CHAPTER 15: Mood and Emotion

• Emotions activate physiologic, cognitive, and behavioral outputs that facilitate adaptive responses to salient external and internal stimuli.

• A crucial emotion, important in several mental disorders, is fear. The neural circuitry of fear is well understood because fear can be reliably elicited in animal models, and because its effects can readily be measured.

• Information about threatening stimuli is transmitted from the thalamus and cerebral cortex to the amygdala where it is processed; neurons carrying fear-related information then project to diverse downstream sites in the brain responsible for adaptive responses.

• Anxiety, a state characterized by arousal, vigilance, physiologic preparedness, and, in humans, negative subjective states, may share some critical circuits with fear.

• Because of the evolutionary conservation of key neural circuits, animal research on fear has relevance to humans. Several anxiety disorders may involve abnormal regulation of amygdala-based fear circuitry.

• Mood disorders are divided into unipolar disorders, which are characterized by depression only, and bipolar disorder, which is diagnosed if the person has ever had an episode of mania.

• Mood disorders are influenced by both genes and environment, with genes playing a greater role in bipolar than in unipolar disorders.

• Animal models to study mood regulation and mood disorders are far from perfect. However, in concert with human experiments involving functional neuroimaging, studies of postmortem brain tissue, and clinical trials of deep brain stimulation, a picture of mood-regulating circuits is emerging.

• A subset of individuals with major depression exhibit excessive activation of the hypothalamic–pituitary–adrenal axis; thus, certain cases of depression share some physiologic mechanisms with chronic stress.

• Most of the effective pharmacologic treatments for depression act on protein targets within monoamine synapses, generally enhancing neurotransmission by norepinephrine, serotonin, or both. A similar role for dopamine is postulated but unproven.

• Although the initial molecular targets of antidepressants are well characterized, the actual mechanism of action is not understood. The several-week latency of onset of therapeutic effects suggests that slowly developing adaptive responses to initial enhancement of monoamine neurotransmission are required for efficacy.

• Current research aimed at developing more effective antidepressants with novel mechanisms of action is focused on several forebrain regions and the actions of numerous neurotransmitter systems, neurotrophic factors, cytokines, intracellular signaling pathways, and transcriptional regulatory mechanisms.

• The discovery of ketamine, an NMDA glutamate receptor antagonist, as a rapidly acting antidepressant has opened up new avenues in depression and antidepressant research.

Emotions are critical to survival and represent transient physiologic, cognitive, and behavioral outputs that constitute adaptive responses to survival-relevant or otherwise salient stimuli. Mood is a term used to characterize the predominant emotional state over time. Moods (eg, happy, sad, irritable) interact bidirectionally with emotional responses to particular stimuli.

Although there are many subtle forms of emotion, they may be divided into two broad categories by their valence. Negative emotions, such as fear, are elicited under normal circumstances by stimuli that connote danger, pain, or other noxious conditions and generally lead to avoidance, escape, or protective responses. Positive emotions are elicited by stimuli that connote food, safety, comfort, or reproductive opportunities and lead to approach behaviors.

Many common human diseases produce pathologic emotional states that may be transient or enduring. Although most individuals with these disorders can be treated, at least in part, with available pharmacologic agents, their mechanisms of action are generally not deeply understood. For example, the initial molecular targets of anxiolytic (antianxiety) and antidepressant drugs have been determined, but the mechanisms by which these drugs ultimately produce their therapeutic effects have yet to be adequately characterized.

Emotion processing circuits in the brain appraise the valence and potency of stimuli and activate appropriate responses. The neural substrates of emotion involve, in part, evolutionarily old brain regions lying deep to the neocortex 15–1, including the amygdala, hippocampus, parahippocampal gyrus, and cingulate gyrus. These structures have strong interconnections with the hypothalamus, ventral striatum (nucleus accumbens), and the orbital and medial prefrontal cortex. Although the older term “limbic system” (comprising an inexact collection of forebrain structures) is still in use, suggesting some central processor for emotion, it is clear based on lesion studies in animals, strokes, and other brain injuries in humans, and functional neuroimaging that different emotions (eg, fear, disgust, trust) utilize distinct circuits involving limbic structures, frontal regions of cortex, and the hypothalamus.

