Friday, 11 January 2013

Depression beyond the monoamines

Depression is a symptom which commonly occurs co-morbid with many chronic conditions such as CFS. Depression can result from either psychological or physiological stressors, and therefore may result from the experience of a chronic illness or directly from the pathophysiological processes involved in that illness (e.g. inflammation).

The monoamines in depression
The major dominating depression hypothesis in biological science over the past half century has been the monoamine hypothesis (1965>). This hypothesis posits that depression is caused by deficiency of monoamine neurotransmitters; of which serotonin has gleaned most interest. This hypothesis was based primarily upon serendipitous findings that serotonin boosting drugs are somewhat effective in treating depression; even to this day most antidepressants target monoamine systems. The monoamine hypothesis has been extremely easy to ‘sell’ since it presents a seductively simple and reductionist neurobiological conceptualisation of mood. Indeed through the pharmaceutical media this hypothesis has become ingrained into the consciousness of mass culture (for review see 1). However nowadays it is completely outdated and overly simplistic. While changes to monoamine systems are certainly involved in mood disorders, the idea that for instance a gross brain serotonin deficiency underlies depression is flawed for several basic reasons discussed immediately below, and for reasons relating to the breadth of complex changes occurring in depression discussed later.

Several basic observations challenge the importance of serotonin to depression. Studies through the late 1900s showed that inducing serotonin or dopamine deficiency in healthy, depressed or recovered depression patients only produced depressive symptoms in recovered patients who had been treated by drugs acting upon the respective monoamine system 2. More recent acute tryptophan depletion (ATD) experiments in healthy individuals have revealed effects limited to subtle changes in cognitive bias 3–6. Furthermore, even a severe deficit of serotonin resulting from a genetic deficiency of sepiapterin reductase is not associated with depression but instead symptoms relating to sleep, cognition and appetite 7. Basic observations relating to antidepressants also challenge monoamine hypotheses of depression. For instance despite rapid blockade of serotonin reuptake, the therapeutic effect of SSRIs is delayed by weeks. Moreover, modulation of serotonin and monoamines does not appear important for the antidepressant activity of various atypical agents in behavioural models and clinical use (e.g. Tianeptine) 8.

Perhaps the best support for gross monoamine deficiency in depression are in vivo reports of increased MAO-A activity 9–11 and inconsistent reports of lowered serum tryptophan 12; suggesting increased metabolism and decreased synthesis of serotonin respectively. In reality dysfunction of neurotransmitter systems in depression can occur at multiple levels beyond their basic metabolism (i.e. synthesis, reuptake and catabolism). For instance the serotonin system comprises of a family of 5-HT (1-7) receptors further divided into subtypes which are heterogeneously distributed in the body and activated by serotonin (5-HT). All these receptors have differing effects on the postsynaptic neuron and mainly modulate central glutamatergic neurons (e.g. pyramidal cells) and GABAergic interneurons throughout the brain. Overall in vivo brain imaging studies looking directly for monoamine dysfunction in depression have so far failed to find consistent changes 13; however some receptor-level studies implicate expression changes to receptors such as 5-HT1A and 5-HT2/4/7 14–16. Taken together all these studies above both justify and limit the role of serotonin in depression, especially when considered in context of the plethora of other abnormalities found in depression some of which are discussed below.

New paradigms for understanding depression
It has become increasingly clear that there is far more to depression than simple gross chemical imbalances. In the brain, at the molecular level depression is associated with changes to many signaling systems relating to neurotransmitters (e.g. glutamate, GABA and monoamines), neuropeptides (e.g. neuropeptide Y) and growth factors (e.g. BDNF, GDNF, VEGF, IGF-1 and FGF-2). Moreover, the depressed brain is also associated with neuro-inflammation and impaired energy metabolism and redox 17–19. At the neuroanatomical level depression is associated with glial loss, altered neuronal morphology, and atrophy to structures such as the PFC, ACC and hippocampus 20–22. At a functional level depression is associated with altered regional connectivity and neurocircuitry 20. Increasing recognition of the importance of these changes in depression has led to several notable new depression hypotheses over the past decade, all of which broaden and deepen our understanding of mood disorders. These include neurotrophic/neuroplastic hypotheses (circa 2000>) 22,23, inflammatory hypotheses (circa 2005>) 12,24, and most recently glutamate/NMDA hypotheses of depression (circa 2005>) 25–27. Some elements of these hypotheses will be briefly discussed below.

Neuroplasticity in depression
A crucial mechanism underlying the activity of serotonergic antidepressants is their ability to modulate neuroplasticity and related signaling pathways. Indeed nNOS antagonism and activation of neurotrophic pathways have been shown to be required for the antidepressant activity of serotonergic drugs 28,29. The effects of monoaminergic drugs on neuroplasticity occur slowly, hence the slow-onset antidepressant effects. However this is not true of directly targeting the glutamate system, i.e. the central system involved in neuroplasticity. It has been repeatedly demonstrated that a single sub-anaesthetic dose of the NMDAR antagonist Ketamine can send treatment resistant depression (TRD) patients into remission within hours, an effect which is sustained for over a week. The effects of Ketamine and other NMDAR antagonists are mediated via rapid changes to neuroplasticity, such as spinogenesis and synaptogenesis in the PFC 30. Unfortunately these powerful drugs are typically too dangerous for clinical use, but remain important as proof of concept drugs for rapid antidepressant activity. For reviews of glutamate and neuroplasticity in depression see 22,30,31.

Inflammation & oxidative stress in depression
Inflammation is another increasingly hot topic in depression research; for reviews see 19,32. Serotonergic antidepressants attenuate stress-induced neuro-inflammation (e.g. iNOS and NADPH oxidase) and related oxidative stress in behavioural models. Further, peripheral inflammation induces sickness and depressive behaviours in models and humans. For instance treatment with the cytokine IFN-α induces depression in humans which correlates with CSF KA and quinolinic acid (NMDAR agonist) concentrations rather than serotonin depletion 33. This new depression pathway is supported by a recent study which found increased microglial quinolinic acid in sub-regions of the ACC in severe depression 34. Ultimately the increasing association of depression with inflammation may explain its comorbidity with various medical conditions associated with systemic inflammation, including gut disorders 32.

In summary, the monoamine hypothesis has been an important step in the evolution of our neurobiological understanding of mood disorders; although our complacence and attachment to it has perhaps closed many minds. There is far more to depression than simple gross chemical imbalances. At the molecular level depression may result from various stressors which can alter cellular metabolism and neuroplasticity. These changes can then facilitate the characteristic changes to brain neurocircuitry which underlie the depressive phenotype.

References
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