Recent developments in the psychobiology and ...

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Review

1. Introduction 2. Current pharmacotherapy 3. Current evidence-based strategies in the treatment of major depressive disorder

Recent developments in the psychobiology and pharmacotherapy of depression: optimising existing treatments and novel approaches for the future

4. Side effects and discontinuation

P Farvolden1,2†, SH Kennedy2,3 & RW Lam4

5. Monoamines and the

1†Centre for

neurobiology of major depressive disorder 6. Beyond monoamine hypotheses of the pathogenesis depression 7. Other neurotransmitters and neuromodulators implicated in major depressive disorder 8. Deconstructing depression 9. Promising new agents 10. Newer approaches 11. Expert opinion

Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada, M5T-1R8, of Psychiatry, University of Toronto, 3University Health Network & 4Department of Psychiatry, University of British Columbia, BC, Canada

2†Department

Effective antidepressants include monoamine oxidase inhibitors and tricyclic antidepressants, selective serotonin re-uptake inhibitors and novel agents, including serotonin and noradrenaline re-uptake inhibitors. Although effective, current treatments most often produce partial symptomatic improvement (response) rather than symptom resolution and optimal functioning (remission). While current pharmacotherapies target monoaminergic systems, different symptoms of major depressive disorder (MDD) may have distinct neurobiological underpinnings and other neurobiological systems are likely involved in the pathogenesis of MDD. In this article a review of current pharmacotherapeutic options for MDD, current understanding of the neurobiology and pathogenesis of MDD and a review of new and promising directions in pharmacological research will be provided. It is generally accepted that no single neurotransmitter or system is responsible for the dysregulation found in MDD. While agents that affect monoaminergic systems will likely continue to be first-line treatments for MDD for the foreseeable future, a number of new and novel agents, including corticotropin-releasing factor antagonists, substance P antagonists and antiglucocorticoids show considerable promise for refining treatment options. In order to better understand the neurobiology and treatment response of MDD, it is probable that more sophisticated theory-driven typologies of MDD will have to be developed. Keywords: affective disorders, agonists, antagonists, antiglucocorticoids, benzodiazepines, brainderived neurotrophic factor, corticotropin-releasing factor, dopamine, depression, GABA, glutamate, monoamine oxidase inhibitors, neuropeptides, nicotine, noradrenaline, psychopharmacology, serotonin blockers, serotonin re-uptake inhibitors, serotonin, substance P, treatment, tropic factors Expert Opin. Investig. Drugs (2002) 12(1): 1. Introduction

Ashley Publications www.ashley-pub.com

With a prevalence rate of ∼ 5% worldwide, major depressive disorder (MDD) is the most common mood disorder [1]. MDD and dysthymia are distinguished from bipolar disorders by the absence of manic, mixed or hypomanic episodes [2]. MDD occurs in women at approximately twice the rate as men [1]. The average age of onset of MDD is in the third and fourth decade and the average length of an untreated major depressive episode (MDE) is 6 – 24 months [1]. While the severity, quality and duration of depressed mood are prominent, other important features of MDD 2002 © Ashley Publications Ltd ISSN 1354-3784

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Recent developments in the psychobiology and pharmacotherapy of depression: existing treatments & novel approaches

include vegetative (e.g., sleep, appetite, weight, energy and sex drive), cognitive (e.g., attention span, frustration, tolerance, memory, negative distortions), impulsive (e.g., suicide, homicide), behavioural (e.g., motivation, pleasure, interests) and somatic symptoms (e.g., headaches, stomach aches and muscle tension) [4]. To date, somatic symptoms, including unexplained muscle pain, have been under-recognised in patients with MDD [5]. Recurrence of depressive episodes in people who recover from an index episode is the norm with recurrence rates of at least 50% in the long term [6]. Studies show that patients with MDD spend up to 59% of the time experiencing residual symptoms of depression. Thus, MDD is often a chronic illness that consists of several MDEs and profoundly affects quality of life [7]. Effective treatments for MDD include pharmacotherapy as well as psychotherapy, including cognitive-behavioural therapy (CBT) and interpersonal psychotherapy (IPT). Limited access to evidence-based psychotherapy, however, means that pharmacotherapy is often the most practical treatment option [9]. The ‘good news’ is that 2/3 of patients with depression will respond in the acute phase to most antidepressant therapies, as compared to a 1/3 response rate for placebo. Of those treated, ≥ 90% of patients may eventually respond to optimally managed antidepressant medications and antidepressant maintenance therapy significantly reduces relapse rates [10]. The ‘bad news’ is that up to 40% have not achieved remission, increasing risk for relapse: 20 – 30% of patients who initially respond to treatment fail to maintain a response for 18 months and 10 – 20% will continue to be non-responders with a very poor prognosis [10,11]. In addition, while current antidepressants are efficacious, they still have a lag time to onset of clinical response (2 – 4 weeks) and are associated with a number of side effects that reduce treatment adherence. In summary, significant challenges to the understanding and treatment of MDD remain. Although efficacious, current treatments often produce partial or limited symptomatic improvement (response), rather than remission. A better understanding of the pathophysiology of MDD should lead to more effective treatments. In this article, current pharmacotherapeutic options for MDD, the neurobiology and pathogenesis of MDD and new and promising directions in pharmacological research will be reviewed. 2. Current

Serotonergic agents

Primary receptors & mechanism

Drug name

SSRIs

5-HT re-uptake inhibitor

Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline

SNRIs

5-HT and to a lesser extent NA and DA re-uptake inhibitor

Venlafaxine XR

Roughly equivalent 5-HT and Duloxetine NA activity

Novel agents

NA and to a lesser extent 5-HT re-uptake inhibitor

Milnacipram

NA and DA re-uptake inhibitor Antagonist at inhibitory α2 receptors on both NA and 5-HT neurons, as well as 5-HT2A 2C antagonist 5-HT2 receptor antagonist, antagonist at inhibitory α2 receptors Selective NA re-uptake inhibitor (NRI)

Bupropion Bupropion SR Mirtazapine

Agents MAO inhibitor (MAOI) targeting MAO MAO-A inhibitor (RIMA)

Mianserin Reboxetine Phenelzine Tranylcypromine Moclobemide

Tricyclic Various combinations of antidepressants 5-HT, NA and DA re-uptake inhibitors

Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Maprotiline Nortriptyline Protriptyline Trimipramine

Dopaminergic agents

Amineptine Amisulpride

DA re-uptake inhibitor D3 and D2 antagonist

5-HT: Serotonin; DA: Dopamine; MAO: Monoamine oxidase; NA: Noradrenaline; RIMA: Reversible monoamine oxidase-A inhibitors; SNRIs: Selective noradrenaline re-uptake inhibitors; SSRIs: Selective serotonin re-uptake inhibitors.

pharmacotherapy

Table 1 presents a summary of current pharmacotherapies for

MDD and their main postulated mechanism of action. The classical tricyclic and heterocyclic antidepressants (TCAs; amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline and trimipramine) block various combinations of the noradrenaline (NA), serotonin (5-HT) and dopamine membrane transporters, while monoamine oxidase inhibitors (MAOIs) (phenelzine, tranylcypromine) irreversibly block the enzymes responsible for the breakdown of NA, 5-HT and 2

Table 1. Current agents in the treatment of depression.

dopamine. These agents, however, are now regarded as second or third line agents because of their side effect burdens [12]. Due to the potentially hazardous drug and dietary interactions with MAOIs, a new subclass of reversible monoamine oxidase-A inhibitors (RIMAs) has been developed. However, only moclobemide has been licensed internationally for the treatment of MDD. The selective 5-HT re-uptake inhibitors (SSRIs) (including citalopram, its enantiomer escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) are currently considered as first-line agents for the treatment of depression. Although

