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Neurobiological aetiology of mood disorders 

Neurobiological aetiology of mood disorders
Chapter:
Neurobiological aetiology of mood disorders
Author(s):

Guy Goodwin

DOI:
10.1093/med/9780199696758.003.0088
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Introduction

Neurobiology provides an explanation of behaviour or experience at the level, either of systems of neurones or individual cells. The current era of progress is driven by contemporary cognitive neuroscience and a rapid evolution in the platform technologies of imaging and genetics. These will allow us to improve our accounts of the functional anatomy of the component elements of mood and its disorder, their functional neurochemistry and, in all probability, give meaning to what a cellular account of depressive illness may eventually describe. This chapter will offer a partial and personal view of these developments to date.

There are now authoritative models of causation in mood disorder, established from well designed, large-scale twin studies (see Chapter 4.5.5). These inform the classical formulation of mood disorder as requiring a vulnerability, a precipitating factor or factors, and maintaining factors which prevent spontaneous recovery. Neurobiology will be addressed under these headings.

Vulnerability to mood disorder

The key vulnerability factors appear to be genes, temperament (also in substantial part genetic), and early adversity. There has been limited work on the neurobiology of these risk factors, as opposed to the vast effort to understand the depressed phenotype. However, for potential prevention either of onset or relapse, such factors appear more logical targets for current research effort and will be covered first. Success in depression would parallel that seen in moving the management of heart disease from the acute episode of infarction to the treatment of metabolic risk factors.

(a) Genetics

Neurobiology has informed the genetic search for candidate genes, starting with the human serotonin transporter (SERT) gene (see Chapter 4.5.5). There has been a terrific proliferation of possible genetic effects deriving from neurobiological theories designed either to explain elements of the actions of psychotropic drugs, the depressed phenotype or from animal experiments. The latter are limited by the validity of animal models of depression per se. Some of the former will be noticed below.

Genes making small contributions to the risk of psychiatric disorder are emerging from direct analysis of the genome (see Chapter 2.4.2). Consistent findings must inform biological investigations in future. At this point it is uncertain whether insights will come from studying variation in individual genes, as has often been assumed, or from a much more complex understanding of cellular function regulated only in part by genetic variation. On the latter assumption the role of genetic hits is to direct attention to processes which may go wrong in the relevant disease. For mood disorder, these seem likely to be developmental or related to stress regulation.

(b) Temperament

The way in which genes may regulate the expression of vulnerability traits is suggested by animal studies. For example, when animals are selected for differences in emotional behaviour they also show different hypothalamic–pituitary–adrenal (HPA) axis function. Specifically, Roman high- and low-avoidance rats differentially acquire a two-way active avoidance response in a shuttle box. High-avoidance animals show greater prolactin and HPA axis responsivity to stress compared with low-avoidance animals. However, young Roman strain rats show identical HPA axis reactivity, although prolactin responses and behaviour are different.(1) In other words, reactivity to the environment may share a measure of common genetic control across physiological and behavioural domains, but HPA abnormality per se develops secondary to emotional experience, or at least is magnified by it.

In human studies, neuroticism is an old psychological construct often criticized as reflecting an average or habitual mood state rather than a truly independent risk. We have studied extremes of the dimension (high and low N) in young subjects before the onset of depression and in older groups who may or may not have experienced depressive episodes. Interestingly, high neuroticism with or without a history of depression is associated with increased awakening cortisol(2) in mature subjects, but not in subjects under 20 years of age, echoing the rodent finding. Thus, N has a purely biological consequence that develops with emotional experience, but is independent of depression per se.

What the neuroticism construct has also lacked hitherto has been a plausible psychological dimension. Cognitive bias relevant to the onset of depression can be detected in young high N subjects. In emotional categorization and memory tasks, high N volunteers were faster to classify dislikeable self-referent personality characteristics and produced fewer positive memory intrusions. They also had a higher threshold for identifying happy faces. This suggests the hypothesis that risk for depression is largely manifest as reduced positive processing of emotional information(3); increased negative processing appears to develop only after the actual experience of depression. Neural biases underlying this behaviour are even more readily detected.(4) Our hypothesis is that high neuroticism is not just an habitual low mood but is biologically founded in negative biases in attention, processing, and memory for emotional material. Indeed, there is now genetic evidence favouring a common genetic locus in human beings and rodent.(5) How emotional bias translates into either low-level symptoms or a full mood episode will be of great interest. Furthermore, depressive episodes per se appear to have an impact on brain function, and increase the risk of further relapse (see below).

(c) Early adverse experience

Adverse childhood experience was identified in genetically uncontrolled studies as a risk factor predisposing women to subsequent depression (Chapter 4.5.5) and has been confirmed in genetically informative designs.(6) In a clinical context, such developmental or social effects are usually viewed as separable from biology. Indeed, their very existence is usually taken to validate a ‘social’ approach to psychiatry. From a more unified point of view, however, one would predict measurable neurobiological consequences. In fact, such effects have proved to be more profound than most biologists anticipated.

