavioral effects may be causally related to neurogenesis. Additionally, in the mice bred with a genetic impairment in the 5-HT1A receptor, the SSRI fluoxetine had no impact on BDNF synthesis, but the TCA imipramine did, indicating that activation of 5-HT1A receptors is not a major component in the mechanism of action of TCAs (AV 2).10 This finding suggests that a multiple-action antidepressant, such as a TCA, may be able to override a patient’s inherited impairment in a particular type of neurotransmission.
Studies11,12 have examined the effect of antidepressant treatment on serum BDNF levels in humans with MDD. In these studies, patients with depression initially had significantly lower levels of serum BDNF than subjects in control groups, but, after antidepressant treatment, no statistical difference in BDNF levels was found between the groups. Additionally, increases in serum BDNF levels were significantly correlated with parallel decreases in HDRS scores for those patients who remitted with antidepressant treatment. However, while it is plausible that increasing BDNF can be helpful in depression by restoring normal physiology in certain areas of the brain, in other areas of the brain, BDNF can have depressogenic effects. Currently, determining serum BDNF levels is not useful in treating patients clinically and research correlating BDNF levels in plasma with levels in different regions of the central nervous system is needed.
Neuroplasticity and Novel Targets for Pharmacotherapy
Antidepressants may have neuroprotective effects in humans. For instance, a significant positive correlation was demonstrated between the number of untreated days of depression and a reduction in hippocampal volume in patients with MDD (P = .0006); however, no such correlation was found between the number of days of treated depression and loss of hippocampal volume.13 Findings such as these represent a shift in focus for the treatment of depression from correcting monoamine deficiencies to countering the effects of stress and enhancing neuroplasticity.14
Future targets for antidepressant pharmacotherapies include corticotrophin-releasing hormone antagonists, BDNF modulators, and NMDA antagonists. For example, in a randomized, placebo-controlled study,15 patients with treatment-resistant depression were given an intravenous infusion of ketamine, an anesthetic and a powerful antagonist of the NMDA glutamate receptor. Within 24 hours, 71% of the patients treated with ketamine met depression response criteria and 29% met remission criteria; 35% of subjects maintained their response for at least 1 week. Although ketamine could not have routine therapeutic application, this study demonstrated efficacy of a novel mechanism of action. Medications with novel mechanisms of action may be the most promising possibilities for improving the efficacy, safety, and tolerability of antidepressant therapeutic interventions for patients with depression.
For Clinical Use
- Current antidepressants, which primarily affect 5-HT and NE neurotransmission, differ in safety and tolerability but demonstrate approximately equivalent efficacy in treating depressive symptoms
- Antidepressants influence the expression of gene activity and enhance neuroplasticity
- Novel targets for antidepressants include BDNF modulation and glutamate receptor antagonists
fluoxetine (Prozac and others), ketamine (Ketalar and others), imipramine (Tofranil and others)
5-HT = serotonin, BDNF = brain-derived neurotrophic factor, BrdU = 5-bromo-2’-deoxyuridine, HDRS = Hamilton Depression Rating Scale, MDD = major depressive disorder, NE = norepinephrine, NMDA = N-methyl-D-aspartate, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant,
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- Mega MS, Cummings JL, Salloway S, et al. The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci. 1997;9(3):315–330.
- Sheline YI, Barch DM, Donnelly JM, et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001;50(9):651–658.
- Delgado PL, Moreno FA. Noradrenaline dysfunction in depression: implications for treatment [abstract from the 22nd Annual Meeting of the CINP]. Int J Neuropsychopharmacol. 2000;3(suppl S1):S1–S420.
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- Juric DM, Miklic S, Carman-Krzan M. Monoaminergic neuronal activity-up-regulates BDNF synthesis in cultured neonatal rat astrocytes. Brain Res. 2006;1108(1):54–62.
- Czéh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A. 2001;98(22):12796–12801.
- Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301(5634):805–809.
- Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(2):261–265.
- Gonul AS, Akdeniz F, Taneli F, et al. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci. 2005;255(6):381–386.
- Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160(8):1516–1518.
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- Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–864.