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each SSRI belongs to a different chemical family and has unique secondary binding properties, each selectively and potently inhibits 5-HT re-uptake, as compared to effects on NA, adrenergic (α1,) histamine 1 (H1) and muscarinic cholinergic receptors [10,12]. Novel agents (non-TCA agents with noradrenergic or mixed actions) are also effective antidepressants. Bupropion and bupropion SR are prodrugs for the more active hydroxy bupropion that acts via NA and dopamine re-uptake blockade [13]. Mianserin [10,12] and mirtazapine are antagonists of the inhibitory α2 adrenergic (α2) receptors on both NA and 5-HT neurons and they are also antagonists of 5-HT2A/2C and H1. Antagonising α2 autoreceptors effectively disinhibits noradrenergic neurons and increases the production of NA. In addition, α2 antagonists disinhibit 5-HT neurons directly via α2 antagonism of heteroreceptors and indirectly via increased NA input, thereby increasing 5-HT release in the dorsal raphe nucleus (DRN). The combined actions of α2 antagonism result in the dual enhancement of 5-HT and NA release [14]. Reboxetine is a selective NA re-uptake inhibitor (NRI), while venlafaxine is a dual 5-HT and NA re-uptake inhibitor (SNRI). Venlafaxine shares the 5-HT and, to a lesser extent, the NA and dopamine re-uptake inhibitory properties of the classical TCAs but does not antagonise α1, cholinergic or H1 receptors. The relative effect of the NA action of venlafaxine is dose related. At low doses it primarily blocks 5-HT re-uptake, with its NA re-uptake blocking properties emerging only at higher doses [15]. Duloxetine represents a new SNRI with balanced NA and 5-HT re-uptake blocking properties at therapeutic doses. Milnacipram (available in France and Japan) also has dual re-uptake blocking effects, although these preferentially favour NA over 5-HT. In summary, the acute effects of the currently available effective antidepressants include blocking monoamine re-uptake, α2 receptors and/or monoamine oxidase (MAO). In contrast to the weight of evidence for the efficacy of current pharmacotherapies, recent enthusiasm for alternative medicine approaches based on meta-analyses of preliminary studies [16] has been diminished by reanalyses [17] and two negative results from US trials of St John’s wort [18,19].

Current evidence-based strategies in the treatment of major depressive disorder 3.

3.1 Relative efficacy of

current pharmacotherapies A number of randomised controlled trials (RCTs) and metaanalyses have reported comparable efficacy between SSRIs and TCAs [20]. Although there has been some suggestion of a slight advantage to TCAs in severely depressed patients [21], other data suggest that paroxetine is as effective as TCAs in hospitalised depressed patients [22]. Similarly, there are a number of meta-analyses and replicated RCTs that have reported similar efficacy of novel agents as compared to TCAs [21-26]. There is growing evidence that rates of remission but not necessarily response are higher with venlafaxine than SSRIs

[27-29].

Despite suggestions that antidepressants such as venlafaxine may involve different modes of action at different dosages [15], a meta-analysis failed to demonstrate any relationship between dosage and response when individual drug dosages were converted to imipramine equivalents [29], although the different methods used to establish dosing equivalence and to categorise antidepressants may account for these data. 3.2 Augmentation and combination

strategies Strategies for treatment-resistant depression (TRD), such as, failure to respond to adequate trials of antidepressant monotherapy, include augmentation with non-antidepressant agents and combination of two or more antidepressants. Current evidence supports lithium [30] and triodothyronine (T3, liothyronine) [32] as effective augmentation strategies in up to 60% of patients who are refractory to TCAs. However, there have only been two reports of lithium augmentation in SSRI non-responders (with citalopram [33] and fluoxetine [34]), and there are only limited data to support lithium or T3 augmentation of the novel-action antidepressants. There is growing interest in augmentation with novel antipsychotics in TRD, with preliminary studies suggesting that a combination of olanzapine and fluoxetine is more effective than either drug alone [35]. Although combining antidepressants with different mechanisms of action is an heuristically attractive strategy, there is still little evidence to support its efficacy in TRD. Open studies have been reported for combinations of SSRI plus moclobemide, bupropion plus SSRI or venlafaxine, TCA plus venlafaxine and for mirtazapine plus venlafaxine. However, the only positive RCTs involve SSRI plus mirtazapine/mianserin combinations [12]. More controlled research on combination and augmentation strategies with SSRIs and novel antidepressants is required. 3.3 Maintenance therapies

In recent years, recommendations regarding the continuation of antidepressant therapy following response have been extended. In the treatment of a single episode of acute depression, the risk of relapse is highest in the first six months following remission [36]. As a result, patients should stay on antidepressants for a minimum of 6 months or more following remission. Indeed, current evidence suggests that patients with any significant risk factor for relapse (e.g., severe, chronic or frequent episodes, older age etc.) should be maintained on medication for a minimum of 2 years following remission [37,38]. 4. Side

effects and discontinuation

Anticholinergic and cardiovascular side effects are most prevalent with TCAs, while gastrointestinal and other side effects are more problematic with SSRIs and other novel agents. Although sexual dysfunction and weight gain are common

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Recent developments in the psychobiology and pharmacotherapy of depression: existing treatments & novel approaches

side effects of TCAs and MAOIs [28,39-41], they are increasingly recognised in treatment with SSRI and novel agents. Current data suggests that antidepressant drug-related sexual dysfunction is more frequent in men as compared to women [39,42]. Between 30 and 50% of patients on SSRIs experience impairment of desire and orgasm [39,43], while bupropion [44,45], nefazodone [46], moclobemide [28,39] and mirtazapine [47] appear to cause significantly less dysfunction. Venlafaxine appears to be intermediate in its effects on women [39]. It is well documented that weight gain during treatment with TCAs is a significant issue [48]. There is more mixed evidence regarding weight gain during maintenance treatment with SSRIs [49,50]. Nefazodone appears to be weight-neutral [51], while bupropion SR appears to be either weight-neutral or perhaps weight loss-inducing [52]. Venlafaxine may also be weight-neutral, although as yet long-term data are not available [51]. Moclobemide may result in less weight gain as compared to conventional MAOIs [53]. Mirtazapine appears to result in significant weight gain as compared to placebo [54]. A practical implication for clinicians is the frequency with which side effects result in drug discontinuation. The range for TCA discontinuation in RCTs is 19 – 31% and the range for SSRI discontinuation is 15 – 25% [55-57], suggesting a modest difference in favour of the SSRIs. There is currently insufficient evidence for the novel agents. However, side effects and discontinuation remain a significant challenge, particularly in promoting maintenance pharmacotherapy for MDD. 5. Monoamines and the neurobiology of major

depressive disorder The postulated mechanisms of action for currently recognised antidepressants extend beyond a common hypothesis for the pathogenesis of MDD and its reversal by antidepressant therapies. However, current understanding of the mechanisms of pharmacotherapy for depression is characterised by an emphasis on increasing synaptic availability of 5-HT, NA and possibly dopamine, while minimising side effects. 5.1 Serotonin

5-HT plays an important role in social dominance and affiliative behaviour. Indeed, the behavioural effects of the range of normal serotonin levels in primates and humans can be well characterised. They seem to guide social behaviour oriented to social status. In particular, dominant social status is associated with high serotonin levels, while low serotonin levels are associated with subordinate status. Additionally, dominant social status seems to be achieved at least partly by affiliative behaviour. [58,59]. The majority of 5-HT cell bodies in the brain are in the DRN. Projections from the DRN to the frontal cortex may be important for regulating mood, whereas projections to basal ganglia, especially 5-HT2A receptors, may help control movement and obsessions and compulsions. Considerable evidence 4