Variations in maternal care produce individual differences in neuroendocrine responses to stress in rats. The offspring of mothers that exhibited more licking and grooming of pups during the first 10 days after birth showed, in adult life, reduced plasma ACTH and corticosterone responses to acute stress.(7) In addition, there was increased hippocampal glucocorticoid-receptor messenger RNA (mRNA) expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotrophin-releasing hormone (CRH) mRNA. Greater early maternal attention also substantially reduced subsequent behavioural fearfulness in response to novelty, increased benzodiazepine receptor density in the amygdala and locus coeruleus, increased α‎2-adrenoreceptor density in the locus coeruleus, and decreased CRH receptor density in the locus coeruleus. Thus, maternal care serves to programme behavioural responses to stress in the offspring by altering the development of the neural systems that mediate fearfulness.

When BALB/cByJ mice were raised by an attentive C57BL/6ByJ dam, their excessive stress-elicited HPA activity was reduced, as were their behavioural impairments. However, cross-fostering the more resilient C57BL/6ByJ mice to an inattentive BALB/cByJ dam failed to elicit behavioural disturbances. In other words, vulnerable offspring may have their problems exacerbated by maternal behaviour, while early-life manipulations may have less obvious effects in relatively hardy animals.(8) Whether separation or stress paradigms in rodents can be taken as precise models of the mechanisms underlying the risk of mood disorder or other psychiatric problems cannot yet be decided, but their general relevance to the human case seems obvious. At present, data in human subjects is limited but findings that relate to the better characterized animal models are emerging.(9)

In fact, epidemiological data have linked increased risks of cardiovascular, metabolic, neuroendocrine, and psychiatric disorders in adulthood with an adverse foetal environment as well. Glucocorticoid excess may be the mechanism.(10) Low-birth-weight babies have higher plasma cortisol levels throughout adult life, which suggests a permanent change in HPA function. Whether such effects and later effects of environmental stress in childhood can in part mediate co-morbidity between a range of psychiatric and physical disorders is of growing contemporary interest. It is unclear how, over- or underactivity in stress regulation contributes to psychiatric disorder: both appear to be implicated since awakening cortisol responses may be blunted in subjects with early adversity(9) or enhanced in at risk neurotic individuals.

Gene–environment interaction is the likely basis of the neurobiology of mood disorder. In general terms this must be correct. Either the genetic/biological or the environmental factors could be targets for prevention. Whether the genetic mechanisms can be brought into sufficient focus to allow specific new pathways to be identified remains the major current challenge. It is often assumed that mediating characteristics or the endophenotype may have a simpler genetic architecture than the disease itself: unfortunately, the evidence so far gives reason for caution. This debate is currently very polarized between optimists (see Chapter 2.5.3 by Meyer-Lindenberg & Goldberg) and pessimists (see Chapter 2.4.2 by Flint). The genetic and developmental routes into distal common pathways regulating stress responses may be very numerous. Disorders that are both common and very variable in expression, such as depression, may turn out to have little specificity that is worth talking about. Every illness may be an ensemble of many specific factors, none of which is individually going to lead to a more focused treatment or a better prediction of treatment response.

Precipitating factors: the neurobiology of life events

Like early adversity, the role of life events in depression has been affirmed in genetically controlled studies. Life events are relevant to almost all first episodes of depression, but are less significant in its recurrence. The biology of life events is subsumed in the biology of stress, at best a clumsy term. In human studies it will be always difficult to isolate the critical ingredients of a particular psychological stress from the individual differences that stressed individuals bring to their experience. There have been few recent contributions to the field of direct relevance to depression.(11) However, a key clinical feature of the illness course in depression is the association of life events most strongly with first episodes of depression. Subsequent episodes appear to need a less substantial environmental trigger, as if the patient becomes sensitized.(12) Patients with a strong family history may effectively be presensitized. Accordingly the effect of life events and the brain changes that occur with repeated or chronic illness is of great relevance to prevention and reduction of the risk of future episodes.

Maintaining factors: biological studies of the depressed state

In the majority of biological studies of affective disorder, patients have been studied when ill and compared with normal controls. Over the years, this kind of design has produced a range of positive findings, usually of modest effect. It remains true to say that no biological changes have ever been found that distinguish between depressed patients and controls better than does the clinical assessment of the patients. What is also curious, and not a little tantalizing, is the impression that some symptoms may, in part, represent biological adaptations directed to put things right. Thus, on the one hand, there may be consistent effects upon hormone secretion or sleep that represent phenomena of illness. On the other, deliberate changes in hormone status or sleep deprivation may modify the state of depression. Depression is also so common in its less severe forms, that it is tempting to see it as a biologically adaptive mechanism in response to loss or social defeat. Informative animal analogues might be expected to exist, but theoretical comparisons with other biological models such as early separation in primates or hibernation in bears are limited by the species gap.(13)

However, what makes depression the clinical burden it is, remains its tendency to persist and sometimes become chronic. The biological factors contributing to this are still poorly understood, but they would provide an obvious target for novel drug development. In general it is not yet obvious which symptoms of acute depression are related to this key biology and which are either irrelevant or even adaptive. If there is now a consistent interest, it has been stimulated by the gradual acceptance that some cells divide to produce neurones in the mature brain, especially in the hippocampus. It is very tempting to suppose that the plastic effects maintaining the unwanted brain state in depression may be related to neurogenesis or its failure, which is a beautiful hypothesis requiring confirmation by direct evidence.

