Mood disorders rank among the leading causes of disability worldwide and are the leading cause of suicide. Based on symptoms and patterns of familial transmission, these disorders can be assigned to one of two broad categories. Individuals with unipolar depression experience episodes of depression only; those with bipolar disorder experience at least one episode of mania, and most commonly experience multiple episodes of depression and mania 15–5. Yet it must be emphasized that these clinical entities, much like anxiety disorders, represent a heterogeneous group of disparate pathophysiologic processes. Moreover, roughly half of individuals with mood disorders also experience significant symptoms of anxiety and vice versa, which emphasizes the limitations of current diagnostic schema in psychiatry.
15–5Mood Disorders ||Download (.pdf) 15–5 Mood Disorders
|Major depression |
|Characterized by sad mood or loss of interest in pleasurable activities (anhedonia), accompanied by abnormalities of sleep, appetite, energy, sex drive, and motivation. Other features may include psychomotor retardation or agitation, and abnormal thoughts, such as guilt, hopelessness, and suicidal ideas. Psychotic symptoms occur only in the most severe cases |
|Represents chronic milder depression. Its course is often punctuated by episodes of major depression |
|Bipolar disorder (manic-depressive illness) |
|Characterized by episodes of mania, with or without distinct episodes of depression. The symptoms and signs of depression are the same whether the disorder is unipolar or bipolar. Mania is characterized by euphoria or irritability, increased energy, and a decreased need for sleep. Patients often are intrusive, hypersexual, and impulsive; they have inflated self-esteem, which may be delusional. Cognitively, they are distractible; their speech is often rapid and pressured. Psychotic symptoms are common |
Bipolar disorder is highly heritable with roughly 65% to 80% of risk for the disorder being genetic. An increasing number of risk genes have been identified in recent years. Most of these genetic variations also confer risk for schizophrenia, further questioning today’s classification of mental illness. Given the significant overlapping genetic contributions to bipolar disorder and schizophrenia, and the centrality of psychosis to both syndromes, the former—although classically considered a mood disorder—is discussed with schizophrenia and other psychotic illnesses in Chapter 17.
Depression is much less heritable than bipolar disorder, with perhaps 35% of the risk being genetic and the remainder coming from a host of environmental factors or perhaps stochastic (random) processes during development. Given the heterogeneity and relatively low genetic risk of depressive syndromes, it is not surprising that convincingly replicated risk genes have not yet been identified.
Mood disorders are characterized by an episodic course, although they can become chronic. A striking feature of mood disorders is that their symptoms appear to reflect abnormal functioning in many different regions of the brain. Sleep disturbances may be traced to alterations in brainstem monoamine or cholinergic nuclei or to disruptions of the circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus (Chapter 13). Changes in appetite and energy may reflect abnormalities in various hypothalamic nuclei. Depressed mood and anhedonia (lack of interest in pleasurable activities) in depressed individuals, and euphoria and increased involvement in goal-directed activities in patients who experience mania, may reflect opposing abnormalities in the nucleus accumbens, medial prefrontal cortex, amygdala, or other structures. Anxiety, which is a common symptom of depression, may reflect abnormalities in the functioning of the amygdala and BNST, as previously mentioned. The excessive release of stress hormones, such as cortisol, which occurs in many individuals with mood disorders, may result from hyperfunctioning of the PVN of the hypothalamus, hyperfunctioning of the amygdala (which activates the PVN), or hypofunctioning of the hippocampus (which exerts a potent inhibitory influence on the PVN). Alterations in the content of thought, which are a cardinal feature of depression and mania, most likely reflect abnormal functioning of several areas of the cerebral cortex. A neurobiologic explanation of mood disorders must be able to demonstrate how diverse brain regions are affected, why associated abnormalities are episodic, and how both genes and environment can affect the pathogenesis of these disorders. Circuits that can directly or indirectly influence all of the structures affected by these disorders are currently a focus of research. Because of their widespread projections, and because of their role in antidepressant action, monoamine systems in the brain historically have been thought to play an important role in the pathophysiology of mood disorders. Even if they are not the primary cause of mood disorders, monoamine systems may serve to generalize an abnormality initiated elsewhere so that it affects much of the rest of the brain.
One obstacle to research in depression has been a lack of good animal models. Several tests (eg, forced swim or learned helplessness) are used to predict antidepressant responses in rodents, but are limited in terms of whether they model depression per se 15–4. Models in which rodents are subjected to various types of chronic stress more accurately reflect certain aspects of depression and have greater etiologic validity given the role of stress as a risk factor for the illness, although they are not yet validated clinically. Animal models are even more problematic for bipolar disorder: it has not yet been possible to show convincingly alternating episodes of depressive- and manic-like behaviors in an animal.
