Neurobiology of depression

While many brain regions have been implicated in regulating emotions, we still have a very rudimentary understanding of the neural circuitry underlying normal mood and the abnormalities in mood that are the hallmark of depression. It is likely that many brain regions mediate the diverse symptoms of depression. This is supported by human brain imaging studies, which have demonstrated changes in blood flow or related measures in several brain areas, including regions of prefrontal and cingulated cortex, hippocampus, striatum, amygdala and thalamus to name a few (Liotti and Mayberg 2001). Anatomic studies of the brains of depressed patients have reported abnormalities in many of these same brain regions (Zhu, Klimek et al. 1999; Rajkowska 2000; Manji, Drevets et al. 2001). Knowledge of the function of these brain regions under normal conditions suggests the aspects of depression to which they may contribute. Neocortex and hippocampus may mediate cognitive aspects of depression such as memory impairments and feelings of worthlessness, hopelessness, guilt, doom and suicidality. The striatum (particularly the ventral striatum and nucleus accumbens) and amygdala and related brain areas are important in emotional memory, and could as a result mediate the anhedonia (decreased drive and reward for pleasurable activities), anxiety and reduced motivation that predominate in many patients. Given the prominence of so called neurovegetative symptoms of depression, including hyper or hyposomnia, changes in appetite as well as a loss of interest in sex and other pleasurable activities, a role of hypothalamus has also been speculated. Of course, these various brain regions operate in a series of highly interacting parallel circuits, which perhaps formulates a neural circuitry involved in depression (Figure 1).

Introduction

Figure 1. Neurotransmitter abnormalities and brain regions implicated in depression (numbers indicate important interactions).

1. Abnormalities in reciprocal activity of noradrenaline (NE) and acetylcholine (Ach) cause short REM latency and negative mood.

2. 2. Low levels of serotonin or lack of sensitivity to serotonin receptors linked to depression

3. Stress activates locus coeruleus (L.C.) and hypothalamus-pituitary-adrenal (HPA) axis causing release of epinephrine and ultimately depletion of NA

4. Serotonin and NE activity modulate activity of nucleus raphe, which in turn alters release of sex steroids possibly contributing factor in observed sex differences in depression.

5. Increase in GABA receptors generates a cascade of noradrenergic activity through L.C.

6. Reduction of dopamine activation of neurons in nucleus accumbens is related to the appearance of anhedonic behaviours.

There is also significant evidence for an enhanced activity of the hypothalamus- pituitary- adrenal (HPA) axis in MDD. This enhanced activity has been associated with a greater frequency of episodic release of cortisol, marked reductions in bone mineral density compared to matched controls and increased adrenal glands volumes. Evidence has also emerged that corticosteroid receptor function is impaired in many patients with major depression and in man healthy individuals at increased genetic risk for a depressive disorder (Holsboer 1999). Furthermore, clinical and pre-clinical data suggest that unrestrained secretion of corticotrophin releasing factor

Introduction

(CRF) in CNS produces several signs and symptoms of depression through continuous activation of CRF receptors (Zobel, Nickel et al. 2000).

Monoamines have been the primary focus of the earlier etiological theories of MDD. Although the monoamine depletion hypothesis now seems to be oversimplified view of pathophysiology of MDD, one should acknowledge the therapeutic significance of the hypothesis. The putative role of serotonin (5-HT) in MDD has been extensively studied, partly because of the broad therapeutic effects in depression of drugs such as selective serotonin reuptake inhibitors (SSRI). Some, but not all studies have shown reduced endocrine responses to indirect or direct serotonin agonists. Post-mortem studies have shown both an increase in the density of 5-HT2 receptor binding sites, and a decreased number of serotonin transporter binding sites (Owens and Nemeroff 1994) as well as an increase in the serotonin 5-HT_1A autoreceptors in the dorsal raphe of suicide victims with MD (Stockmeier, Shapiro et al. 1998). This evidence is supported by imaging studies which have evidenced widespread reductions in serotonin 5HT1A autoreceptor binding (Sargent, Kjaer et al.

2000) and reduced density of serotonin transporter binding sites (Malison, Price et al. 1998).

Other neurotransmitter systems have also been investigated. Post-mortem studies have shown a selective increase in the high affinity conformation of the brain α2A-adrenoceptors as well as decreased binding to norepinephrine transporters in locus coeruleus of depressed patients (Klimek, Stockmeier et al. 1997). The latter finding was interpreted as suggesting a compensatory down regulation of this transporter protein in response to an insufficient availability of norepinephrine at the synaptic level (Klimek, Stockmeier et al. 1997).

Janowsky and colleagues have suggested that the regulation of acetylcholine may also play a role in MDD. Cholinergic agonists cholinesterase inhibitors and acetylcholine precursors have all been shown to worsen mood in MDD (Janowsky, Risch et al. 1983; Duberstein, Conwell et al. 1993). Moreover depressed patients show a heightened response to muscarinic cholinergic agonists as evidenced by worsening of mood, anergia, papillary construction sleep and β endorphin release (Janowsky, el-Yousef et al. 1972; Dilsaver and Coffman 1989). Furthermore, abnormalities in levels of cortical choline an

Introduction

acetylcholine precursor have been reported in several imaging studies (Charles, Lazeyras et al. 1994; Steingard, Yurgelun-Todd et al. 2000).

Despite the fact that the role of dopamine in depression has been studied extensively over the past several decades, the evidence of its involvement in MD is still discussed. In vivo receptor labelling studies have shown increased dopamine D2 binding in the right striatum of MDD patients, although a recent study has found higher striatal dopamine transporter density in major depression. The evidence aroused from animal models has been described in discussion section.