(a) The depressed state: functional anatomy

Perfusion or metabolic imaging can indirectly detect changes in neuronal activity (see Chapters 2.3.6 and 2.3.8). Signals can be well localized, but their meaning is ambiguous. They may reflect either reversible changes in function or a semi-permanent loss of neuronal connectivity. Reductions in function in anterior brain structures have been typical in major depression. Hypoperfusion tends to be greatest in frontal, temporal, and parietal areas and most extensive in older patients; high Hamilton scores tend to be associated with reduced perfusion.(14) Reductions in frontal areas may be more likely in patients with impoverished mental states. Thus, neuropsychological testing in major depression shows evidence of slowing in motor and cognitive domains, with additional prominent effects on mnemonic function that are most marked in the elderly. These effects are correlated with reduced frontal perfusion in the elderly. In younger patients, there may actually be increased perfusion in the frontal and cingulate cortex. Metabolic increases in the cingulate gyrus have been associated with a good treatment response.(15) Highly localizing findings have been unusual, however. The only exceptions have been within-subject changes on recovery in the mesial frontal cortex and perhaps the basal ganglia.(14)

There has been a dramatic expansion of imaging studies of emotional processing in normal volunteers, now usually with fMRI (see Chapters 2.3.8 and 2.5.4). It is well summarized by meta-analysis of over 300 such emotion induction and cognitive task. Emotion induction resulted in inferior medial activation and cognitive tasks resulted in dorsolateral activation.(16) However, the broad spread of precise loci of activation means that localization within the frontal lobes has proceeded little further. It may explain the diffuse reports typical of the depression literature. Nevertheless, a focus on limbic activity has led to quite specific, quasi- neurological hypotheses about connectivity in frontal areas and to treatment innovation: deep brain stimulation adjacent to subgenual cingulated cortex (Brodmann area 25).(17) How effective, and how localized this treatment effect really is, will be an important challenge to the field. However, it underlines that ‘functional imaging’ of brain perfusion primarily informs anatomy.

Isotope-based imaging of receptor occupation could more plausibly offer mechanistic understanding of psychiatric disorder. In depression, it has progressed with the availability of suitably informative ligands. However, the field generally tends to employ small sample sizes, and fundamental advances are difficult to identify. Single-photon emission tomography (SPET or SPECT) with the dopamine D2/3 ligand [123I]IBZM showed increased binding in the striatum.(18) There were significant correlations between IBZM binding in the left and right striatum and measures of reaction time and verbal fluency, but not of mood as such. This finding has been confirmed with a PET ligand.(19) Increased D2/3 binding in the striatum probably reflects a reduced dopamine function, whether due to a reduced release or secondary upregulation of receptors. Binding to the 5-HT1a receptor appears to be reduced in unipolar depression, an effect also present in recovered atients.(20)

In recent years, new SPET and PET ligands for the serotonin and dopamine transporter have become available (see Chapter 2.3.6 by Grasby). For the serotonin transporter in acute depression, the story is not consistent.(21,22) Binding to the dopamine transporter appears to correlate with depressive symptoms in healthy volunteers.(23) Hence trait effects may confound state effects and vice versa. Isotope-based imaging has been slow to develop a wide choice or availability of ligands, hence its role has been largely to follow rather than stimulate new ideas. Its specificity does mean that it can critically test hypotheses about specific receptors.

Such ligands have not yet made an impact on treatment strategies, as dopamine receptor ligands have for the antipsychotics. However, there are interesting preliminary conclusions: for example, drugs that bind to the serotonin transporter appear to saturate the site at therapeutic doses and increase the availability of dopamine reuptake sites.(24)

In summary, functional imaging has served to implicate frontal and limbic rather than posterior brain areas, in broad confirmation of anatomical conclusions derived from observing the effects of lesions or brain stimulation. Relevant neuropsychological challenges are now being incorporated into imaging protocols and we have the first example of an imaging-led treatment innovation—deep brain stimulation. Finally, ‘functional’ abnormalities may importantly predict structural abnormality in depression.

(b) Neuroendocrine challenge tests

Secretion of hormones in the anterior pituitary is under control, both direct and indirect, of central neuronal cell bodies that may project relatively widely within the brain. The secretion of a given hormone in response to specific precursors or agonists for individual neurotransmitter receptors has been proposed as a way of testing the security of such connections. Hormone secretion provides a bioassay of the system of interest. There is a measure of consensus about the findings in major depression, which, indeed, forms the most consistent basis for our understanding of disturbed neurotransmission in depression. However, the approach no longer leads the neurobiology, and merits consideration instead, in the more specific context of neuroendocrine function (see Chapter 2.3.3). The main findings are described below.

Neuroendocrine drug challenge suggests attenuated seroto-nergic function and increased cholinergic function in depression. Reduced responses to adrenergic and dopaminergic challenge also suggest impaired neurotransmission. Interpretation of tests with agonists is always difficult, because blunting may occur in an overactive system that has been downregulated. In addition, if the secretion of the assay hormone itself is actually directly affected by the state of depression, interpretation in terms of specific neurotransmitter abnormalities may be misleading. This is a particular problem for ACTH/cortisol responses (see below). In fact, enthusiasm for neuroendocrine surrogate markers of monoamine transmission within the brain has probably diminished in recent years, but the paradigm of drug challenge nevertheless remains interesting. We must assay brain responses of the monoamine projections more centrally involved in mood regulation.