15–4 The Search for Animal Models of Depression
A major obstacle to research on depression has been the lack of good animal models. Three tests that are commonly used to predict the efficacy of antidepressant drugs illustrate the weaknesses in current models. The Porsolt test, or forced swim test, involves placing a rodent in a bucket of water. Most rodents struggle for a time before adopting a floating position without further struggle. The administration of an antidepressant, regardless of the type, increases the amount of time the animal spends struggling. Consequently, it has been hypothesized that such drugs cause these animals to avoid “despair” and to work harder and refuse to give up. This interpretation is not at all obvious. Moreover, the effects of the antidepressants administered during this test are observed immediately, even though their clinical effects in humans require long-term administration.
Two other tests, tail suspension and learned helplessness, are very similar. In the tail suspension test, mice hung upside down by their tails after a time stop struggling; an acute antidepressant dose increases the time they struggle. In learned helplessness, rodents are repeatedly given a mild foot shock but are not permitted to escape from the environment in which they receive the shock. After a suitable training period, these animals are permitted to escape after receiving a shock. Under these circumstances, a subpopulation of rodents fails to attempt escape, that is, they show signs of having “given up.” Acute or subchronic administration of an antidepressant facilitates escape behavior.
All clinically validated antidepressants are active in these tests. However, this should not be surprising because only compounds that are active in the tests are pursued as antidepressants for human use. This has created a “catch-22.” Although these tests are good predictors of available antidepressants, it is not known whether they can detect the effectiveness of agents with truly novel mechanisms of action. A non-monoamine–based agent, for example, might be effective in humans despite its failure to produce expected results in these tests. On the other hand, these tests have detected antidepressant-like activity of numerous novel, non-monoamine–based manipulations, but these various manipulations have not yet been validated clinically with the recent exception of ketamine. Hence, another catch-22.
The novelty suppressed feeding test measures the time it takes a mouse to approach food in a novel environment. An attractive feature of this test is that chronic, but not acute, administration of an antidepressant reduces this latency. However, acute administration of anxiolytic drugs causes the same effect, and this test, like the despair-based tests outlined above, are performed in normal animals.
Recent research has focused on developing models of depression that have greater validity and that can be reversed only with long-term antidepressant administration. Several chronic stress models have been proposed, some of which involve animals subjected to variable types of stress for relatively long periods of time (weeks to months), termed chronic unpredictable stress. Another model involves exposing animals to highly aggressive dominant males, a paradigm referred to as social defeat. An attractive feature of both paradigms is that the resulting behavioral abnormalities respond to chronic (not acute) antidepressant drugs and not anxiolytic drugs. Another advantage of social defeat is that it induces a broad range of behavioral abnormalities, some of which persist for several months, an outcome not seen in most other chronic stress models. Social defeat can also be used to identify subgroups of mice that are resilient, that is, they avoid most of these deleterious symptoms. Finally, several types of early life stress, such as separating newborn pups from their mothers, or even stressing pregnant dams, have been shown to produce lifelong changes in stress-related responses in the adult offspring. The hope is that the identification of human depression genes of strong effect and high penetrance, once placed into mice, will facilitate efforts to develop bona fide animal models of this syndrome and indeed of valid subtypes of the disorders.
Historically, a substantial focus of clinical research has reflected attempts to document abnormalities in monoamine systems in depression based on the knowledge that all clinically available antidepressant drugs target norepinephrine or serotonin, and perhaps less commonly dopamine, systems. Accordingly, a large number of studies have examined monoamine turnover, monoamine receptors on accessible peripheral blood cells, and the neuroendocrine and behavioral effects of various pharmacologic challenges such as the depletion of monoamine systems. Many of these active challenges can provoke symptoms or alter physiologic responses, but they have yielded little specific information about disease pathophysiology and have failed to prove primary abnormalities in monoamine systems as a cause for depression. Moreover, many antidepressant drugs have proved efficacious for a wide range of emotional and other disorders beyond depression, including panic disorder, GAD, OCD, PTSD, eating disorders, enuresis (bed wetting), and chronic pain syndromes. Thus, serotonin and norepinephrine are not exclusively related to depression. Rather, it appears that modulation of the brain’s serotonergic or noradrenergic systems can result in palliative effects on many pathophysiologic mechanisms.
Current Antidepressant Drugs
Antidepressant drugs are a heterogeneous group of compounds that are effective in the treatment of depression 15–6. As previously mentioned, most are also effective in the treatment of anxiety disorders, and serotonin-selective agents (ie, clomipramine and SSRIs) are effective in the treatment of OCD. Based on structural and neurochemical properties, antidepressant drugs often are subdivided into groups that include the older tricyclic and related cyclic antidepressants, SSRIs, selective norepinephrine reuptake inhibitors (NRIs), SNRIs, MAOIs, and miscellaneous antidepressants whose acute mechanisms of action are unknown. The chemical structures of representative antidepressants are shown in 15–6.
Chemical structures of representative antidepressants.
15–6Commonly Used Antidepressant Medications
Tricyclic antidepressants inhibit serotonin and norepinephrine reuptake to varying extents 15–4 and 15–6. They also antagonize several neurotransmitter receptors, particularly muscarinic cholinergic, H1 histaminergic, and α1 adrenergic receptors; such antagonism explains their many side effects, including sedation, dry mouth, and constipation. SSRIs were developed to selectively inhibit the serotonin transporter, without activity at cholinergic, histaminergic, or adrenergic receptors; their use has represented a rational means of avoiding some of the side effects associated with tricyclic agents. Likewise, reboxetine and atomoxetine are NRIs that lack many side effects associated with tricyclic agents by avoiding activity at the same receptors. Venlafaxine and duloxetine inhibit both serotonin and norepinephrine reuptake and also lack many of the side effects of tricyclic antidepressants. The newer drugs have their own side effects, such as sexual dysfunction with SSRIs, but the side effects are generally better tolerated by most patients. The development of MAOIs resulted from the serendipitous discovery in the 1950s that the antitubercular drug iproniazid alleviated depression, and the subsequent discovery that such alleviation stems from MAO inhibition (Chapter 6).
The mechanisms of action of other antidepressant agents, which often are described as atypical, remain poorly understood. Bupropion, an aminoketone, is an effective antidepressant that does not produce appreciable direct effects on the serotonin or norepinephrine systems. Its effectiveness has been attributed to its inhibition of dopamine reuptake; however, this is unlikely, because cocaine also inhibits dopamine reuptake but does not serve as an effective antidepressant, and because brain imaging studies have shown minimal occupancy of the dopamine transporter at clinically effective doses. Mirtazapine, also an effective antidepressant, is reported to be an antagonist at α2-adrenergic and 5HT2A and 5HT3 serotonin receptors; however, the relationship between these actions and its antidepressant effects has not been ascertained. Trazodone and nefazodone, both triazoloperidine derivatives of only modest efficacy, influence serotonin systems in several ways.
There is currently no way to predict whether a given patient with depression will respond to one or another type of antidepressant drug. Moreover, as best as can be extrapolated from large clinical studies, it would appear that most patients with depression respond to roughly equivalent degrees to treatment with an SSRI, NRI, or SNRI. Despite these observations, many patients must try several antidepressants, even several drugs of the same class (eg, multiple SSRIs), to obtain maximum clinical benefit. The biologic basis of these phenomena remains poorly understood. Although a large majority (perhaps 80% or more) of all patients with carefully diagnosed depression show partial improvement to available antidepressant medications, fewer than half show full remission. Those that do not are said to have “treatment-resistant depression”; however, there is currently no diagnostic test or biomarker available today that can predict subsequent antidepressant responsiveness.
ECT, which typically involves a series of six to nine generalized seizures under light anesthesia over 2 to 3 weeks, remains one of the most effective treatments for depression, but its therapeutic effects are usually short-lived; for this reason, ECT is often combined with a chemical antidepressant. ECT no longer induces a motor seizure because of the concurrent use of muscle paralyzing agents such as succinylcholine (Chapter 9); to be effective, however, it must produce electroencephalographic evidence of a seizure. The mechanism by which ECT treats depression is unknown. As described, DBS of several limbic brain areas is in early trials for treatment-resistant depression. There is also interest in magnetic stimulation therapies, transcranial magnetic stimulation (rTMS) or magnetic seizure therapy (MST), but the efficacy of these treatments is not yet established. Antidepressant activity of vagal nerve stimulation (VNS) has been reported, but the effects seem to be modest at best in most patients.
Monoamine systems and antidepressant action
Altered synaptic levels of modulatory neurotransmitters, such as serotonin or the catecholamines, have a marked influence on behavior, which they regulate through their effects on information processing in multiple circuits that underlie sensation, cognition, emotion, and motor and neuroendocrine outputs. However, their actions must be understood in the proper context. Historically, hypotheses linking mood disorders to norepinephrine and serotonin systems in the brain were overly simplistic, based not on the anatomy and physiology of these systems but on pharmacologic observations alone. It was observed, for example, that approximately 15% of patients who received long-term treatment with the antihypertensive drug reserpine developed a syndrome indistinguishable from naturally occurring depression; concomitantly it was discovered that reserpine depletes neurons of norepinephrine, serotonin, and dopamine (Chapter 6). Likewise, studies of the first antidepressants revealed that they influence monoamines; for example, it was discovered that MAOIs inhibit the enzyme that metabolizes monoamine neurotransmitters, as mentioned earlier. Furthermore, it was proposed that because this enzyme is located in certain presynaptic terminals, its inhibition prolongs the life of monoamine neurotransmitters in the presynaptic cytoplasm and in turn increases the amount of these transmitters available for packaging into vesicles and subsequent release. Similarly, it was discovered that imipramine and other tricyclic antidepressants inhibit the reuptake of norepinephrine and serotonin in varying ratios. Because reuptake was known to be the primary mechanism by which the synaptic actions of monoamines are terminated, it was posited that tricyclic antidepressants act by increasing the amount of these neurotransmitters in synapses.
Pharmacologic observations such as these led to a simple hypothesis: depression is the result of inadequate monoamine neurotransmission, and clinically effective antidepressants work by increasing the availability of monoamines. Yet this hypothesis has failed to explain the observation that weeks of treatment with antidepressants are required before clinical efficacy becomes apparent, despite the fact that the inhibitory actions of these agents—whether in relation to reuptake or monoamine oxidase—are immediate. This delay in therapeutic effect eventually led investigators to theorize that long-term adaptations in brain function, rather than increases in synaptic norepinephrine and serotonin per se, most likely underlie the therapeutic effects of antidepressant drugs. Consequently, the focus of research on antidepressants has shifted from the study of their immediate effects to the investigation of effects that develop more slowly.
The anatomic focus of research on antidepressants also has shifted. Although monoamine synapses are believed to be the immediate targets of antidepressant drugs, more attention is being given to the target neurons of monoamines, where chronic alterations in monoaminergic inputs caused by antidepressant drugs presumably lead to long-lasting adaptations that underlie effective treatment of depression. The identification of molecular and cellular adaptations that occur in response to antidepressants, and the characterization of resulting functional changes in the cells and circuits in which they occur, has been the goal of more recent investigations.
However, despite a great deal of research and the demonstration of numerous molecular and neural pathways required for the long-term actions of antidepressant drugs in animal models, it has not yet been possible to definitively establish any such mechanism as the basis of antidepressant efficacy in the clinic. This experience raises the possibility that studies of currently available antidepressant drugs may not provide new insight into the pathophysiology of depression or the development of more effective treatments. By analogy, as discussed in Chapter 1, studies of furosemide’s effects on the kidney are not likely to increase our understanding of congestive heart failure. Accordingly, there has been an increasing shift of attention in the field away from studies of antidepressant drugs and monoamine systems per se to exploration of other circuits and molecular pathways that underlie depression-related behavioral abnormalities in animal models and in depressed humans based on neuroimaging, postmortem research, and experimental therapeutics. The work described toward the beginning of the chapter on mood-regulating circuits that involve the subgenual cingulate gyrus (where DBS treats a subset of depressed patients), for instance, represents a significant advance over a narrow focus on monoamine function.
The remainder of this chapter is devoted to a discussion of current efforts in antidepressant research that are based on newer theories of the pathophysiology of depression. Before proceeding with this material, a series of clinical studies conducted 10 to 20 years ago, which supports a role for serotonergic and noradrenergic systems in antidepressant action, deserves comment. According to these studies, patients with depression who respond to treatment with an SSRI exhibit a brief relapse when their body stores of tryptophan, the precursor of serotonin, are depleted (Chapter 6). In contrast, such tryptophan depletion does not cause relapse in patients treated with NRIs. Moreover, patients treated with NRIs experience relapse in response to inhibition of catecholamine synthesis with α-methylparatyrosine (AMPT), an inhibitor of tyrosine hydroxylase (Chapter 6), whereas patients treated with SSRIs do not. Overall, these findings confirm that monoamine systems are required substrates for the clinical efficacy of today’s antidepressants. The brief relapses observed may represent withdrawal phenomena akin to those associated with benzodiazepine antagonists. However, this line of research has not revealed the specific changes in the brain that mediate clinical responses to antidepressants and has not offered information about the pathophysiology of depression.
Antidepressant Discovery Efforts
A major challenge associated with research on depression and antidepressant action is the difficulty to relate experimental findings in laboratory animals to depressed humans. Changes in the levels of most neurotransmitters and neurotransmitter receptors currently cannot be measured in specific brain regions of living human patients. Changes in postreceptor signaling pathways and gene transcription are even more difficult to trace. Advances in PET, single-photon emission computed tomography (SPECT), and magnetic resonance spectroscopy (MRS) technology may eventually enable us to assess some of these modes of regulation. In addition, more sophisticated functional imaging methods are making it possible to define with increasing accuracy abnormalities in specific neural circuits in depression and their reversal by antidepressant treatment. In parallel, optogenetic and related approaches, which make it possible to manipulate precisely defined brain circuits on millisecond time scales (Chapter 2), offer the potential of relating brain imaging in humans with neural circuit function in animal models.
Another challenge in antidepressant research, as mentioned, is the inherent limitation of animal models, since key symptoms of depression (eg, suicidality, guilt, hopelessness, sadness) are inaccessible in animals 15–4. Moreover, given the lack of bona fide depression risk genes of strong effect and high penetrance, most depression and antidepressant research has involved the use of normal laboratory animals. The brain of a human at risk for depression is unlikely to respond to chronic stress in the same way as the brain of a normal rodent; likewise, the brain of a depressed human is unlikely to respond to a drug treatment in the same way as an unaffected human or rodent. Indeed, antidepressants administered to humans without depression produce no discernible responses (ie, no changes in mood and related behaviors) other than typical side effects. Recent efforts focused on more ethologically valid animal models of depression, such as those involving several forms of early life stress or chronic exposure to social stress, offer promise as a window into at least certain subtypes of depression and related disorders that are associated with stress 15–4.
The increasing expense and associated regulatory burden of clinical studies are further major obstacles in antidepressant drug discovery efforts. As will be seen in the discussion that follows, numerous neurotransmitter systems and biochemical pathways have been implicated in depression and antidepressant responses in animal models, but have not been adequately evaluated in the clinic. The field has moved increasingly away from smaller, exploratory clinical studies to large efficacy trials that can cost >$50 million. This divide between the laboratory and clinic needs to be addressed, and recent collaborative efforts involving the National Institutes of Health, the pharmaceutical and biotechnology industries, and academia are showing signs of promise.
The discussion that follows reviews current major efforts in antidepressant drug discovery that are grounded in pathophysiologically based investigations of depression and related syndromes that span animal and human inquiry.
Neuroendocrine abnormalities associated with depression
Abnormal, excessive activation of the HPA axis (see Chapter 10, 10–3) occurs in approximately half of all individuals who experience an episode of major depression. These individuals may exhibit increased cortisol production, as measured by increases in free cortisol in urine, and a reduced ability to suppress plasma cortisol, adrenocorticotropic hormone (ACTH), and β-endorphin after administration of dexamethasone, a potent synthetic glucocorticoid. Direct and indirect evidence suggests that these individuals also exhibit hypersecretion of CRF. Moreover, ACTH responses to intravenously administered CRF are blunted, and concentrations of CRF in cerebrospinal fluid (CSF) tend to be increased. As previously indicated, increases in cortisol induce catabolism, suppress the immune system, and may have temporary elevating effects on mood, energy, and cognition. Although short-term administration of glucocorticoids often produces euphoria and increased energy, the impact of long-lasting increases in endogenous glucocorticoids produced during depression can involve complex adaptations such as those that occur in Cushing syndrome (Chapter 10). For example, evidence indicates that prolonged increases in cortisol may be damaging to hippocampal neurons and can suppress hippocampal neurogenesis (the generation of new neurons postnatally). Because the hippocampus is required for feedback inhibition of CRF neurons 15–7, episodes of depression could conceivably produce a vicious cycle of impaired feedback regulation of the HPA axis and thus predispose to future recurrences.
Limbic control of the hypothalamic–pituitary–adrenal (HPA) axis shown in rat brain. Neurons of the paraventricular nucleus (PVN) of the hypothalamus containing corticotropin-releasing factor integrate information relevant to stress. Prominent neural inputs include excitatory afferent signals from the amygdala and inhibitory (though indirect) afferent signals from the hippocampus. Other important inputs are received from ascending monoamine pathways and from the periphery, the latter of which include inhibitory inputs from circulating endogenous glucocorticoids such as cortisol (Chapter 10).
Significant parallels exist among melancholic depression, the stress response, and behavioral and physiologic effects produced by CRF injected into cerebral ventricles. These include increased arousal and vigilance, decreased appetite, decreased sexual behavior, and increased heart rate and blood pressure. Thus, even if hypothalamic abnormalities are not a primary cause of depression, they very likely contribute to the generation of serious symptoms and have an impact on the course of depression and its somatic sequelae. Accordingly, pharmacologic agents currently under investigation have been designed to correct some of these abnormalities. Although mifepristone (RU486) is marketed as an abortifacient based on its progesterone receptor antagonist properties, it is also a glucocorticoid receptor antagonist and has shown some promise in patients with severe, psychotic depression. CRF1 receptor antagonists have also been in development for depression as well as anxiety; however, studies of such drugs have to date been disappointing, as mentioned earlier. This experience may reflect the complex actions of CRF1 receptors: they mediate not only activation of the HPA axis but also several extrahypothalamic neural circuits, with the overall consequence of CRF1 antagonism perhaps not being antidepressant. More recently, attention has been given to CRF2 receptor antagonists in the treatment of depression, although it remains uncertain whether this mechanism will be any more effective than blockade of CRF1 receptors.
Neurotrophic hypotheses of depression and antidepressant treatment
Research over the past 15 years has demonstrated in laboratory animals that chronic exposure to stress causes morphological changes to several types of forebrain neurons. Stress decreases the dendritic arborizations of pyramidal neurons in certain subfields of the hippocampus and prefrontal regions of cerebral cortex, while it increases dendritic growth of pyramidal neurons in the amygdala and medium spiny neurons of the nucleus accumbens. In each case, there is evidence that directly links these morphological changes to the deleterious behavioral effects of stress. Such research has prompted efforts to delineate the molecular basis of these morphological maladaptations and mine those findings for the development of new antidepressants.
One mechanism that contributes to stress-induced atrophy of hippocampal neurons is dysregulation of the HPA axis discussed in the previous section. Under normal physiologic circumstances, glucocorticoids secreted by the adrenal cortex serve a negative feedback function: they increase the activity of hippocampal neurons and thereby enhance hippocampal inhibition of HPA activity 15–7. However, sustained elevation of glucocorticoids, which occurs in response to prolonged and severe stress and characterizes a subset of depressed patients, induces atrophy of hippocampal neurons 15–8, thus reducing inhibitory control that the hippocampus exerts on the HPA axis, further increasing the levels of circulating glucocorticoids and resulting in additional damage to the hippocampus.
Model of the neurotrophic hypothesis of antidepressant treatments and stress-related disorders. The major cell types in the hippocampus and the effects of stress and antidepressant treatments on CA3 pyramidal cells are shown. The three major subfields of the hippocampus—CA3 and CA1 pyramidal cells and dentate gyrus granule cells—are connected by the mossy fiber (mf) and Schaffer collateral (SC) pathways. Chronic stress decreases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which in turn may contribute to the atrophy of CA3 neurons and their increased vulnerability to a variety of neuronal insults. Chronic elevation of glucocorticoid levels is also known to decrease the survival of these neurons. In contrast, antidepressant treatments increase the expression of BDNF, as well as that of the BDNF receptor, TrkB, and prevent the downregulation of BDNF elicited by stress. Such activity may increase the dendritic arborizations and survival of the neurons, or help repair or protect the neurons from further damage.
The growth factor, brain-derived neurotrophic factor (BDNF; Chapter 8), has also been implicated in mediating the effects of stress on the brain. Exposure to acute or repeated stress decreases expression of BDNF in pyramidal and dentate gyrus neurons of hippocampus as well as in pyramidal neurons of prefrontal cortex. In contrast, long-term administration of most antidepressants increases BDNF expression in these brain regions, and prevents the downregulation of BDNF that occurs in response to stress. Such bidirectional regulation of BDNF has been validated in human hippocampus and prefrontal cortex examined postmortem, with decreased BDNF observed in depressed patients and elevated BDNF observed in patients successfully treated with antidepressants. As well, forebrain knockout of BDNF blocks antidepressant-like behavioral responses in animal models and in rarer cases has been shown to increase the susceptibility of rodents to some forms of chronic stress. These findings support the hypothesis that antidepressants work in part by upregulating BDNF in hippocampus and prefrontal cortex and by thereby repairing stress-induced damage to these regions and protecting vulnerable neurons from further damage (see 15–8).
Likewise, a host of other growth factors and cytokines have been related to alterations in hippocampal neuron morphology in response to stress and antidepressant treatment and to the behavioral actions of antidepressants in animal models. Examples include vascular endothelial growth factor (VEGF), nonacronymic VGF, and interleukin-1 (IL-1), among others (Chapter 8).
An extension of the neurotrophic hypothesis of depression is the proposal that hippocampal neurogenesis is the required “slow step” in the action of antidepressants. In adult mammals, new neurons are born, albeit at low levels, and incorporated into working neural circuits in two discrete brain areas, the subventricular zone in close proximity to the striatum and the subgranular zone of the hippocampal dentate gyrus. In adult rodents, primates, and perhaps humans, neurons arise from progenitor cells in the subgranular zone and migrate into the granule cell layer of the dentate gyrus. The function of these new hippocampal neurons is unclear, but they have been implicated in the ability of the hippocampus to establish new memories, particularly related to timing. Stress, in part through increased circulating levels of glucocorticoids and decreased local expression of BDNF and other growth factors, decreases hippocampal neurogenesis, while some—but not all—antidepressant medications increase hippocampal neurogenesis. There is also evidence in rodents that inhibition of hippocampal neurogenesis impedes the action of certain antidepressant treatments. However, the role played by neurogenesis in the adult hippocampus—both in controlling normal hippocampus function and in contributing to antidepressant action—remains unproven.
Neurotrophic hypotheses of depression have not yet led to new treatments for the disorder. This is partly due to the considerable challenges in generating agonists of BDNF or another growth factor (Chapter 8). It is also likely due to the knowledge that such growth factors exhibit dramatic regional differences in their regulation and, in turn, their control of stress responses. As just one example, increased, not decreased, levels of BDNF occur in nucleus accumbens of rodents in response to chronic stress and of depressed humans at autopsy. Moreover, increased levels of BDNF in nucleus accumbens promote depression-like behavioral abnormalities, while knockout of BDNF from this brain region produces antidepressant-like effects, in animal models. These findings are directly opposite to those obtained in equivalent studies of hippocampus. Such regional differences in BDNF regulation and action greatly complicate efforts to develop a depression therapy focused on this growth factor.
Abnormalities in brain reward mechanisms
Based on the observation that anhedonia is one of the most common symptoms of depression, increasing attention has been given to derangements in the brain’s reward circuits as the basis of such impaired reward and its reversal by antidepressant treatment. Indeed, increasing evidence from human brain imaging studies, analysis of postmortem human brain tissue, and investigations in animal models support the robust contribution of dopamine neurons in the VTA and their major targets in the nucleus accumbens to stress and antidepressant responses. The role of BDNF, noted above, acting in this neural circuit in mediating depression- and antidepressant-like behavioral responses is one clear demonstration of the importance of brain reward mechanisms in depression. A major current effort in the field is to identify additional stress-regulated neurotransmitter systems, growth factors, and other signaling mechanisms in reward circuits that can be harnessed in antidepressant drug discovery. One example is the development of κ opioid receptor antagonists as novel antidepressants. Such antagonists exert antidepressant-like effects in animal models by blocking the actions of dynorphin, which is induced in nucleus accumbens by stress and acts through κ opioid receptors on VTA dopamine neurons to suppress dopamine neurotransmission.
One interesting finding to date is that many stress-induced adaptations in the VTA and nucleus accumbens differentiate those rodents that are susceptible to the deleterious effects of chronic stress and those that are resistant (ie, resilient). These findings raise the possibility that one might develop better antidepressant drugs not only by finding new ways to reverse the harmful effects of stress but also by replicating ways in which inherently more robust individuals avoid these harmful outcomes.
The past decade has revealed the potent influence on the VTA–nucleus accumbens reward circuit of several peptides that are known for their role in controlling food intake and peripheral metabolism and that are produced in the periphery or in the hypothalamus (Chapter 10). This is not surprising, because these factors, which presumably reflect physiologic measures of hunger or satiety, interface with brain systems that control motivational drive and reward. Thus, hypothalamic neurons expressing peptides such as melanocortin, melanin-concentrating hormone, or orexin (hypocretin) send dense projections to the VTA and nucleus accumbens. Likewise, peripheral peptides, such as leptin (derived from fat) or ghrelin (from stomach epithelium), control the activity of this reward circuit, largely indirectly via their effects in hypothalamus. Each of these feeding peptides has been shown to regulate depression-like behavior in animal models by influencing the VTA–nucleus accumbens circuit, raising the possibility that drugs targeting these peptide systems might serve as novel antidepressants. High levels of comorbidity between depression and obesity further support an interplay between feeding systems and the brain’s reward circuitry. Of particular interest is the speculation that perturbation of feeding mechanisms might produce very different effects in different subtypes of depression. It is conceivable that individuals in whom depression is characterized by reduced activity and weight gain respond differently to such perturbations than individuals who exhibit increased activity, anxiety, and weight loss.
Clinical data have long suggested a relationship between inflammatory responses and depression. Patients with autoimmune disorders are at increased risk for depression, and elevated levels of several cytokines (Chapter 8), including several interleukins (eg, IL-1 and IL-6) and tumor necrosis factor-α (TNF-α), have been reported in the peripheral blood of a subset of depressed patients. There is also now evolving evidence from animal studies that increased levels of peripheral cytokines induce depression-like behavioral abnormalities and that correction of elevated cytokine levels exerts antidepressant-like effects. These findings have immediate therapeutic implications, since antibodies that neutralize these cytokines are in clinical use for a range of autoimmune illnesses. Whether measures of peripheral inflammatory markers will prove to be a valid biomarker of a subtype of depression, and predict possible antidepressant responses to anticytokine antibodies or related approaches, remains to be seen. Meanwhile, this work has stimulated research into the mechanisms by which peripheral cytokines control mood-related behavior. One possibility, established for the pro-fever actions of peripheral cytokines, for instance, is that a cytokine in the general circulation controls neurons in periventricular regions of the brain (eg, in hypothalamus) where the blood–brain barrier is less developed (Chapter 10). Those neurons would then influence forebrain regions involved in mood regulation.
Intracellular signaling targets
A vast amount of research is focusing on intracellular signaling pathways and regulation of gene transcription in mediating depression pathology and antidepressant responses. This work derives from two rationales. First, it reflects efforts to understand how glucocorticoids, BDNF, cytokines, and many other neurotransmitters, neurotrophic factors, and hormones control depression-related symptoms. Second, it reflects open-ended discovery science to identify the range of proteins and biochemical pathways involved in depression and antidepressant responses. The goal in both cases is to identify protein targets for novel antidepressants. The considerable challenges in developing medications aimed at intracellular targets are discussed in Chapter 4; nevertheless, several findings deserve mention here.
One way to control BDNF activity is to target the molecular pathways through which stress and antidepressants control BDNF expression in brain. According to one scheme proposed for hippocampus, the cAMP intracellular signaling pathway and the transcription factor, cAMP response element binding protein (CREB) (Chapter 4), which activates BDNF gene expression, play a major role 15–9. This has stimulated interest in phosphodiesterase (PDE) inhibitors, which by blocking the breakdown of cAMP would promote activity of the cAMP–CREB pathway, as novel antidepressant agents. There is early clinical evidence for the efficacy of rolipram, an inhibitor of many PDE4 isoforms, in treating depression; however, its use was associated with unacceptable side effects (eg, nausea and vomiting). Whether it will be possible to develop more selective PDE inhibitors that are more effective and also better tolerated remains to be seen. A caveat of this work is that while the cAMP–CREB pathway would exert antidepressant effects by inducing BDNF in hippocampus, it might worsen depression by inducing BDNF in nucleus accumbens.