Appraisal of a stimulus (eg, as dangerous, novel, or desirable) requires that highly processed sensory and cognitive information from the association cortex gain access to emotion processing circuits, which then activate adaptive responses. These downstream responses include stimulation of arousal and attention, mediated via activation of monoamine, cholinergic, and other widely distributed neurotransmitter systems in the brain (Chapter 6) as well as by activation of the autonomic nervous system (Chapter 9) and certain neuroendocrine systems (Chapter 10). Strong emotion suppresses ongoing behaviors in favor of automatic defensive or approach behaviors. Experiences encoded under the influence of strong emotion also lead to the enhancement of diverse types of memory processes to make subsequent responses to similar stimuli maximally efficient (Chapter 14). Whether in avoidance of a predator or in hunting food, a few hundred milliseconds can have enormous implications for success and even survival.

Fear

Research on fear in animal models has relevance to humans in both health and disease because of the evolutionary conservation of significant aspects of fear circuitry across mammalian species. Fear can be roughly divided into innate fear and learned (or conditioned) fear. Innate fear is exemplified by the inborn avoidance of brightly lit, open spaces by rodents. Conditioned fear results when an animal learns to associate predictive stimuli with danger, harm, or pain. Fear conditioning has been exploited in the laboratory to delineate fear circuitry in the brain 15–1.

Experiments in rat and mouse models have indicated that information about threatening stimuli is transmitted from the sensory thalamus and sensory and association areas of the cerebral cortex to the lateral nuclear complex of the amygdala (there are some species-specific differences in the organization of the amygdala), the amygdala’s major input nuclei. Information is processed and sent by both direct and indirect routes to the central nucleus, the major output nucleus of the amygdala, although important information bypasses the central nucleus and is transmitted directly to effector sites of the fear response. Efferent projections from the lateral and central amygdala activate numerous effector sites for cognitive, physiologic, and behavioral aspects of the fear response 15–2.

Projections to the lateral hypothalamus mediate activation of the sympathetic nervous system, and projections to the paraventricular nucleus (PVN) of the hypothalamus induce the synthesis and release of corticotropin-releasing factor (CRF) (Chapters 7 and 10). The release of CRF activates a cascade that ultimately leads to the release of glucocorticoids from the adrenal cortex. Glucocorticoids cause the body to enter a catabolic state; they suppress inflammatory responses and heighten arousal. The hypothalamic–pituitary–adrenal (HPA) axis often becomes chronically hyperactive in individuals with depression, as discussed in subsequent sections of this chapter. Because CRF also serves as a neurotransmitter for neurons in the central nucleus of the amygdala, through which it may contribute to fear and anxiety, CRF antagonists were considered as potential antidepressants and anxiolytics, although clinical trials have been disappointing.

Projections from the amygdala to the periaqueductal gray matter (PAG) in the core of the brainstem activate descending analgesic responses that involve endogenous opioid peptides, which can suppress pain in response to intense fear and stress (Chapter 11). Projections to a different region of the PAG activate species-specific defensive responses, such as behavioral freezing in rats and mice. Projections to the noradrenergic locus ceruleus, the serotonergic raphe nuclei, and the dopaminergic ventral tegmental area (VTA) increase arousal and vigilance and enhance the formation of explicit and implicit memories of circumstances under which danger has occurred (Chapter 6).

Under normal circumstances, fear responses enhance survival. It has been hypothesized, however, that abnormal fear processing gives rise to disabling anxiety disorders.

Anxiety

Anxiety is a state of preparation for danger, which is characterized by arousal, vigilance, physiologic preparedness, and, in humans, negative subjective states that are qualitatively similar to those associated with fear. Yet anxiety differs from fear in that it is triggered in the absence of an immediately threatening stimulus. Anxiety can be elicited by diverse cues ranging from the specific to the general. Moreover, in circumstances in which there are no “safety” signals, the state of anxiety may be prolonged.

The circuitry underlying anxiety may differ from that of fear responses in that the bed nucleus of the stria terminalis (BNST) may partly take the place of the central nucleus of the amygdala in giving rise to projections involved in physiologic and behavioral expressions of anxiety. The BNST is considered an extended region of the amygdala, and indeed resembles the central nucleus of the amygdala with regard to its cellular organization; yet it is hypothesized that this area may respond to less specific stimuli than the central nucleus and thus may mediate the more generalized symptoms of anxiety. CRF may act in this region to induce anxiety-like behaviors. Examples of animal tests of anxiety-like behavior are shown in 15–2.

Anxiety and Emotional Memory

The memories produced by fearful situations have both a cognitive and an emotional component. The cognitive component, which depends at least in part on the hippocampus, records the precise setting in which danger was experienced and details of the experience. The emotional component of fear-related memories, which depends in part on the lateral nuclear complex of the amygdala, activates physiologic and behavioral responses to danger when learned predictors of danger are encountered. Normally, we experience the cognitive and emotional components of fear-related memories as completely intertwined, but their dependence on different circuits can be revealed by lesions. Patients who have had lesions of the amygdala from stroke, viral infections, or head injury lack autonomic and other conditioned responses to previously learned fearful stimuli, even though their declarative memory (their ability to consciously recall a specific stimulus) is intact. Conversely, patients with hippocampal lesions may not consciously recall exposure to fear-associated stimuli, but retain their autonomic responses.

The cognitive component of memories encoded under strong emotion is markedly enhanced compared with ordinary memories. Contrast, for example, the memories of Americans for the details of where they were on the morning of September 11, 2001 versus September 10, 2001. Based on pharmacologic experiments in human subjects and invasive experiments in rodents, this enhancement has been shown to depend on the brain’s monoamine systems. For example, this enhancement can be blocked by β- or α₁-adrenergic receptor antagonists such as propranolol and prazosin, respectively, administered systemically or directly into the amygdala prior to certain stages of memory consolidation. Evidence is suggestive that such adrenergic antagonists might be efficacious under realistic circumstances in humans, although the results are not yet conclusive. It is important that these drugs do not cause amnesia; the hoped-for goal is to cause traumatic memories to recede to the level of ordinary memories, perhaps decreasing the risk and severity of posttraumatic stress disorder (PTSD; 15–3).

Positive emotional experiences also promote memory. Under normal circumstances these memories produce reinforcement in response to natural rewards such as food, safety, and mating opportunities. Just as abnormal function of fear circuitry can produce disabling symptoms, abnormal stimulation of reward circuitry by certain drugs may be a central cause of addiction. Interestingly, the amygdala, acting in concert with the brain’s reward circuitry, has been implicated in mediating such reward-enhanced memory formation (Chapter 16).

Mood Regulation

Compared with the neural mechanisms that underlie fear, those that underlie mood are less well understood, in large part due to the greater difficulty in modeling mood in animals. Experimental models of fear and anxiety in animals do not have obvious counterparts that might facilitate the investigation of moods such as sadness or happiness. Yet considerable overlap or interaction likely exists among the neural systems that regulate emotions such as fear and anxiety, and moods such as sadness. Not only do moods and emotions influence each other, but anxiety and mood disorders also often co-occur in the same individuals and appear to have shared genetic risk factors. Because of the lack of fully convincing animal models of mood, much of the investigation of mood regulation has required the use of noninvasive neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in studies of human subjects. Accumulated data suggest that circuits involved in mood regulation and mood disorders include the orbital and medial prefrontal cortex, the cingulate gyrus, amygdala, ventral striatum, hippocampus, and hypothalamus.

PET studies focused attention on the region of the anterior cingulate gyrus that bends under the genu of the corpus callosum (subgenual cingulate cortex), also known as Brodmann area 25 based on traditional mapping of the cerebral cortex 15–1 and 15–3. One subregion of the anterior cingulate gyrus is activated by pain. Others are activated when task performance deviates from successful attainment of goals. Thus, the anterior cingulate cortex may monitor performance for signs of failure, just as the amygdala monitors sensory inputs for signs of threat. This cortical region exhibits, on average, increased levels of metabolic activity in major depression, which return to normal with successful pharmacologic treatment. It is also activated in normal subjects in response to scripts that induce sadness 15–3. Based on these findings, patients with unremitting major depression, who have not achieved relief from multiple drugs, psychotherapy, or electroconvulsive therapy (ECT), have been treated by deep brain stimulation (DBS) with placement of the stimulating electrode within the subgenual cingulate cortex 15–4. Such DBS might work by quieting an overactive region. These trials of DBS corroborate imaging findings in suggesting that the subgenual cingulate cortex is a critical node in mood-regulating circuits in the brain. Related studies have suggested that DBS of another site in brain—the anterior limb of the internal capsule, which includes the nucleus accumbens, a major brain reward region—may also have mood-elevating effects. These studies have prompted investigation of still additional regions of the brain that might be targeted for DBS treatment of depression. One possibility, now under investigation, is the lateral habenula. This region, which sits near the dorsal thalamus, is believed to induce aversive emotional responses via glutamatergic innervation of GABAergic neurons in the VTA, which then suppress VTA dopamine neurons.

Anxiety disorders refer to a heterogeneous group of conditions, each of which features some type of anxiety as a prominent symptom 15–1. The current categorization of these disorders is based exclusively on syndromal groupings of subjective and behavioral symptoms and may not reflect underlying genetic and neurobiologic features. Thus, the classification should be considered provisional and should not guide all scientific investigation. Family and twin studies suggest a genetic component of risk for these disorders. Nonetheless, the lack of objective markers for phenotyping and the likely genetic complexity of all common behavioral disorders (involvement of numerous genetic and nongenetic factors of small effect) have, to date, impeded the discovery of bona fide risk genes of strong effect. Neuroimaging studies using PET or fMRI have demonstrated hyperactive responses of the amygdala in humans with PTSD, both in response to scripts recalling their trauma and in response to more generalized stimuli such as fearful faces. Overall it appears that patients with certain anxiety disorders exhibit hyperresponsiveness of amygdala-based fear circuitry and decreased activity of medial and orbital prefrontal cortical regions that normally serve to suppress fear and anxiety. However, greater specificity is needed in delineating the neural circuits underlying the range of anxiety symptoms and disorders. Several neurotransmitter systems have been implicated in these abnormal amygdala responses, in both humans and animal models, although more research is needed to establish the cellular and molecular pathophysiology of anxiety disorders.

Despite gaps in our understanding of the genetics and pathophysiology of anxiety disorders, several highly effective treatments are available. Acute anxiety, for example, is successfully treated with benzodiazepines, generalized anxiety disorder (GAD) with antidepressant drugs or benzodiazepines, panic disorder with long-term administration of antidepressants or with high-potency benzodiazepines (often in combination with cognitive–behavioral therapies), and obsessive–compulsive disorder (OCD) with long-term administration of selective serotonin reuptake inhibitor (SSRI) antidepressants or the serotonin reuptake inhibitor tricyclic antidepressant clomipramine together with behavioral therapies. Treatment of PTSD remains challenging, although SSRIs and perhaps other antidepressants provide modest relief. For some patients, cognitive–behavioral therapies are highly effective adjuncts or alternatives to medication therapy; the efficacy of these therapies emphasizes the importance of learning and memory in the pathogenesis of many anxiety disorders. Although neurobiologic causes of anxiety are not well understood, much is known about the mechanisms by which pharmacologic agents act to reduce anxiety. Therefore, the discussion that follows approaches the topic of anxiety disorders from a treatment perspective.

Molecular Pharmacology of the GABA_A Receptor

As discussed in Chapter 5, the GABA_A receptor, like many other ligand-gated channels, is a heteropentamer with its subunits arranged like staves around a barrel. Four major types of GABA_A receptor subunits—α, β, γ, and ρ—are known, and multiple subtypes have been identified. GABA_A receptors containing ρ subunits are expressed in the retina and sometimes referred to as GABA_C receptors. They play no role in neuropsychopharmacology and will not be discussed further. Significant binding sites on the GABA_A receptor complex are summarized in 15–2. Benzodiazepines bind to a site on the α subunit of the GABA_A receptor complex and thereby increase the affinity of the β subunit for GABA; a γ subunit must be present in the heteropentamer for benzodiazepine binding and must therefore allosterically regulate the binding site on the α subunit. Benzodiazepines facilitate the ability of GABA to activate the GABA_A receptor’s intrinsic Cl⁻ channel and in turn facilitate inhibitory neurotransmission. In the absence of GABA, benzodiazepines exert little effect on GABA_A receptors.

Competitive antagonists of anxiolytic benzodiazepines have been discovered and include agents such as flumazenil. These antagonists do not exert independent effects on GABA_A receptor function, but competitively block effects on the receptor produced by benzodiazepine agonists such as diazepam. Clinically, flumazenil is useful in the treatment of benzodiazepine overdoses; however, this drug can precipitate withdrawal in benzodiazepine-dependent patients in much the same way that opiate antagonists such as naloxone produce withdrawal symptoms in opiate-dependent patients (Chapter 16).

Inverse agonists, which decrease GABA-activated Cl⁻ conductance, bind at or near the benzodiazepine binding site on the GABA_A receptor α subunit but exert opposite effects on receptor function compared with those produced by benzodiazepines (see 15–2). The prototypical inverse agonist is β-carboline-3-carboxylic acid ethyl ester (β-CCE or β-carboline). β-CCE is proconvulsant. It is also proconflict when administered to animals undergoing the conflict test. During this test, which is used to screen for benzodiazepine effects in animals, a rat presses a lever for food or water and simultaneously receives a shock, which tends to inhibit further pressing of the lever. The pairing of these events is believed to create a state of conflict in the animal, which is faced with both the desire for food and the expectation of punishment. Benzodiazepines are anticonflict: they release behaviors inhibited by conflict. Thus, under the influence of a benzodiazepine, the rat continues to eat or drink despite the threat of punishment. β-CCE exerts the opposite effect in this assay. In nonhuman primates, β-CCE produces dose-related behavioral agitation and increases plasma cortisol, blood pressure, and heart rate. In human volunteers, inverse agonists produce sympathetic arousal and intense feelings of inner tension and impending doom.

Effects of GABAergic Drugs on Anxiety

Benzodiazepines

Benzodiazepines are a class of drugs with anxiolytic, sedative, muscle relaxant, and anticonvulsant properties 15–3. Benzodiazepines also produce anterograde amnesia, a property that is exploited when high-potency, short-acting benzodiazepines are used as preoperative anxiolytics, but that otherwise represents an unwanted side effect. All benzodiazepines exert their pharmacologic effects by facilitating GABA_A receptor function, as previously mentioned. A series of chemically distinct (nonbenzodiazepine) compounds, such as zolpidem, eszopiclone, or zaleplon, bind to the same site on the GABA_A receptor and exert similar pharmacologic effects. Many benzodiazepines and other drugs that bind to the benzodiazepine site are available for clinical use; the major distinguishing features of these agents are their pharmacokinetic properties. Some of these drugs exhibit particularly short half-lives, and thus are desirable for use as hypnotics or sleeping pills; examples include zolpidem, eszopiclone, and the benzodiazepine lorazepam. Drugs with longer half-lives are preferable for generalized anxiety; examples include diazepam and chlordiazepoxide. Alprazolam and clonazepam are widely prescribed for the treatment of panic disorder because of their high potency. Benzodiazepines also differ based on their affinity for different GABA_A α subunits, as will be discussed below. The chemical structures of representative benzodiazepines used in the treatment of anxiety disorders appear in 15–5; the structures of related agents that are more commonly used to treat insomnia are provided in Chapter 13.

The diverse clinical effects of benzodiazepines and chemically unrelated drugs that bind the benzodiazepine site are mediated by GABA_A receptors of different subunit composition expressed in partly different regions of the brain. Anxiolytic properties of benzodiazepines at least in part reflect actions in the amygdala. GABAergic inhibition of serotonergic, noradrenergic, and many other types of neurons that project to brain structures involved in emotional processing also may contribute to anxiolysis. Sedative and amnestic actions are exerted in more widespread locations, including the cerebral cortex. Anticonvulsant actions of benzodiazepines are believed to occur in the cerebral cortex, hippocampus, or amygdala.

The binding site for benzodiazepines was first identified by means of radioreceptor binding assays. It is best conceptualized as an allosteric regulatory binding site on the GABA_A receptor. Evidence that this site is related to the clinical efficacy of benzodiazepines was drawn from classic pharmacologic investigations that demonstrated that the affinities of various benzodiazepine drugs for this site neatly corresponded to their clinical potencies (eg, clonazepam > lorazepam > diazepam > oxazepam). However, these early studies were carried out before the molecular cloning of multiple subtypes of benzodiazepine binding sites (ie, multiple α subunits of the GABA_A receptor). Based on in vitro binding studies and in vivo observations performed on mice with a gene knockout (α₁, α₅, α₆ subunits), or with knockin (α₁, α₂ α₃, α₅ subunits) mutations that destroy benzodiazepine binding sites with point mutations, it has been possible to investigate the pharmacology of benzodiazepines and related drugs and to link specific α subunits with certain clinical effects. Diazepam and other benzodiazepines in current use have high affinity for GABA_A receptors containing α₁, α₂, α₃, or α₅ subunits. Zolpidem and eszopiclone, widely used hypnotics, have higher affinity for GABA_A receptors containing an α₁ subunit. One goal of current research is to design drugs selective for particular α subunits, thus limiting side effects. The α₁ subunit has been associated with hypnotic effects, the α₅ subunit with some of the cognitive effects, and the α₂ and α₃ subunits with anxiolysis. A drug selective for α₂ subunit containing GABA_A receptors might produce anxiolysis without sedation and anterograde amnesia. Indeed, alprazolam and clonazepam may exert greater anxiolysis versus sedation due to higher affinity for α₂-containing GABA_A receptors.

Barbiturates

Like benzodiazepines, barbiturates interact with the GABA_A receptor; however, they bind to a physically different site on the receptor, which is believed to be in close proximity to the Cl⁻ channel (see 15–2; also see Chapter 5). Whereas benzodiazepines increase the likelihood that Cl⁻ channels will open in a GABA-dependent manner, barbiturates increase not only the probability that they will open but also the duration of their opening. Moreover, at high doses barbiturates can act independently of GABA; consequently, they can lead to far greater inhibition of the nervous system than can benzodiazepines. Accordingly, a much greater risk of serious respiratory depression and death is associated with barbiturate overdose. Overdoses of benzodiazepines can result in coma but very rarely cause death unless combined with the use of a cross-reactive substance such as a barbiturate or alcohol. Many barbiturate-like drugs, including methaqualone (Quaalude), ethchlorvynol, meprobamate, and chloral hydrate, were introduced into clinical practice in the past with the hope that their use might result in fewer side effects and less abuse compared with barbiturates. None have stood the test of time; today barbiturates and related compounds are rarely used for sedation or anxiolysis. Short-acting barbiturates currently are used primarily for anesthesia. A prototypical agent used for this purpose is pentobarbital. A long-acting barbiturate, phenobarbital, is still used for certain seizure disorders (Chapter 19).

Neuroactive steroids represent yet another class of molecules that modulate the function of GABA_A receptors; however, their precise mechanisms of action remain unknown. These molecules are discussed in greater detail in Chapter 10.

Alcohol

Concentrations of ethanol produced in humans from the consumption of alcoholic beverages (millimolar range) facilitate the GABA-mediated opening of GABA_A receptor Cl⁻ channels. Thus, it should not be surprising that a reduction in anxiety is among the most prominent effects of ethanol, at least at low doses and while blood levels continue to rise. This characteristic helps to explain why ethanol is widely self-administered to enhance social interaction. When ethanol is taken with benzodiazepines or barbiturates, its effects are greatly intensified because each of these agents alters GABA_A receptor conformation to increase the efficacy of the others. Because of this cross-reactivity, which is synergistic, mixtures of these drugs can be lethal. Such cross-reactivity is exploited in ethanol detoxification regimens, which typically replace ethanol with a benzodiazepine that is then slowly tapered. Benzodiazepines, such as chlordiazepoxide, are used for detoxification because they have a longer half-life than ethanol; thus, they permit a smoother detoxification process (ie, less risk of withdrawal symptoms), cause fewer side effects, and may reduce the likelihood of relapse.

Tolerance and Dependence Associated With Benzodiazepines

Benzodiazepines, barbiturates and related compounds, and ethanol can produce tolerance to many of their behavioral effects, although tolerance does not seem to occur to the anxiolytic and amnestic effects of benzodiazepines. In addition, the drugs can cause physical dependence, which leads to potentially fatal withdrawal syndromes on cessation of their use. Barbiturates and ethanol, and rarely benzodiazepines, can also produce compulsive use, that is, addiction (Chapter 16).

The molecular mechanisms that underlie tolerance and dependence elicited by benzodiazepines are still not understood despite a great deal of research. Tolerance and dependence likely are not associated with changes in total levels of GABA_A receptors, but may involve altered phosphorylation of receptor subunits, altered subunit composition of the receptors, or adaptations in any of several other neurotransmitter systems.

Nonbenzodiazepine Anxiolytics

Considerable effort has been devoted to the development of anxiolytic agents with novel mechanisms of action. One popular mechanism was CRF₁ receptor antagonism, although clinical trials have been disappointing as noted earlier. Another mechanism in clinical use, albeit with only modest efficacy, is partial agonism at 5HT_1A serotonin receptors. This mechanism is exemplified by buspirone 15–5, an azaspirodecanedione marketed as an anxiolytic. 5HT_1A receptors serve as autoreceptors on serotonin neurons and also as postsynaptic receptors (Chapter 6). When administered to animals, buspirone has a taming effect on rhesus monkeys, inhibits conditioned avoidance responses in rats, and reduces shock-elicited fighting in mice. However, it is generally ineffective as an anticonflict agent in rats and monkeys. Buspirone is approved for use in the treatment of GAD, although it is less effective than benzodiazepines or SSRI antidepressants when used for this or related purposes. The major advantage of buspirone and SSRIs compared with benzodiazepines is that they are less likely to give rise to dependence, and they are virtually without abuse liability.

Another target under consideration for anxiolytic drugs is the adenosine A₁ receptor (Chapter 8). Adenosine is a purine neurotransmitter that inhibits the release of other neurotransmitters, including acetylcholine, norepinephrine, glutamate, dopamine, 5HT, and GABA, in specific regions of the brain through actions at its A₁ receptor. This action is mediated through the opening of K⁺ channels, the inhibition of Ca²⁺ channel opening, and the inhibition of adenylyl cyclase—all by means of the G_i/o family of G proteins. Adenosine is sedative, anticonvulsant, analgesic, and anxiolytic. Adenosine receptor antagonists, including methylxanthines such as caffeine and theophylline, produce stimulant effects. Large doses of caffeine are anxiogenic, and high doses administered into the brain may produce seizures. Although the role of adenosine in human anxiety is unclear, A₁ adenosine receptor agonists may prove to be useful in the treatment of various types of anxiety disorders.

Several other targets are being evaluated for treatment of anxiety. Agonists at opioid receptor like-1 (OPRL-1, also referred to as the nociceptin or orphanin FQ receptor) reduce fear memory consolidation in animals and may be useful in the treatment of PTSD. Drugs that mimic the actions of certain neurosteroids, with antianxiety-like actions in animals, are also in development.

Treatment of Anxiety Disorders

As previously suggested, both benzodiazepines and some antidepressants have efficacy in the treatment of anxiety (see 15–1). Although beyond the scope of this text, it is important to point out that cognitive and behavioral psychotherapies, focused on the management of symptoms, are very useful in the treatment of anxiety disorders and OCD. The preferred pharmacologic treatment for GAD, panic disorder, and PTSD is an antidepressant, generally an SSRI or newer serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine. Older antidepressants, such as tricyclics and monoamine oxidase inhibitors (MAOIs), are efficacious but have less tolerable side effects for many patients. The most common alternative for GAD is a low-potency benzodiazepine, such as diazepam; for panic disorder the most common alternatives are high-potency benzodiazepines such as alprazolam or clonazepam. The benzodiazepines have the advantage of rapid onset (hours vs weeks for antidepressants), but the disadvantages of sedation (at least initially, before tolerance occurs), cognitive impairment, and, especially for the high-potency drugs, dependence.

Social anxiety disorder is characterized by a persistent fear of experiencing humiliation in one or more social situations in which an individual may be exposed to scrutiny by others. It can be treated by cognitive–behavioral therapies, antidepressants, or benzodiazepines. One interesting exception is a form of social anxiety called performance anxiety, such as stage fright. This is generally associated with sympathetic arousal giving rise to a pounding heart, dry mouth, and tremor. Because benzodiazepines can adversely affect mental acuity, preferred pharmacologic treatment is with a β-adrenergic receptor antagonist such as propranolol taken immediately prior to the performance.

Obsessive–Compulsive Disorder

OCD is characterized by (1) recurrent intrusive thoughts that an individual recognizes as products of his or her own mind (obsessions); and (2) repetitive, seemingly purposeful behavior designed to prevent or neutralize a dreaded occurrence, often as a consequence of the obsession (compulsions). Although it traditionally has been classified as an anxiety disorder based on the anxiety that drives the compulsions, growing evidence suggests that OCD differs from other anxiety disorders with regard to its neurobiologic substrates. Current evidence, based largely on structural and functional imaging, and to a lesser degree on animal models, suggests that OCD results from abnormal functioning of striatal–thalamic–prefrontal cortical circuits (Chapter 14). Tourette syndrome, also believed to reflect abnormal striatal functioning, is characterized by multiple tics, but also may feature obsessive–compulsive symptoms. In contrast, the other anxiety disorders appear to represent abnormal function of amygdala-based fear circuitry, as discussed earlier.

OCD currently is treated with SSRIs at high doses, or with the tricyclic drug clomipramine, which also preferentially inhibits the 5HT transporter 15–4. Cognitive–behavioral therapy has proven to be useful in the treatment of some patients, especially with regard to reducing or eliminating compulsive rituals. Treatment of Tourette syndrome focuses on the use of various antipsychotic drugs as well as α₂-adrenergic agonists, such as clonidine or guanfacine (Chapter 14). How these various drugs alleviate the symptoms of OCD or Tourette syndrome remains unknown. DBS of the anterior limb of the internal capsule, effective for some patients with depression (see above), can also ease the symptoms of OCD and Tourette syndrome.

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.

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.

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.

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 5HT_2A 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.

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.

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.

Inflammatory mechanisms

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.

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.

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.