(c) Hypercortisolaemia

About half of all patients with major depression have a raised cortisol output, which tends to return to normal on recovery. It is most consistently associated with an ‘endogenous’ pattern of illness (see Chapter 4.5.3). While cortisol is always regarded as a ‘stress’ hormone, and is secreted in response to various types of acute stress, the stresses that commonly result in long-term hypercortisolaemia are poorly understood. The idea that there is a relatively specific link between chronic high cortisol levels and mood disorder is notably persistent. In major depression there is peripheral hypertrophy of the adrenal glands, measurable in MRI body scans, and an enhanced response to corticotrophin. The MRI change, like the hypercortisolaemia itself, reverses on recovery.(25)

Suppression of cortisol secretion occurs normally via glucocorticoid receptor-mediated inhibitory feedback to the hypothalamus; it is readily produced by dexamethasone, which is a potent exogenous glucocorticoid (the dexamethasone suppression test (DST)). For example, Non-suppression of endogenous cortisol after dexamethasone occurs in Cushing's disease. It implies either reduced feedback and/or enhanced central drive to release cortisol. It was initially observed that the 1-mg DST showed high specificity (96 per cent) and sensitivity (67 per cent) as a putative diagnostic test for melancholia.(26) At this point of time the result attracted intense interest, but has since proved difficult to generalize. The high specificity established against normal controls was less against other patient groups. Thus, DST non-suppression has not been accepted as a diagnostic test. This failed effort to give medical respectability to psychiatric diagnosis came to devalue what remains an important observation. Non-suppression usually reflects hypercortisolaemia, which is itself a robust phenomenon of mood disorder that requires explanation like any other core biological symptom. Other symptoms that we identify as part of the depressive syndrome lend themselves less easily to investigation. The DST also has potential clinical uses beyond diagnosis. DST non-suppression predicts a low placebo response rate to drug treatment,(27) and hypercortisolaemia predicts a low rate of clinical response to psychological intervention.(28)

It remains unclear whether cortisol contributes to the clinical state of depression by a direct action on the brain. Exogenous cortisol administration is associated with affective symptoms, and chronic excessive cortisol secretion commonly appears to produce depressive symptoms in Cushing's disease. An HPA axis programmed to hypersecrete cortisol under stress could be a pathogenic mechanism explaining why depression or mania develops. This view has provoked efforts to treat mood disorder by inhibition of cortisol synthesis with metyrapone or blocking the post-synaptic receptors. The effects of such manipulations appear primarily, and unexpectedly, to influence cognitive function more than mood per se. Thus the anti-glucocorticoid, mifepristone improved spatial working memory in bipolar depression(29) and the anti- mineralocorticoid, spironolactone significantly impaired selective attention and delayed recall of visuospatial memory in healthy volunteers without effects on CCK-induced panic anxiety.(30)

There is a final twist: when depressed patients are given large doses of cortisol they tend to show acute mood enhancement(31) and oral dexamethasone has been reported to elevate mood in major depression, especially in hypersecretors.(32) This leads to the converse hypothesis that an HPA axis appropriately adapted to chronic stress early in development might be unable to mount a normal effective response to acute stress later in life. Cortisol may then be seen as a euphoriant (or antidepressant), and hypercortisolaemia as an antidepressant response of the stress-regulating mechanisms of the brain. Based on this view, all cortisol levels seen in depression may be set inappropriately low for the ongoing stress, however high or low they are compared with the normal range.

Whether one supposes cortisol levels to be set too high or too low in depression, it remains inconvenient that either a suppression or an augmentation of steroid effect seems, initially at least, to elevate mood. A way out of this complication may lie in cortisol's action on two receptors in the brain (the glucocorticoid and mineralocorticoid receptors) that may have opposite actions. However, we still need better-controlled replicated data on the effects of steroid manipulations, both in at-risk subjects and in major depression. It is also possible that peripheral cortisol levels are largely irrelevant to the brain and that receptor regulation may critically modulate their central action: one challenging hypothesis is that antidepressants work through changing receptor disposition.(33)

An increased cortisol production is associated with an increased release of hypothalamic β‎-endorphin and probably a pulsatile increase in ACTH. The paraventricular nucleus of the hypothalamus represents the highest level of dedicated neurones in the HPA axis. The neurosecretory cells of the paraventricular nucleus release the peptides CRH and AVP into the portal hypophyseal blood. These hormones in turn stimulate the release of ACTH from the anterior pituitary. Major depression is characterized by a blunted ACTH response to CRH, an elevated level of CRH in the cerebrospinal fluid, and increased numbers of neurones expressing CRH mRNA in the paraventricular nucleus of the hypothalamus post-mortem.(34) CRH is not confined to the paraventricular nucleus, but is expressed in a variety of other central nuclei whence it can produce anxiogenic behavioural effects. CRH receptors, which exist in two forms, are widely distributed in the hypothalamus and cortex. A related peptide, urocortin, has a similar pharmacology. Knocking out the CRH-1 receptor gene in mice impaired the HPA stress response and reduced anxiety-like behaviour. Non-peptide antagonists of CRH action, and of other peptide hormones implicated in stress responses have been taken very seriously as putative anxiolytics or antidepressants.(35) If effective, they will be among the first of a new generation of truly novel treatments based on peptide neurotransmission. The failure to see new compounds of this general kind by now is disappointing, and in the case of a neurokinin antagonist, aprepitant, there has been a high profile failure in major depression.(36)

(d) Thyroid abnormalities

In unselected major depression, thyroid hormone levels are usually normal, but there may be abnormalities of the thyrotropin (thyroid-stimulating hormone) response to thyrotropin-releasing hormone. The thyrotropin response is blunted in a significant number of patients, but this effect is poorly understood and has few accepted clinical associations. In contrast, a subgroup of patients may show an enhanced thyrotropin response with normal thyroid hormone levels (referred to as grade II hypothyroidism). These associations and the use of thyroid hormones in treatment suggest that there is more to be learned in this area (see Chapter 4.5.8).