implicates the 5-HT2A and 5-HT2C receptors in MDD [60,61]. Long-term antidepressant treatment may decrease 5-HT2A receptor binding and 5-HT2C receptor desensitisation [60,62-64]. According to the ‘dual 5-HT-fear hypothesis’, the ascending 5-HT pathway from the DRN that innervates the amygdala and frontal cortex facilitates conditioned fear. This function of 5-HT is likely mediated by 5-HT2A/5-HT2C and 5-HT1A postsynaptic receptors. The pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress and 5-HT1A receptors are likely to be the main target of the MRN-hippocampal pathway [65]. A reduction in 5-HT1A receptor binding potential in the midbrain is seen in MDD and chronic antidepressant administration may compensate for, rather than normalise, blunted 5-HT1A functioning [66]. The reduction in firing of neurons in the DRN following chronic SSRI administration may be explained by the desensitisation of somatodendritic 5-HT1A autoreceptors [67,68]. Agonism of 5-HT1A receptors, such as with buspirone, produces anxiolytic effects [69]. Alternatively, the critical effect of chronic SSRI administration may be desensitisation of terminal 5-HT1B receptors [70]. In animal models, 5-HT1B and 5-HT1D autoreceptors in the DRN modulate 5-HT levels [71,72]. The 5-HT5A receptor is localised in brain areas implicated in the pathogenesis of MDD including the raphe nucleus (RN) and the suprachiasmatic nucleus (SCN) of the hypothalamus [73,74]. The localisation of 5-HT5A receptors in the RN suggests a possible autoreceptor function to control the activity of ascending 5-HT neurons, while localisation in the SCN may suggest a potential role in the control of circadian rhythms [75]. In animal models, 5-HT 7 receptor mRNA is located primarily in the thalamus, hypothalamus and cortical regions and especially in the SCN [76], suggesting that 5-HT7 receptors may play an important role in the regulation of circadian rhythms and a potential role in the pathogenesis of MDD [77,78]. 5.2 Noradrenaline NA modulates 5-HT and dopamine release, particularly in the thalamocortical regions. Most of the cell bodies for NA neurons are located in the locus coeruleus (LC) with 5-HT enervation providing inhibitory modulation of LC activity. The LC-NA system importantly determines activation of the autonomic nervous system and is centrally important in the control of attention (arousal), concentration, mood, emotions, sleep, blood pressure and pain regulation. Dysfunction of the LC-NA pathways appears to play an important role in negative affect states including depression [79]. Different noradrenergic pathways mediate different functions. For example, different projections from the LC to frontal cortex are thought to be responsible for the effects of NA on mood and attention. Moreover, different receptors may be responsible for mediating the effects of NA in the frontal cortex, perhaps postsynaptic α1 receptors for mood and postsynaptic α2 receptors for attention and cognition

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Stress appears to upregulate α2 receptor binding in the prefrontal cortex [80-82].

[10].

5.3 Dopamine Social status in monkeys is at least partly determined by agonistic interactions reflected in dopamine D2 striatal differences [83]. Both the prefrontal cortex and the ascending dopamine system have been found to play an important role in the control of behavioural approach [84-86]. Dopamine release in the nucleus accumbens (NA) underlies response approaches and guidance towards positive incentives [87]. Interestingly, dopamine pathways may mediate the ‘incentive salience’ to otherwise neutral events rather than the hedonistic or pleasurable aspects of the reward stimuli per se, with the implication that reward can be dissociated into separate components of ‘wanting’ versus ‘liking’ [88]. Dopamine transmission is reduced in MDD and may underlie symptoms of anhedonia and anergia. D2 agonists, such as pramipexole, are effective in the treatment of depression [89] and chronic treatment with antidepressant drugs produces a sensitisation of behavioural responses to agonists acting at dopamine D2/D3 receptors within the NA as well as 5HT2C antagonism that increases dopamine release in the NA [87]. Indeed, some have suggested that current antidepressants are effective only insofar as they promote functional subcortical dopamine transmission [90].

Beyond monoamine hypotheses of the pathogenesis depression 6.

No monoamine deficiency hypothesis can account for the pathophysiology of MDD. Research has implicated a number of transmitter systems and brain structures, as well as intracellular and tropic processes in the pathogenesis of MDD. What follows is a brief review of relevant research and a summary of future promising directions for optimising existing treatments and developing novel agents [91-95]. 6.1 Stress and

the pathogenesis of depression In addition to a genetic vulnerability for depression, adverse early life experiences appear to predispose susceptible individuals to depression. Pathways may be activated later in life as a result of negative life events, including chronic social stress, social isolation and social defeat. In the absence of negative life events, people with the diathesis may avoid the risk for developing depression. In short, current evidence suggests that the pathophysiology of MDD is related to the brain’s response to stress [96,97].

6.1.1 Stress and the hypothalamic pituitary axis NA, adrenaline and cortisol are associated with a nonspecific hyperexcitability to fear-inducing stimuli [98-100]. Evidence to implicate the role of central nucleus of the amygdala in the fear response has prompted investigation of one of its principle neuromodulators, corticotropin-releasing factor (CRF).

CRF released by the paraventricular nucleus (PVN) of the hypothalamus activates the pituitary-adrenal response via adrenocorticotropic hormone (ACTH) [101]. The hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal medullary system (SAM) are centrally important in stress responses. There is considerable interplay between the LC, which provides central regulation of the SAM, and the parvocellular neurons, which regulate the HPA. The SAM, by triggering catecholamine release, activates the acute stress response, while the HPA governs longer term responses to stress. Studies of HPA functioning in MDD have revealed various abnormalities consistent with hyperactivity for neuronal CRF, including elevated urinary and serum cortisol levels, dexamethasone non-suppression, adrenal gland hyperplasia and blunted ACTH release in response to CRF challenge [102]. In animal models, CNS administration of CRF results in behavioural symptoms of stress, while chronic social stress results in altered feedback to LC-NA and CRF systems [101]. Activation of the HPA axis results in glucocorticoid production, which is controlled via an autoregulatory negative feedback system of glucocorticoid receptors located in the hippocampus, hypothalamus and pituitary, and is mediated by two different types of receptors: Type I mineralocorticoid receptors (MR), which are fairly well localised in the hippocampus, and Type II glucocorticoid receptors (GR), which are more broadly distributed. MR appear to be involved in the control of basal levels of cortisol, while GR appear to be involved in the control of circadian rhythms and stress induced cortisol production [103]. Although centrally important in acute adaptation to stress, chronically elevated glucocorticoid production has a variety of negative effects [99]. Sustained elevations of corticosteroid production result in neuronal cell death in certain brain regions, including hippocampal CA3 neurons and the dendate gyrus. Interestingly, corticosteroids also appear to affect receptor synthesis, including α2, β2, 5-HT1A and 5-HT1B receptors. Corticosteroids likely increase the excitability of CA1 hippocampal pyramidal cells via the 5-HT1A receptor. 6.1.2 Stress and the orbital cortex The use of structural neuroimaging techniques (magnetic resonance imaging and computerised tomography) has revealed a number of structural changes in limbic and prefrontal cortical (PFC) structures in MDD. There is also evidence for a reduction of cortical volume, glial cell counts and/or neuron size in the subgenual PFC, orbital cortex, dorsal anterolateral PFC and amygdala [96,104-108]. MDD is also associated with a reduction in glial volumes in the orbital and medial PFC, ventral striatum and hippocampus and enlargement of third ventricles [109]. Although the presence of severe white matter hyperintensities does not appear to predict a negative response to antidepressant treatment [110], given their role in regulating synaptic glutamate concentrations, energy homeostasis and release of tropic factors, glia may be an important factor in the pathophysiology of MDD [111,112]. The PFC regions implicated in