Long-term adaptations to antidepressant treatment in hippocampus. Antidepressants acutely increase levels of serotonin (5HT) and norepinephrine (NE) by inhibiting the reuptake or breakdown of these monoamines. Such increases activate several 5HT and NE receptors, including those coupled to cAMP and Ca2+ pathways. (Gx refers to a variety of G proteins that can influence Ca2+ pathways.) Long-term antidepressant administration decreases the function and expression of certain 5HT and NE receptors, such as β-AR and 5HT2. In contrast, the cAMP pathway is upregulated in the hippocampus and frontal cortex by long-term treatment, resulting in increased levels of adenylyl cyclase and cAMP-dependent protein kinase A (PKA), as well as increased expression and function of the transcription factor CREB. The observation that the cAMP cascade is enhanced after long-term antidepressant treatment indicates that the functional output of 5HT and NE may be upregulated, even though levels of certain 5HT and NE receptors are downregulated. Brain-derived neurotrophic factor (BDNF) and TrkB represent two of many potential targets of CREB. Antidepressant-induced upregulation of BDNF and TrkB may influence the function and survival of vulnerable hippocampal and cortical neurons (see 15–8).
Several other transcription factors, acting in any of several brain regions, have been shown to mediate susceptible versus resilient responses to chronic stress and to be required for antidepressant responses in susceptible animals. Prominent examples include ΔFosB, NF-κB, and β-catenin (Chapter 4). While these factors, like CREB, play region-specific roles that would make them difficult to target per se, genome-wide mapping of their target genes in depression models or human brain tissue could reveal novel druggable targets. There is also interest in harnessing epigenetic mechanisms in antidepressant drug discovery efforts. As discussed in Chapter 4, transcription factors work in concert with complex mechanisms that control chromatin structure to determine the transcriptional activity of individual genes. Work in animal models has demonstrated robust antidepressant-like actions of drugs that inhibit histone deacetylases (HDACs) or DNA methyltransferases (DNMTs), as just two examples. Given the ubiquity of these enzymes, it is unlikely that HDAC inhibitors or DNMT inhibitors will be safe enough to treat depression; nevertheless, this research has opened up new avenues of investigation that continue to generate considerable interest.
Glutamatergic neurotransmission and synaptic plasticity
Recent clinical findings have sparked interest in neurobiologic systems that were previously unexplored in relation to depression. A dramatic example is the observation that subanesthetic, subpsychotomimetic doses of intravenously infused ketamine (a noncompetitive NMDA receptor antagonist whose actions are similar to those of phencyclidine; Chapter 5) produce a rapid but transient antidepressant effect in treatment-resistant depression. These striking effects suggest that depressive symptoms can be improved rapidly by altering glutamate signaling. Ketamine’s antidepressant properties have been recapitulated in animal tests of antidepressant action such as the forced swim test, where the ability of ketamine to reduce immobility requires intact AMPA glutamate receptor signaling in forebrain regions and is associated with increased levels of BDNF expression and increased dendritic growth. The mTOR signaling pathway has been implicated in mediating these actions 15–10. However, it remains unproven whether these various effects of ketamine in animal models are responsible for the drug’s impressive clinical efficacy.
Hypothetical mechanism of ketamine’s antidepressant effects. It is speculated that ketamine increases extracellular glutamate levels in prefrontal cortex, possibly via antagonism of NMDA receptors on GABAergic interneurons resulting in disinhibition of glutamaterigc transmission. This leads to activity-dependent release of BDNF and stimulation of TrkB signaling cascades, including AKT, that activate the mTOR translational system in dendrites of neurons. Induction of translation would then increase levels of the AMPA receptor subunit GluA1 and other synaptic proteins, providing the machinery required for increased synaptogenesis and spine formation. (Reproduced with permission from Duman RS, Li N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci. 2012;367(1601):2475–2484.)
These clinical and preclinical findings have prompted several lines of investigation. Efforts are under way to deliver ketamine repeatedly, intravenously or perhaps intranasally, in order to maintain an antidepressant response. Efforts are also under way to develop other drugs that might mimic ketamine’s actions but would be more amenable to traditional oral formulations. There is interest in so-called AMPAkines, positive allosteric modulators of AMPA glutamate receptors, or antagonists of specific NMDA glutamate receptor subtypes (eg, NR2B antagonists). mTOR itself would not be a viable path forward, since mTOR agonists would have significant cancer risks, but perhaps proteins downstream of mTOR and enriched in brain might be feasible targets.
The discovery that ketamine exerts rapid antidepressant effects, and clearly does not act via initial effects on the brain’s monoamine systems, coupled with the demonstrated efficacy of DBS in treatment-resistant depression, has stimulated a new generation of research into the biology of depression and the search for antidepressant therapies with novel mechanisms of action. Interestingly, there are early reports of other rapidly acting, non-monoamine–based antidepressant effects in humans, including muscarinic cholinergic antagonists such as scopolamine and GABA-acting general anesthetic agents, which are also the subject of current investigation.