(e) Sleep disturbance

Sleep is often disturbed in depression but in a variety of ways. Early-morning waking is the most typical in endogenous or melancholic depression, with the sleep patterns in such patients being similar to those seen in patients with mania. Trouble getting to sleep, frequent awakenings, and unsatisfactorily prolonged sleep are also commonly seen in depression. Like other biological manifestations of the disorder, the extent to which sleep is simply a consequence of the state of depression or a contribution to its biology is uncertain. Patients with severe depression or mania may respond to sleep deprivation with a transient elevation in mood. It implies that the sleep–wake cycle is directly involved with mood regulation and its disorder.

In severe depression (melancholia) the typical effects are a reduction in the total length of slow-wave sleep and a shortened latency in the appearance of rapid eye movement (REM) or dreaming sleep.(37) The cholinergic projections from the hindbrain may be REM-ON cells, while serotonergic and noradrenergic cells may be REM-OFF cells. The disturbed sleep of depression could be due to an increased cholinergic and/or a decreased serotonergic/noradrenergic drive; simplistic though it sounds, the experimental evidence is supportive. Depressed patients challenged with a cholinergic agonist in the second non-REM period enter REM significantly faster than psychiatric and normal control subjects. The reduced sensitivity of the noradrenergic system is suggested because clonidine fails to suppress REM in depressed patients compared with controls.(38) Tryptophan depletion (to attenuate 5-HT function) partially mimics the changes seen in depression in recovered patients.(39)

Sleep tends to recover on recovery from depression, and the tricyclic antidepressants in particular suppress REM sleep. However, sleep disturbance may be an early predictor of relapse, and disturbed sleep parameters predict a poor response to cognitive behaviour therapy.(40) Indeed, depressed patients may have inherently weak slow-wave sleep processes because unaffected subjects with a family history of depression show reduced slow-wave sleep and increased REM density in the first sleep cycle(41).

Interest in sleep as a fundamental key to understanding mood disorder has waned in the last two decades. However, its neurobiology is increasingly well understood, and its time may come again.

(f) Monoamine metabolite turnover

The earliest studies to investigate the actions of tricyclic antidepressants highlighted their actions on the turnover of the monoamine metabolites in animal brain. The ‘monoamine theory of depression’ proposed the reduced functioning of monoamine transmission in depression. Therefore it was natural to seek relevant measures of monoamine chemistry in the cerebrospinal fluid of patients and controls. The study of what became irreverently known as ‘neural urine’ and indeed of urine itself, since peripheral measures of monoamine turnover are also potentially relevant, virtually defined a decade of biological psychiatry in the 1970s and 1980s. Drugs had similar effects on neurotransmitter turnover as seen in animal studies, demonstrating that the human techniques were sufficiently sensitive. Indeed the monoamine theory is, at its best, a theory about drug action because the monoamine and metabolite changes produced by illness in patients have proved remarkably unconvincing.(42) The findings for the noradrenaline metabolite MHPG and the 5-HT metabolite 5-hydroxyindoleacetic acid were negative. The dopamine metabolite homovanillic acid did show the predicted decrease, but only significantly in women. There were trends to modest increases in all the major metabolites in mania. Although disappointing, cerebrospinal fluid studies could never reflect the activities of smaller groups of neurones localized in areas critical for the modulation of mood. Such a focus is only possible in isotope imaging (PET or SPET) or better post-mortem studies of the brain.

(g) Tryptophan depletion

The most convincing evidence that 5-HT is intimately involved in mood disorder has come from depletion of tryptophan, the amino acid precursor of 5-HT. The level of tryptophan in both peripheral blood and the brain can be driven to very low levels by a short-term low-protein diet and subsequent loading with large neutral amino acids. These compete with tryptophan for access to the brain amino acid transporter and also increase its peripheral metabolism, which results in the reduced synthesis and release of 5-HT. Initial observations appeared to bear primarily on the mechanism of drug action. Thus, patients who had recovered from major depression while taking a serotonin-selective reuptake inhibitor experienced a clear-cut return of severe symptoms lasting for several hours after tryptophan depletion. This finding has now been critically extended to patients with a history of recurrent major depression who were euthymic but not taking any medication.(43) Prominent objective symptoms of retardation and cognitive distortion returned in a stereotyped and severe way, reflecting previous symptoms. The effects on mood in patients who have had a previous episode of depression are qualitatively different from the more minor changes seen in normal female controls or even subjects with a strong family history. This may imply the formation of a form of neurobiological template, which increases the vulnerability to subsequent relapse or recurrence. The immediacy of the link between neurotransmitter function and symptoms may be the reason why patients with recurrent major depression need long-term treatment with antidepressant drugs to remain well.

(h) Does mood disorder have a functional neuropathology?