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Recent developments in the psychobiology and pharmacotherapy of depression: existing treatments & novel approaches

the pathogenesis of MDD appear to have a role in reducing the autonomic and endocrine response to stress and in inhibiting response to fear-conditioned stimuli [113]. For example, during experimentally induced negative mood and anxiety states in normal subjects, metabolic activity increases in the posterior and lateral orbital cortex, as in subjects with MDD. Usually, the magnitude of posterior/lateral orbital metabolism is inversely correlated with ratings of depression severity, sadness or obsessive thinking [104,105]. Changes in metabolism in orbito-frontal cortex and caudate nucleus correlate with obsessive-compulsive symptoms and such data have contributed to the 5-HT hypothesis of obsessive-compulsive disorder (OCD), involving a cortical-basal ganglia circuit [114-116]. Thus, activation of the orbital cortex during depressive episodes may be the result of endogenous attempts to interrupt non-reinforced, aversive thought and emotion [96]. Alternatively, activation of the orbital cortex during depressive episodes may be the substrate for depressive ruminations. 6.1.3 Stress and the hippocampus Stress results in death and atrophy of hippocampal CA3 pyramidal neurons, likely due to facilitation of glutaminergic functioning and inhibition of glucose transport as well as a decrease in the expression of neurotrophic factors [102,117-120]. A large number of closely related factors provide tropic support for neurons, but attention is currently focused on the role of brain-derived neurotrophic factor (BDNF) in MDD [121]. The target gene for BDNF has been proposed as a possible source of malfunction in signal transduction from monoamine receptors. Normally, BDNF sustains the viability of brain neurons but under stress, the gene for BDNF is repressed, leading to cell death in the hippocampus. Neurotrophic factors may inhibit cell death by activating the mitogen-activated protein kinase (MAPK) and phosphotidylinositol-3 kinase (PI-3K)/Akt signalling pathways [96]. MAPK signalling inhibits cell death partly by increasing the expression of the antiapoptic protein Bcl-2 [122,123]. Indeed, the neurotrophic factor/MAPK/Bcl-2 signalling cascade may have a critical role in neuronal survival [124]. Decreased neurogenesis may also be important in the pathogenesis of MDD [125,126]. In the adult primate brain, considerable neurogenesis occurs in the subventricular zone and the subgranular layer of the hippocampus [127,128]. A decrease in neurogenesis follows stress, an effect likely mediated by glucocorticoids [127]. It may be that antidepressant treatment decreases intracellular concentrations of cortisol by inhibiting GR [129]. 6.1.4 Neurotrophic

factors, neurogenesis, neuroplasticity and current antidepressants Preclinical evidence suggests that current antidepressants enhance neurogenesis and neuroplasticity, especially in the hippocampus. Antidepressant treatment may upregulate the cyclic AMP-CREB cascade (and therefore BDNF) [125], increase regeneration of catecholamine axon terminals in the

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cortex and enhance the proliferation, plasticity and resiliency of hippocampal CA3 pyramidal neurons [125,130,131]. Alternatively, current antidepressants may be effective insofar as they upregulate GR, enhance hypothalamic-pituitary-adrenal (HPA) axis feedback inhibition and normalise HPA axis functioning [103]. Similar neurotrophic and neuroprotective effects have been reported for lithium and valproate, although the therapeutic action of lithium may have more to do with effects on GABAergic and glutamatergic functioning [131-133].

Other neurotransmitters and neuromodulators implicated in major depressive disorder 7.

7.1 Inositol

Inositol is a second messenger precursor that has demonstrated efficacy in the treatment of MDD and OCD. Inositol may act on the 5-HT system via the intracellular phosphatidyl inositol second messenger cycle, serving as a second messenger for 5-HT2 receptors, in contrast to SSRIs, which act via inhibition of 5-HT re-uptake [195]. However, inositol augmentation does not appear to be an effective strategy in SSRIresistant treatment [134]. 7.2 GABA and glutamate

Through its actions as a major inhibitory neurotransmitter, GABA modulates an array of behavioural and physiological mechanisms including sleep, feeding behaviour, aggression, sexual behaviour, pain, cardiovascular regulation, thermoregulation and mood [135]. While current evidence suggests that abnormalities in GABAergic transmission are more important in the neurobiology of anxiety because of functional relationships to benzodiazepine (BZ) receptors. However, GABAergic pathways are widely distributed in the CNS and interact with 5-HT neurons in the prefrontal cortex, with NA neurons in the hippocampus and cortex and with dopamine neurons in striatal pathways. The GABAergic system is also modulated by both acute and chronic stress. In addition, GABA-mimetic agents resemble antidepressants in their ability to prevent or reverse many of the behavioural manifestations of depression in animal models. Depressed patients have lower plasma and CSF GABA concentrations as compared to non-depressed subjects and chronic administration of antidepressant drugs induce marked changes in GABAergic functioning [131]. These changes on antidepressants may occur via effects on neurosteroids, such as allopregnanolone (ALLO), which facilitates GABAergic functioning [136]. Glutamate may play a role in MDD. Several effective antidepressants induce adaptational changes in ligand binding to the glutamate NMDA (N-methyl-D-aspartate) receptor complex [137] and in NMDA receptor mRNA levels [138]. Competitive and functional antagonists at the NMDA receptor induce antidepressant-like effects in animal models. Thus, ionotropic and metabotropic glutamate receptors may play a role in the action of antidepressants [139-141]. For example, in

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animal models administration of (S)-3,5-dihydroxypenylglycine (DHPG), an agonist for group I metabotropic glutamate receptors (mGluRs), leads to enhanced phosporylation of DARPP-32 (dopamine and cAMP-regulated phosphoprotein, 32 kDa) [142]. Interestingly, DARP-32 has been found to be essential for dopaminergic and serotonergic transmission, and chronic administration of fluoxetine regulates the phosphorylation state of DARP-32 in the prefrontal cortex, hippocampus and striatum [143,144]. 7.3 Neurokinins/tachykinins,

neuropeptide Y and other polypeptides The tachykinin family (Tks) includes substance P, as well as the neurokinins (NKs) [145]. The biological actions of Tks are mediated via the activation of three G-protein-coupled seventransmembrane domain receptors designated as NK1, NK2 and NK3 [146]. Substance P and NK receptors are widely distributed in the CNS, where they function as neurotransmitters or neuromodulators [147]. In the amygdala, substance P is concentrated near the cell bodies of both dopaminergic and noradrenergic neurons [145]. There appears to be a heavy distribution of the NK1 receptor in the RN and these NK1 receptors appear to be involved in stress-induced activation of ascending central pathways in the LC [148]. Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family that includes peptide YY (PYY) [149]. NPY is widely distributed in the brain, including the cerebral cortex, hippocampus, thalamus and brainstem [150]. NPY is colocalised with NA cell bodies in many brain regions and there is some evidence to support a role for NPY in anxiety and depression [151-153]. Stress and desipramine affect NPY mRNA levels and these effects depend on baseline corticosterone fluctuations [154]. Baseline NPY concentrations are altered in the hippocampus in animal models of MDD and different antidepressant treatments enhance the potential for NPY activity in the hippocampus via distinct mechanisms [155-158]. Finally, there has been some interest in the possible role for the octapeptide form of cholecystokinin (CCK-8) in MDD and the potential use of peptidase inhibitors compared with exogenous agents in depression [159]. 7.4 Phospholipid metabolism Phospholipids play key roles in signal transduction responses to dopamine, 5-HT, glutamate and acetylcholine. The unsaturated fatty acid components of phospholipids are abnormal in depression, with deficits of eicosapentaenoic acid and other omega-3 fatty acids and excesses of the omega-6 fatty acid (arachidonic acid). Treatment with eicosapentaeoinic acid has been reported to improve depression [160]. Indeed, there is some interest in the use of fish oil, a source of these phospholipids, in MDD [161]. A number of possible abnormalities in enzymes responsible for metabolising phospholipids (e.g., phospholipase A2 and coenzyme A-independent transcyclase) might explain these findings [160].

7.5 Imidazoline receptors Imidazoline receptors (IRs) are a novel family of non-adrenergic receptors with a high affinity for some prototypic α2 adrenergic agents. In humans, IRs are found especially in the hippocampus and platelets. Studies of treated patients with MDD suggest upregulation of the I1 subtype of IR. In addition, antidepressant response is accompanied by downregulation of these receptors. Plasma agmatine, the decarboxylated derivative of the amino acid arginine, is believed to be an endogenous ligand for IRs. There is some potential for IR as a state marker for MDD, but this approach has so far yielded no potential antidepressants [162].

8. Deconstructing

depression

No current model of MDD adequately accounts for all of the available evidence. Indeed, MDD is regarded as a heterogeneous syndrome and different symptoms are likely modulated by different neurobiological systems. It may be that a disruption of the homeostatic relationships between several major transmitter systems underlies the pathogenesis of MDD [163]. Stahl has recently proposed a model for MDD that involves the existence of a NA deficiency syndrome characterised by impaired concentration, difficulties with working memory and speed of information processing, psychomotor retardation, fatigue and apathy, as well as a 5-HT deficiency syndrome comprised of depression, anxiety, panic, phobias, obsession, compulsions and food craving [10]. Such a theory is testable, given the availability of SSRIs and NRIs as distinctive treatment options. One aspect of Stahl’s synthesis that is especially intriguing is the association between obsessional thinking and the serotonergic system. Perhaps SSRIs specifically target the self-focused rumination often observed in MDD via serotonergic effects in the same corticolimbic circuits implicated in OCD [164-166]. Similarly, there may be distinct roles for 5-HT and dopamine in the pathogenesis of MDD. For example, Gray [167] argues that there are two primary systems that guide all behaviour: a behavioural activation (BA) system and a behavioural inhibition (BI) system. The BI system is sensitive to cues for punishment, while the BA system is sensitive to cues for reward. Perhaps the BA (dopamine) and BI (5-HT) are mutually antagonistic systems that regulate social and affiliative behaviours [167,168]. Reductions in avoidance (BI; 5-HT) or increases in reward driven behaviour (BA; dopamine) may lead to similar changes in affiliation and social dominance, with important implications for MDD symptomatology. The effects of acute and chronic stress on the brain is clearly important in the pathogenesis of MDD. Nemeroff [97], among others, has proposed a diathesis stress model in which a vicious cycle of increased CRF activity in the presence of receptor sensitivity following early trauma is an important determinant of the onset of MDD [131]. It is tempting to create a model for the pathogenesis of MDD in which 5-HT is related to social dominance and

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Recent developments in the psychobiology and pharmacotherapy of depression: existing treatments & novel approaches

rumination, dopamine is related to behavioural approach and anhedonia, and the NA-CRF and the GABA/benzodiazepine (BZ) systems play relatively nonspecific roles in mediating reactions to stress and perhaps behavioural inhibition. Alternatively, according to Harro and Oreland [169], a primary dysfunction of the LC may result in the core symptoms of depression in the following way: as a result of a combination of hereditary factors and stress, tonic activity of the LC diminishes due to an enhanced autoinhibition of NA neurons in the LC. This process weakens the control of neural processing in the association cortex, leading to more stereotyped information processing, including inappropriate and self-reinforcing feelings of guilt and hopelessness and disabling problems with attention and concentration. Strong stimuli, mediated either by release of glutamate or activity of an overactive CRF system, produce burst firing of LC neurons and, due to enhanced postsynaptic response, further anxiety, which could be closely linked to both dysfunctional NA and 5-HT neurotransmission. The supersensitivity of 5-HT2 receptors as a result of low serotonergic tone may be responsible for anxiety symptoms, which may be exacerbated by ineffective 5-HT1A receptor-mediated control. Reduced dopaminergic neurotransmission, as a result of low tonic stimulation rate of the ventral tegmental area, may serve as the basis for anhedonia and difficulty in allocating attention. As it appears that the reactivation of memories triggers a β-adrenoreceptor-mediated cascade [170], the supersensitivity of β-adrenoreceptors may also account for cognitive schemata characteristic of depression, which may reinforce the essential brainstem dysfunctions. Long-term depression, via CRF-induced enhancement of excitatory amino acid neurotoxicity, may lead to effects on LC and hippocampal neuronal composition. When repeated episodes of depression lead to weakening of the potential for NA output, TRD develops, necessitating additional treatments. There is increasing interest in the regionally selective reductions in structural plasticity and cellular resiliency in MDD [131]. The reduction in neural plasticity and resiliency may be due to monoaminergic dysfunction or may be the fundamental aetiological process in MDD. The intracellular signalling cascades that regulate neurotrophic and neuroplastic events also affect other systems [171]. Thus, alterations in these signalling pathways may account for the diverse changes and dysfunctions observed in MDD [131]. Whatever the primary dysfunction, the symptoms and course of any individual patient likely depends on the particular characteristics, inherited or acquired, of the individuals’ monoaminergic projections and related systems. In order to better understand the neurobiology and treatment response of MDD, more sophisticated typologies of symptoms based on animal models, genetic phenotyping, specific ligands and sophisticated imaging techniques will probably need to be developed. In the meantime, current knowledge suggests a variety of promising new and emerging pharmacological treatments. 8

9.

Promising new agents

9.1 Agents

targeting monoamine systems Continued challenges to the development of agents that affect 5-HT, NA and dopamine include enhanced tolerability to achieve the benefits of chronic administration, including prevention of the neuronal death associated with recurrent depression [171]. There is certainly room to improve the delivery systems for current agents, including extended release formulations, such as once-weekly enteric-coated fluoxetine [173], and active isomers, such as escitalopram [174]. Finally, it is at least theoretically possible to develop agents that target specific monoaminergic pathways. For example, it may be possible to identify unique characteristics of 5-HT2A postsynaptic receptors in the basal ganglia and 5-HT2A postsynaptic receptors in brainstem sleep centres that could be used to develop ‘pathway specific’ serotonergic agents [173]. A summary of agents currently in development for the treatment of MDD and their main postulated mechanism of action is presented in Table 2. 9.1.1 Serotonergic agents Agents that are most promising for development are those that target specific 5-HT receptor subtypes implicated in MDD, as well as agents that affect 5-HT plus one or more of the NA-CRF, GABA/benzodiazepine and dopamine systems. Several postsynaptic 5-HT1A agonists and partial agonists, including flesinoxan, have been removed from clinical development and only one has been approved for the treatment of generalised anxiety disorder (the azapirone buspirone). Gepirone is a postsynaptic 5-HT1A agonist that has been reported to be effective and well-tolerated in the treatment of MDD and an extended release preparation is under continuing investigation [176]. Lesopitron and eptapirone are two postsynaptic 5-HT1A agonists in Phase II clinical trials for depression and anxiety [177,178]. In addition, agents such as the 5-HT1A receptor ligand S15535, may have some potential in the treatment of MDD [179]. There has been some interest in developing agents that act at 5-HT1A as well as 5-HT2 receptors. For example, vilazodone is a 5-HT1A partial agonist/ SSRI that is currently in Phase II trials [180]. SB-236057 is a 5-HT1B agonist that is being investigated for the potential treatment of anxiety and depression [181]. Theoretically, a presynaptic 5-HT1A and 5-HT1D autoreceptor antagonist might work as a rapid-onset antidepressant owing to immediate disinhibition of serotonergic neurons [10]. For example, pindolol may enhance the action of SSRIs through blockade of somatodendritic 5-HT1A autoreceptors in the DRN. [182]. In addition, a number of selective presynaptic 5-HT1A receptor antagonists, including robalzotan (NAD-299) [183], DU 125530 [184] and sunepitron [185], have undergone Phase II and III trials for depression and anxiety. LY 206130 is a presynaptic 5-HT1A antagonist being investigated for the potential treatment of anxiety and smoking cessation [186], SB-224289 has been identified as a 5-HT1 and 5-HT 2 antago-

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Table 2. Potentially promising agents in the treatment of depression.

Serotonergic agents

Primary receptors & mechanism

Drug name

5-HT1A agonist 5-HT1A agonist & antagonist (weak partial agonist) 5-HT1A partial agonist/SSRI 5-HT1A antagonist

Gepirone ER, lesopitron, eptapirone S15535 Vilazodone Robalzotan (NAD-299), sunepitron, pindolol, DU 125530, LY 206130 SB-224289 SB-236057 CP-448187 SB-272183 100907 (M-100907, MDL-100907) SB-200646, SB-242084, SB-243213 Ro 60175, Ro 60-0332 SB206553, SB221284 Deramciclane Flibanserin SB-269970, SB-258719, DR 4004, DR 4365 LY 215840 Duloxetine Modafinil Tianeptine Agomelatine (S 20098)

5HT1A & 5-HT2 antagonist 5HT1B agonist 5-HT1D antagonist 5-HT1A/5-HT1B/5-HT1D antagonist 5-HT2A receptor antagonist 5-HT2C receptor antagonist 5-HT2C agonist 5-HT2C & 5HT2B antagonist 5-HT2A & 5-HT2C antagonist 5-HT2 antagonist, 5-HT1A agonist 5HT7 antagonist 5-HT2 antagonist, 5HT7 antagonist SNRI 5-HT? Increasing 5-HT re-uptake 5-HT2C antagonist and melatonin agonist Noradrenergic agents

NRI Dexnafenadone, tomoxetine β3 agonist SR 58611 5-HT/DA/NA augmenting via antagonism of K+ channels (?) Minaprine

Dopaminergic agents

D3 antagonist,/DA autoreceptor antagonist

DS 121

Agents targeting MAO

MAO-B inhibitor MAO-A inhibitor

Seligiline patch Befloxatone

Neuropeptide receptor ligands & agents targeting HPA axis

CRF1 antagonists

NBI 29356, NBI 37582, NBI 30545, NBI-31199, NBI-31200, NBI-27914, NBI 34041, NBI 103, CRA 1000, CRA 1001, CRA 0165, PD 171729, SC 241, SSR125543A MK 869, L 733060, CP 122721, CP-99994, SR 140333, ML 760735 WO 09727185, SR-48968, SR-48968 derivatives Osanetant (SR-142801) SSR-149415 ORG 34517 & RU 486

NK1 antagonists NK2 antagonist NK3 antagonist V1b antagonist GR antagonist Neuroimmunophilin ligands

FKBP-12 inhibitors, chemoprotectant, neuroprotectant, antiparkinsonian

GPI 1046, GPI 1337, GPI 1842

GABAergic agents

Anticonvulsant agent, GABA modulator Anticonvulsant agent, GABA ligand, GABA modulator GABA agonist Valproic acid prodrug Analgesic, anti-inflammatory, anticonvulsant, GABA modulator

AWD-131-138 SPD-421 Pagaclone, ganaxolone CHF-3098 Gabapentin

Glutamatergic agents

Glutamate antagonist, NMDA antagonist, neuroprotectant, Remacemide hydrochloride anticonvulsant NMDA antagonist Ketamine hydrochloride Metabotropic glutamate receptor 2 agonist LY 354740

GABA & glutamatergic agents

Enhancement of GABA, blocking the effect of glutamate at Topiramate non-NMDA receptors Partial agonist at the ‘-2 and ‘-3 subunits and full agonist at Pagaclone the ‘-4 subunit on the GABA receptor

Nicotinic agents

Nicotinic AChh (?) agonist Nicotinic AChR antagonist

Altinicline, AR-R-17779 Mecamylamine (Inversine)

5-HT: Serotonin; Ach: Nicotinic acetylcholine receptors; CRF: Corticotropin-releasing factor; DA: Dopamine; FKPBP: FK506-binding protein; GR: Glucocorticoid receptor; HPA; hypothalamic-pituitary-adrenal; MAO: Monoamine oxidase; NA: Noradrenaline; NK; Neurokinin; SNRI: Selective noradrenaline re-uptake inhibitor. Expert Opin. Investig. Drugs (2002) 12(1)

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nist [187] and CP-448187 has entered Phase II trials as a presynaptic 5-HT1D antagonist [188]. Since 5-HT1B autoreceptors are also present in the DRN, antagonism of presynaptic 5-HT1A, 5-HT1B and 5-HT1D receptors simultaneously may synergistically enhance 5-HT functioning [189,190]. There are no reports of such combined 5-HT1A, 5-HT1B and 5-HT1D antagonists in humans, but SB-272183 has been investigated in animal models. Given the evidence for the efficacy of nefazodone via 5-HT2A antagonism [191], there has been some interest in the development of selective 5-HT2A receptor antagonists. Ketanserin has been used in essential hypertension but has not been found to be useful for CNS disorders [192]. The highly selective 5-HT2A receptor antagonist 100907 (M-100907, MDL-100907) has been investigated for the treatment of schizophrenia [193], but may be more useful in anxiety, depression and sleep regulation [194]. Flibanserin, a combined 5-HT2 antagonist and partial 5-HT1A agonist has also been evaluated as a potential antidepressant [195]. The use of a number of selective 5-HT2C receptor antagonists has been explored in depression, including SB-200646, SB221284, SB206553, SB-242084 and SB-243213 [196]. Interestingly, 5-HT2C receptor antagonists have been found to stimulate the mesolimbic dopamine system, which argues for their potential utility in MDD [197]. Deramciclane is a 5-HT2A and 5-HT2C antagonist currently in Phase III trials for anxiety [198]. Unfortunately, the 5-HT2C antagonists have tended to interfere with cytochrome P450 isoenzymes. In addition, while the 5HT2C antagonists such as SB-243213 show signs of anxiolytic-like activity in tests for conditioned and phobic-like anxiety in animal models, they seem less effective in tests indicative of antidepressant, antiOCD and antipanic activity [199]. In contrast, the 5HT 2C agonists Ro 60-0175 and Ro 60-0332 have demonstrated potent in vivo activity in animal models of depression, OCD and panic disorders. Such results are consistent with the hypothesis that 5-HT has a complex, dual action on the neural mechanism of anxiety by either facilitating or inhibiting different kinds of anxiety in different brain regions and that 5HT2C receptor subtypes play an important role in the therapeutic properties of SSRIs [199]. Although effective 5-HT3 receptor blockade provides favourable antiemetic and antinausea properties (a desirable aspect of mirtazapine) and despite considerable interest in the potential role of 5-HT3 antagonists, such as ondansetron, tropisetron, R-zacopride and ricasetron, in the treatment of anxiety disorders, there is little evidence for the efficacy of these drugs in the treatment of MDD. Studies of the selective 5-HT7 receptor antagonist SB-269970 have shown antidepressant effects in animal models and similar agents, including SB-258719, DR 4004, DR 4365 and LY 215840 (a 5-HT2/ 5-HT7 antagonist) may have some potential in MDD [177]. The mechanism of action of modafinil, used in the treatment of narcolepsy, is unknown, but it may act on the 5-HT 10

system and have potential utility in the treatment of MDD [273]. Tianeptine is an antidepressant agent with an atypical neurochemical profile. It increases 5-HT uptake in the brain, reduces stress-induced atrophy of neuronal dendrites and reduces both basal and stress-evoked activity of the hypothalamic-pituitary-adrenal (HPA) axis. The fact that enhancers, as well as inhibitors, of 5-HT uptake act as antidepressants, challenges any simple explanation of their mechanism of action [200,201]. There has been great interest in developing dual 5-HT/NA agents. Duloxetine (Ly-248686), a 5-HT and NA re-uptake inhibitor, has been submitted for registration in several countries, including the US [202]. Other dual-acting agents under investigation includes agomelatine (S 20098), a combined melatonin agonist and 5-HT2C antagonist [203]. 9.1.2 Noradrenergic agents Reboxetine, while available in Europe, is unlikely to become available in the US or Canada. However, there is currently great interest in developing compounds that target NA. Dexnafenodone, a selective inhibitor of synaptosomal NA reuptake as well as calcium transport inhibitor, has reached Phase I clinical trials [204]. Tomoxetine is an NRI developed for the treatment of attention deficit hyperactivity disorder with some potential utility in the treatment of depression [205]. β-Adrenergic receptors can be rapidly downregulated by selective agonists. To date it has not been possible to identify β1 or β2 agonists that successfully penetrate the brain and are not cardiotoxic. Pursuing safer β1 and β2 agonists, perhaps as partial agonists, may allow study for antidepressant properties. In the meantime, the β3 agonist SR 58611 has been successfully tested in animal models of depression [206]. Antidepressant profile in rodents of SR 58611A, a new selective agonist for atypical β-adrenoceptors. 9.1.3 Dopaminergic agents One of the important secondary pharmacological characteristics of many SSRIs is dopamine re-uptake blockade, perhaps especially in the case of sertraline [208]. Bupropion seems to be both a dopamine and NA re-uptake inhibitor [209]. Tianeptine may enhance the functional responsiveness of dopamine D2 and D3 receptors. Several agents that affect 5-HT and dopamine re-uptake are currently available in some countries or are undergoing clinical trials including the 5-HT/dopamine/NA agent minaprine [210]. Dopaminergic agents and stimulants have long been used in TRD and have more recently been investigated as a relatively rapid method of relieving depression [89,211,212]. Unfortunately, drugs that target the dopaminergic system, such as amineptine (available in France as an antidepressant), are also potential drugs of abuse [213]. Dopamine agonists such as pergolide, a potent D2 and D2 agonist [214], as well as D2 and 5HT2 antagonists such as pramipexole [89], iloperidone and Org-522 [215], may have a role to play in the management of MDD, but there

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is little promise for such agents as monotherapies [214]. PNU-96391A (DS-121) is a dopamine autoreceptor and D3 receptor antagonist that was being investigated as a potential treatment for depression and psychosis. However, no active development has been reported since 1998. Similarly, the D3 and D3 antagonist amisulpride has been registered as a treatment for dysthymia in Italy and Portugal and showed some promise, but development for other markets have been discontinued [216]. 9.1.4 Selective monoamine oxidase inhibition

At present, only irreversible MAOIs have approval from the US FDA as antidepressants. In addition to phenelzine and tranylcypromine, L-deprenyl (selegiline) is a selective inhibitor of MAO-B approved for the treatment of Parkinson’s disease; a transdermal patch formulation has been reported to be effective in the treatment of MDD in the form of a transdermal ‘patch’ [217]. Pargyline was approved for treatment of severe hypertension but is no longer manufactured. Although manufacturing of isocarboxazid in the US was discontinued in 1990, it was relaunched in 1998. Moclobemide, a RIMA, is available in Europe, Canada, Australia and elsewhere, but not in the US. Brofaromine, another RIMA with demonstrated antidepressant efficacy, is no longer under active investigation. However, a new RIMA compound, befloxatone, has undergone clinical trial evaluation in the US and Europe. 10.

Newer approaches

10.1 Neuropeptide receptor ligands and the hypothalamic-pituitary-adrenal axis The HPA axis provides multiple potential sites of antidepressant development. The use of CRF and arginine vasopressin (AVP) antagonists, glucocorticoid antagonists and cortisol synthesis inhibitors, have all been suggested [218]. The CRF1 receptor on the anterior pituitary appears to downregulate in depression. If so, then CRF antagonists should rectify the HPA disturbance observed in the disorder. CRF or CRF receptor ligands modulate anxiety in humans [219] and there may be a role for non-peptide lipophilic CRF antagonists in the treatment of MDD [220]. Several different companies have been developing small molecule, selective CRF1 receptor antagonists. Despite some demonstration of efficacy of CRF antagonists (e.g., R121919) [221], the development of these agents has been challenging due to problems with lipophilicity and hepatic toxicity [222,223]. In addition, antalarmin, a potent CRF1 antagonist, does not appear to attenuate ACTH response to stress [224,225]. Despite these difficulties a large number of other CRF1 antagonist compounds have been or are currently being investigated, including R121919, SC 241, NBI-103, NBI-104, NBI 37582, NBI-27914, NBI 34041, NBI-29356, NBI-31199, NBI-31200, NBI 30545, CRA 1000, CRA 1001, CRA 0165 and PD 171729. Among

the more promising are NBI-103, a small molecule non-peptide CRF antagonist, currently in Phase II trials for anxiety and depression [103], and the non-peptide CRF1 receptor antagonist SSR125543A [226,227]. Although the NK1 receptor ligands have various and sometimes contradictory effects in animal models, the potential for such agents in MDD merits investigation. Promising agents include the NK1 antagonist MK-869 [148]. Other NK1 antagonists currently under investigation include SR 140333, ML 760735, L 733060, CP 122721 and CP-99994. The most studied NK2 receptor antagonists to date are GR 159897 (development discontinued) and SR 48968. Other NK2 antagonists currently under investigation include WO 09727185, GR-159897, SR-48968 and SR-48968. Osanetant (SR 142801) has been investigated as a NK3 antagonist [228]. Antidepressant treatment may increase intracellular cortisol by inhibiting the L929 membrane GR. While the CRF1 receptor is downregulated in depression, a concomitant upregulation of vasopressin V(1b) receptors also takes place, suggesting that a blockade of the V1b receptor, via agents such as SSR 149415, may be a promising strategy for normalising the endocrine component of MDD [218]. There has been some investigation of antiglucocorticoid treatment in MDD. Most of the studies thus far have used ketoconazol, metyrapone, aminoglutethmide or the exogenous GR receptor antagonist mifepristone (RU-486) as the antiglucocorticoid agent. Mifepristone may be especially useful in treating psychotic depression [229]. Both mifepristone and ORG 2766 have been shown to prolong survival of CA1 neurons following ischaemia [103]. To date, these agents have demonstrated some efficacy but are currently either nonspecific in their actions and/ or associated with serious side effects [131,224,230,231]. Alternative approaches may be possible. For example, membrane transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug-resistant P-glycoprotein, could be targets for antidepressant action [190]. ORG 34517 is considered to have more specific GR antagonist effects and is currently in stage II trials for depression [231] compounds are immunophilin ligands that specifically bind to immunophilins, like FK506-binding protein 12 (FKBP-12). Several lines of evidence show that these ligands exert neurotrophic properties in neural injury models. There has recently been some interest in the chemoprotectant and neuroprotectant effects of the FKBP-12 inhibitors GPI 1046, GPI 1337 and GPI 1842, and such compounds may have potential utility in the management of MDD [232]. GABAergic agents Drugs that act on the GABAergic system can increase GABA synthesis and release (a possible effect of valproate), decrease GABA re-uptake (e.g., tiagabine), decrease GABA catabolism (e.g., vigabatrin) or act on postsynaptic GABA receptors [233]. GABAergic functioning can be enhanced through inhibition of GABA-T, allosteric modulation of Cl- ion permeability and administration of GABA-mimetic agents that act directly at 10.1.1

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Recent developments in the psychobiology and pharmacotherapy of depression: existing treatments & novel approaches

the GABA-binding region. Progabide and fengabine (SL 79229) are two GABA-mimetic compounds evaluated as potential antidepressants. However, no recent work has been reported as a follow-up to these initial studies [234]. Pagaclone, a cyclopyrrolone that acts as partial agonist at the ‘-2 and ‘-3 subunits and a full agonist at the ‘-4 subunit on the GABA receptor, has been found in Phase II trials to be effective in the treatment of panic and it may be effective in MDD [235]. Other potentially interesting compounds include agents currently being developed for the treatment of epilepsy, such as AWD 131-138, SDP-421, CHF-3098 and ganaxolone [236]. However, there is no indication that any agents acting primarily on the GABAergic system are close to being commercially available, although newer anticonvulsants (gabapentin and topiramate) with GABAergic activity have recently attracted attention as potential mood stabilising and antidepressant drugs [237]. The benzodiazepine class of GABAA agonists appears to be ineffective as antidepressants. Despite positive results, the development of the triazolobenzodiazepine adinalozam (deracyn) was discontinued in 1999 due to concerns about dependence. Certain neurosteroids, such as 3α-hydroxy-5αpregnan-20-one (allopregnanolone) and 3 α-21dihydroxy-5αpregnan-20-one (THDOC) are potent GABAA receptor modulators. Endogenous neurosteroids, their analogues and the enzymes involved in neurosteroid synthesis may be promising new targets for pharmacological intervention [238]. 10.1.2 Glutamatergic

agents To date, the main target in the glutamatergic system has been the glutamate NMDA receptors, non-NMDA receptors and metabotropic receptors. Non-NMDA receptors can be further divided into kainate and ‘-amino-3-hydroxy-5-methylisoxazole (AMPA) receptors [239]. Inhibitors of NMDA receptors have had been found to be have unacceptable side effects [240] and interest has turned to agents that modulate the NMDA receptor, especially agents that act at the glycine site [241]. For example, remacemide hydrochloride is a novel water-soluble anticonvulsant that has been investigated for epilepsy. Due to its action at NMDA receptors, remacemide has been proposed as a potentially effective agent for a number of conditions [242]. There is some evidence for the effectiveness of the NMDA antagonist ketamine hydrochloride [230]. However, the psychosis-inducing effects and the potential for abuse of this type of agent limit the applicability of this strategy [230,242]. Although felbamate has been withdrawn from the market due to problems with toxicity, other drugs, such as lamotrigine, which has been associated with attenuation of glutamate excitatory neurotransmission have anxiogenic and antidepressant effects [243,244]. Topiramate is known to enhance the activity of GABA and block the effects of glutamate at non-NMDA receptors [245]. There is probably some promise for agents with both GABAergic and antiglutamaterigic actions, such as topiramate, in the treatment of MDD [237]. 12

Drugs acting at the kainate receptor may prove to be useful in the treatment of MDD, as activation of kainate receptors has been shown to have disinhibitory as well as excitatory effects [246]. The complexity of metabotropic receptor action suggests that antagonists and agonists can have paradoxical effects. However, agents such as LY 354740, a metabotropic glutamate receptor 2 agonist merit further attention in the treatment of MDD [247]. 10.1.3 Tropic agents

Any potential efficacy of CRF antagonists, antiglucocorticoids and glutamate antagonists may be the result of their effects on neuroplasticity and neurogenesis [224]. Although BDNF itself can only cross the blood–brain barrier with difficulty [248,249], there are other small molecules that mimic the actions of nerve growth factor (NGF), including the immunosuppressant FK506 [164], as well as antibiotics like BU 4314 [250]. Masuoka and colleagues (1997) have isolated a novel substance with transforming growth factor (TGF)-β like activity [251]. It seems reasonable to explore whether compounds with BDNF-like activity exert therapeutic benefit in MDD [252]. A number of strategies to enhance neurotrophic factor signalling and to inhibit the activity of GSK-3β are currently under development. In general, these approaches emphasise the development of molecules that affect the activity of growth factors, MAPK cascades and interactions between the Bcl-2 family of proteins [253]. Other compounds worth investigating, given that increasing cyclic AMP levels exerts neurotrophic effects via CREB-mediated Bcl-2 upregulation, are the phosphodiesterase (PDE) inhibitors [123]. Preliminary reports suggested that the PDE4 inhibitor rolipram had antidepressant activity [252]. It also increases the proliferation of cells in the subgranular layer of the hippocampus, and the transgenic expression of the dominant-negative mutant CREB decreases the survival of young neurons. Unfortunately, development of rolipram has been discontinued due to problems with nausea. CNS penetrant, isozyme-selective PDE inhibitors are probably worth investigating [131]. Chronic antidepressant administration in rats leads to upregulation of astrocyte protein S100B and its putative receptor RAGE (receptor for advanced glycation end products). Neuronal RAGE expression and its activation by S100B may promote cell survival, thus there may be some role for this pathway as a target for novel antidepressants [254]. 10.1.4 Agents

that alter phospholipid metabolism It has been proposed that both a deficiency and an excess of certain essential fatty acids may be important in the pathogenesis of MDD [160]. Such an hypothesis suggests a number of potential treatment strategies, including treatment with omega-3 highly unsaturated fatty acids (HUFAs), reduction in intake of omega-6 HUFAs and saturated fats which compete with omega-3 HUFAs for incorporation into phospholipids, inhibition of brain phospholipase A2 (PLA2) and inhibition of coenzyme-A-independent transcyclase (CoAIT), an enzyme

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importantly involved in the transfer of arachidonic acid from ordinary phospholipids to lysophospholips [160]. To date there is no evidence concerning the therapeutic effects of CoAIT inhibition and only epidemiological evidence for the desirable consequences of low total and omega-6 fatty acid intakes. Interestingly, there is evidence that PLA2 inhibition may be effective insofar as one interpretation of the efficacy of lithium augmentation in MDD is that it may work by inhibiting PLA2. There are two very recently reported controlled trials supporting the efficacy of omega-3 fatty acids and ethyl-eicosapentaenoate in MDD [255,256]. In addition, mixed EPA/DHA therapy in patients with treatment-resistant bipolar disorder produced a highly significant effect of omega3 HUFAs in preventing relapse [257]. Because of these results, several other trials are currently in progress [160]. Nicotinergic agents Neuronal nicotinic acetylcholine receptors (nAChRs) represent a large family of ligand-gated channels with diverse structures and properties. Current data implicate nAChRs in the control of acetylcholine, dopamine and NA release, all of which are key neurotransmitters in attention, concentration and memory. Few studies have examined the potential use of nicotinic ligands in the treatment of depression. The nAChR antagonist mecamylamine (Inversine™) may have some efficacy in MDD [258]. SIB-1508Y, a novel subtype-selective ligand for nAChRs has been reported to be effective in the treatment of depression in animal models [259]. Agents, such as nAChR agonist altinicline and the acetylcholine analogue AR-R-17779, a full agonist at α-7 receptors, may also have a role in the treatment of MDD [260,261]. 10.1.5

11.

Expert opinion

In the development of new ‘first-line’ pharmacological treatments for MDD, the 5-HT and NA systems will most likely remain important, especially if agents can be developed with improved tolerability, faster onset of response or greater efficacy. Current agents can also be improved, including use of extended release formulations, such as once-weekly entericcoated fluoxetine, and exploring the utility of isolating active isomers, such as escitalopram. While first-line treatments for MDD in the near future will probably continue to target 5-HT and/or NA and/or

dopamine, the various symptoms of depression are presumably modulated by different neurobiological systems so the focus of drug development will increasingly shift to agents that affect other systems, such as the NA-CRF systems, antiglucocorticoids and agents that affect tropic factors, such as BDNF. Another promising area for development are agents that target the specific 5-HT receptor subtypes and agents that affect 5-HT plus one or more of the NA-CRF, dopamine and glucocorticoid systems. More specifically, the 5-HT1 receptor family appears to be involved in the regulation of 5-HT neuronal activity, the 5-HT2 receptor family appears to be intimately involved in anxiety and fear and the 5-HT7 receptor appears to be important in the regulation of circadian rhythms and sleep. Selective targeting of these receptor subtypes with agents that affect one or more of these 5-HT subtypes, may have considerable potential in the treatment of depressive and anxiety disorders. There is currently great interest in developing compounds that specifically target NA, such as dexnafenodone, tomoxetine and SR58611, and there is certainly merit in continuing to attempt to develop safer β1 and β2 agonists. There will likely continue to be much interest in developing agents that affect 5-HT/NA agents, such as duloxetine. Similarly, while there have been many problems in developing agents that specifically target dopamine, the dual re-uptake blockers of both 5-HT and dopamine, NA and dopamine, as well as triple NA/5-HT/dopamine re-uptake blockers currently undergoing clinical trials, seem quite promising. Despite a lack of current evidence for combination and new augmentation strategies in the treatment of MDD, the use of targeted combined pharmacotherapies will become increasingly utilised for TRD. It is important to remember that neurobiology is not static. Rather, it is dynamically interactive with the environment. For example, some neurotransmitters have been shown to be related to social dominance and also to be exquisitely responsive to social defeat [262,263]. The frontier of MDD research includes developing descriptions of typologies of MDD and describing the dynamic relations among neurotransmitter systems and between brain biology and the environment in those subtypes. Such research, in combination with an ever-increasing array of specific ligands and advances in neuroimaging and genetic research, offers much promise for establishing which specific medications will be effective for whom [264].

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Recent developments in the psychobiology and pharmacotherapy of depression: existing treatments & novel approaches

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••

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Affiliation P Farvolden PhD, CPsych1,2,5†, SH Kennedy MD, FRCPC 2,3 & RW Lam MD, FRCPC4 1Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8, Canada 2Department of Psychiatry, University of Toronto 3University Health Network 4Department of Psychiatry, University of British Columbia †Author for correspondence 51Research Scientist, Clinical Research Department, 250 College Street, Toronto, Ontario, M5T 1R8, Canada Tel.: +416 535 8501 ext. 6181; Fax: +416 979 6821 E-mail: [email protected]