Severe mood disorder is virtually defined by its frequent recurrence or its chronicity. The first episodes of severe depression occur more frequently with increasing age and tend to be more refractory to treatment. Severe mood disorder is associated with ventricular enlargement and sulcal prominence.(44) Late-onset depression is characterized by pronounced impairments in most areas of cognitive function, in particular executive function and processing speed and is increasingly regarded as having a quasi-neurological quality. Indeed, there is an increased rate of white matter lesions, perhaps related to vascular disease, in older patients.(44) The relationship between cognitive deficits and underlying neuropathological changes requires further examination. Elderly patients with early-onset depression demonstrate greater preservation of executive functioning and processing speed, which may reflect partially distinct disease processes possibly mediated by different neuropathological mechanisms.(45) The key hypothesis must be that it is the particular pattern of functional disruption resulting from any cellular pathology that increases the risk of depression. It may be reasonable to describe such a change as a functional neuropathology.

In younger patients, the issue is whether depression per se leads to a functional neuropathology. In patients with unusual refractoriness and chronicity, MRI scanning again suggested reduced grey matter parameters, most significantly in the left hippocampus but also more diffusely in the left parietal and frontal association cortices. Left hippocampal grey matter density was correlated with measures of verbal memory, supporting the functional significance of the imaging changes. In contrast, patients with severe illnesses fully responsive to treatment showed no differences from controls. Any finding in the chronic group could predate the onset of depression, or be the result of the illness process or its treatment. It is fashionable to attribute structural changes in depression to hypercortisolaemia, but in this study that was not the explanation.(46) A failure of BDNF, related neurogenesis or loss of synaptic plasticity is also a possibility. Reduced hippocampal volume is a relatively consistent finding in many studies of modest size which have also implicated inter-linked structures in basal ganglia and thalamus.(47)

Rather surprisingly, a correlation between lifetime duration of illness and memory performance was also seen in a very large outpatient sample studied after recovery from a discrete episode.(48) It favours a toxic link between the burden of depression and cognition, which has implications for public health. It also means that the mechanisms associated with very severe depression are also relevant in less severe ambulant forms.

Post-mortem studies of the brain in mood disorder have been rare and are limited by tissue availability. Such studies in elderly depression have greater potential validity than the much more num-erous investigations of schizophrenia. The Stanley Neuropathology consortium has made samples of tissue widely available from small but well-characterized patient series. In the hippocampus, the most consistent findings are of reduced GABA function and abnormal measures of synaptic density or neuronal plasticity.(49) Such studies have seldom focused on other ‘candidate regions’ such as the inferior frontal or cingulate cortex or amygdale.(50) Several studies suggest a particular involvement of glial cells.(51) Since glia support the energy requirements of neurones, and their deficient function could account for aspects of the imaging abnormalities found in these disorders: elevated levels of glucocorticoids acting on glia could change their function, or glial changes could represent responses to primary neuronal withdrawal (see also Chapter 2.3.5).

Post-mortem studies can also address the neurochemistry, perhaps more directly and completely than other methods. Normal ageing is accompanied by a decline in a variety of indices of monoamine function including presynaptic markers of 5-HT innervation. In a small series of depressed suicides, there were 54 per cent fewer neurones in the dorsal raphe nucleus expressing SERT mRNA compared with controls.(52) Whether a reduced serotonergic innervation is the critical change that increases the vulnerability to mood disorder of patients with advancing years is not yet established. If so, the potential for MDMA to have long-term effects in heavy users is real and worrying.(53)

In suicide, post-mortem findings have broadly paralleled those in depression, with an important emphasis on 5-HT metabolism and neurotransmission (see Chapter 4.15.3). Whether 5-HT neuro-transmission, perhaps like that involving the other monoamines, represents a functional domain implicated independently in a variety of psychiatric syndromes and behaviours remains to be well established.

Conclusions

Mood disorder has an important neurobiological basis. This stretches from a vulnerability, which seems to be attributable to polymorphism in genes critical to stress regulation, through the impact that early experience has on the subsequent programming of the brain for stress responses, to the final responsiveness when encountering particular personal adversity in later life. Biological studies have highlighted the role of key brain areas within the limbic system such as the cingulate cortex and amygdala. We are still a long way from understanding, with any precision, the critical connections and cellular mechanisms, but the function of monoamine neurones generally, and of serotonergic projections in particular, is closely associated with mood regulation. Peptide neurotransmitters have long seemed likely to play a central role in stress regulation, but their potential as targets for antidepressant drug action are yet to be fulfilled. Finally, observations in the most chronic illnesses and in the elderly with depression have highlighted the possibility of a functional neuropathology underlying severe mood disorder. Depression seems to be critically related to the evolving story around neurogenesis in the brain. It is perhaps appropriate that its resolution will require fundamental advances in brain science: psychiatry has always posed, or anyway implied, the most demanding of scientific questions: how does the brain work?

Further information

American College of Neuropsychopharmacology: 5th Generation of progress. Available at: http://www.acnp.org/Default.aspx?Page=5thGenerationChapters

References

1. Castanon, N., Perez-Diaz, F., and Mormede, P. (1995). Genetic analysis of the relationships between behavioral and neuroendocrine traits in Roman high and low avoidance rat lines. Behavior Genetics, 25(4), 371–84.Find this resource:

2. Portella, M.J., Harmer, C.J., Flint, J., et al. (2005). Enhanced early morning salivary cortisol in neuroticism. The American Journal of Psychiatry, 162(4), 807–9.Find this resource:

3. Chan, S.W.Y., Goodwin, G.M., and Harmer, C.J. (2007). Highly neurotic never-depressed students have negative biases in information processing. Psychological Medicine, 37, 1281–92.Find this resource:

4. Chan, S.W.Y., Norbury, R., Goodwin, G.M., et al. (2008). Risk for depression is associated with exaggerated neural responses to fearful facial expressions of emotion. British Journal of Psychiatry (in Press).Find this resource:

    5. Fullerton, J., Cubin, M., Tiwari, H., et al. (2003). Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. American Journal of Human Genetics, 72(4), 879–90.Find this resource:

    6. Kendler, K.S., Kuhn, J.W., and Prescott, C.A. (2004). Childhood sexual abuse, stressful life events and risk for major depression in women. Psychological Medicine, 34(8), 1475–82.Find this resource:

    7. Liu, D., Diorio, J., Tannenbaum, B., et al. (1997). Maternal care, hippocampal glucocorticoid receptors, and hypothalamic–pituitary–adrenal responses to stress. Science, 277(5332), 1659–62.Find this resource:

    8. Caldji, C., Tannenbaum, B., Sharma, S., et al. (1998). Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proceedings of the National Academy of Sciences of the United States of America, 95(9), 5335–40.Find this resource:

    9. Heim, C., Plotsky, P.M., and Nemeroff, C.B. (2004). Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology, 29(4), 641–8.Find this resource:

    10. Seckl, J.R. and Meaney, M.J. (2006). Glucocorticoid ‘programming’ and PTSD risk. Annals of the New York Academy of Sciences, 1071, 351–78.Find this resource:

    11. Biondi, M. and Picardi, A. (1999). Psychological stress and neuroendocrine function in humans: the last two decades of research. Psychotherapy and Psychosomatics, 68(3), 114–50.Find this resource:

    12. Kendler, K.S., Thornton, L.M., and Gardner, C.O. (2000). Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the ‘kindling’ hypothesis. The American Journal of Psychiatry, 157(8), 1243–51.Find this resource:

    13. Tsiouris, J.A. (2005). Metabolic depression in hibernation and major depression: an explanatory theory and an animal model of depression. Medical Hypotheses, 65(5), 829–40.Find this resource:

    14. Goodwin, G.M. (1997). Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression. Journal of Psychopharmacology, 11(2), 115–22.Find this resource:

    15. Mayberg, H.S., Brannan, S.K., Mahurin, R.K., et al. (1997). Cingulate function in depression: a potential predictor of treatment response. Neuroreport, 8(4), 1057–61.Find this resource:

    16. Steele, J.D. and Lawrie, S.M. (2004). Segregation of cognitive and emotional function in the prefrontal cortex: a stereotactic meta-analysis. Neuroimage, 21(3), 868–75.Find this resource:

    17. Mayberg, H.S., Lozano, A.M., Voon, V., et al. (2005). Deep brain stimulation for treatment-resistant depression. Neuron, 45(5), 651–60.Find this resource:

    18. Shah, P.J., Ogilvie, A.D., Goodwin, G.M., et al. (1997). Clinical and psychometric correlates of dopamine D-2 binding in depression. Psychological Medicine, 27(6), 1247–56.Find this resource:

    19. Meyer, J.H., McNeely, H.E., Sagrati, S., et al. (2006). Elevated putamen D-2 receptor binding potential in major depression with motor retardation: an [C-11] raclopride positron emission tomography study. The American Journal of Psychiatry, 163(9), 1594–602.Find this resource:

    20. Bhagwagar, Z., Rabiner, E.A., Sargent, P.A., et al. (2004). Persistent reduction in brain serotonin(1A) receptor binding in recovered depressed men measured by positron emission tomography with [C-11]WAY-100635. Molecular Psychiatry, 9(4), 386–92.Find this resource:

    21. Meyer, J.H. (2007). Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. Journal of Psychiatry & Neuroscience, 32(2), 86–102.Find this resource:

    22. Staley, J.K., Sanacora, G., Tamagnan, G., et al. (2006). Sex differences in diencephalon serotonin transporter availability in major depression. Biological Psychiatry, 59(1), 40–7.Find this resource:

    23. Newberg, A., Amsterdam, J., and Shults, J. (2007). Dopamine transporter density may be associated with the depressed affect in healthy subjects. Nuclear Medicine Communications, 28(1), 3–6.Find this resource:

    24. Shang, Y.L., Gibbs, M.A., Marek, G.J., et al. (2007). Displacement of serotonin and dopamine transporters by venlafaxine extended release capsule at steady state—a [I-123]2 beta-carbomethoxy-3 beta- (4-iodophenyl)-tropone single photon emission computed tomography imaging study. Journal of Clinical Psychopharmacology, 27(1), 71–5.Find this resource:

    25. Rubin, R.T., Phillips, J.J., Sadow, T.F., et al. (1995). Adrenal gland volume in major depression: increase during the depressive episode and decrease with successful treatment. Archives of General Psychiatry, 52(3), 213–18.Find this resource:

    26. Carroll, B.J., Feinberg, M., Greden, J.F., et al. (1981). A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Archives of General Psychiatry, 38(1), 15–22.Find this resource:

    27. Ribeiro, S.C.M., Tandon, R., Grunhaus, L., et al. (1993). The DST as a predictor of outcome in depression: a meta-analysis. The American Journal of Psychiatry, 150(11), 1618–29.Find this resource:

    28. Thase, M.E., Dube, S., Bowler, K., et al. (1996). Hypothalamic–pituitary–adrenocortical activity and response to cognitive behavior therapy in unmedicated, hospitalized depressed patients. The American Journal of Psychiatry, 153, 886–91.Find this resource:

    29. Young, A.H., Gallagher, P., Watson, S., et al. (2004). Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology, 29(8), 1538–45.Find this resource:

    30. Otte, C., Moritz, S., Yassouridis, A., et al. (2007). Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition. Neuropsychopharmacology, 32(1), 232–8.Find this resource:

    31. Goodwin, G.M., Muir, W.J., Seckl, J.R., et al. (1992). The effects of cortisol infusion upon hormone secretion from the anterior pituitary and subjective mood in depressive illness and in controls. Journal of Affective Disorders, 26(2), 73–83.Find this resource:

    32. Dinan, T.G., Lavelle, E., Cooney, J., et al. (1997). Dexamethasone augmentation in treatment-resistant depression. Acta Psychiatrica Scandinavica, 95(1), 58–61.Find this resource:

    33. Pariante, C.M., Thomas, S.A., Lovestone, S., et al. (2004). Do antidepressants regulate how cortisol affects the brain? Psychoneuroendocrinology, 29(4), 423–47.Find this resource:

    34. Mitchell, A.J. (1998). The role of corticotropin releasing factor in depressive illness: a critical review. Neuroscience and Biobehavioral Reviews, 22(5), 635–51.Find this resource:

    35. Nemeroff, C.B. and Vale, W.W. (2005). The neurobiology of depression: inroads to treatment and new drug discovery. Journal of Clinical Psychiatry, 66, 5–13.Find this resource:

    36. Keller, M., Montgomery, S., Ball, W., et al. (2006). Lack of efficacy of the substance P (neurokinin(1) receptor) antagonist aprepitant in the treatment of major depressive disorder. Biological Psychiatry, 59(3), 216–23.Find this resource:

    37. Berger, M. and Riemann, D. (1993). REM sleep in depression—an overview. Journal of Sleep Research, 2(4), 211–23.Find this resource:

    38. Schittecatte, M., Garcia Valentin, J., Charles, G., et al. (1995). Efficacy of the ‘clonidine REM suppression test (CREST)’ to separate patients with major depression from controls; a comparison with three currently proposed biological markers of depression. Journal of Affective Disorders, 33(3), 151–7.Find this resource:

    39. Moore, P., Gillin, J.C., Bhatti, T., et al. (1998). Rapid tryptophan depletion, sleep electroencephalogram, and mood in men with remitted depression on serotonin reuptake inhibitors. Archives of General Psychiatry, 55(6), 534–9.Find this resource:

    40. Thase, M.E., Simons, A.D., and Reynolds, C.F. III. (1993). Psychobiological correlates of poor response to cognitive behavior therapy: potential indications for antidepressant pharmacotherapy. Psychopharmacology Bulletin, 29(2), 293–301.Find this resource:

    41. Lauer, C.J., Schreiber, W., Holsboer, F., et al. (1995). In quest of identifying vulnerability markers for psychiatric disorders by all-night polysomnography. Archives of General Psychiatry, 52(2), 145–53.Find this resource:

    42. Schatzberg, A.F., Samson, J.A., Bloomingdale, K.L., et al. (1989). Toward a biochemical classification of depressive disorders. X.Urinary catecholamines, their metabolites, and D-type scores in subgroups of depressive disorders. Archives of General Psychiatry, 46(3), 260–8.Find this resource:

    43. Smith, K.A., Fairburn, C.G., and Cowen, P.J. (1997). Relapse of depression after rapid depletion of tryptophan. Lancet, 349(9056), 915–19.Find this resource:

    44. Videbech, P. (1997). MRI findings in patients with affective disorder: a meta-analysis. Acta Psychiatrica Scandinavica, 96(3), 157–68.Find this resource:

    45. Herrmann, L.L., Goodwin, G.M., and Ebmeier, K.P. (2007). The cognitive neuropsychology of depression in the elderly. Psychological Medicine, 37, 1693–702.Find this resource:

    46. Shah, P.J., Ebmeier, K.P., Glabus, M.F., et al. (1998). Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression: controlled magnetic resonance imaging study. The British Journal of Psychiatry, 72(172), 527–32.Find this resource:

    47. Sheline, Y.I. (2003). Neuroimaging studies of mood disorder effects on the brain. Biological Psychiatry, 54(3), 338–52.Find this resource:

    48. Gorwood, P., Corruble, E., Falissard, B., et al. (2008). Toxic effects of depression on brain function: impairment of delayed recall reflects the cumulative length of the depressive disorder in a large sample of depressed out-patients. American Journal of Psychiatry, 165, 731–9.Find this resource:

    49. Knable, M.B., Barci, B.M., Webster, M.J., et al. (2004). Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley neuropathology consortium. Molecular Psychiatry, 9(6), 609–20.Find this resource:

    50. Harrison, P.J. (2002). The neuropathology of primary mood disorder. Brain, 125, 1428–49.Find this resource:

    51. Cotter, D.R., Pariante, C.M., and Everall, I.P. (2001). Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Research Bulletin, 55(5), 585–95.Find this resource:

    52. Arango, V., Underwood, M.D., Boldrini, M., et al. (2001). Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology, 25(6), 892–903.Find this resource:

    53. Green, A.R. and Goodwin, G.M. (1996). Ecstasy and neurodegeneration. British Medical Journal, 312(7045), 1493–4.Find this resource: