Evolution of Antidepressant

REVIEW ARTICLE
Invited review: the evolution of antidepressant mechanisms

D.A. Slattery, A.L. Hudson*, D.J. Nutt
Psychopharmacology Unit, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK
Keywords
antidepressant, depression, hypothalamicpituitary adrenal-axis, novel targets
ABSTRACT
Received 24 February 2003; revised 4 June 2003; accepted 16 June 2003
*Correspondence and reprints: a.l.hudson@bristol.ac.uk
Present antidepressants are all descendents of the serendipitous ndings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. The identication of their mechanism of action, and those of reserpine and amphetamine, in the 1960s, led to the monoamine theories of depression being postulated; rst, with noradrenaline then 5-hydroxytryptamine being considered the more important amine. These monoamine theories of depression predominated both industrial and academic research for four decades. Recently, in attempts to design new drugs with faster onsets of action and more universal therapeutic action, downstream alterations common to current antidepressants are being examined as potential antidepressants. Additionally, the use of animal models has identied a number of novel targets some of which have been subjected to clinical trials in humans. However, monoamine antidepressants remain the best current medications and it may be some time before they are dislodged as the market leaders.
INTRODUCTION Over 340 million people are affected by major depression, with females comprising roughly two-thirds of that number. The average age of onset is now in the 1920s compared with the late 1940s before World War II [1]. The World Health Organization estimate that by 2020, unipolar major depression, will become the second largest cause of global disease burden in the world, behind only ischemic heart disease. However, in females and in developing countries unipolar depression is predicted to become the largest cause of disease burden [2]. Therefore, depression represents a major medical and social problem. Despite the last 40 years witnessing the introduction of an agreed criteria, e.g. Diagnostic and Statistic Manual of Mental Disorders, fourth edition, newer, more efcacious treatments and an increased understanding of the neurobiology of depression, studies indicate that roughly 30% of the population do not receive any benet from present drugs [3]. The two original modern drugs used for the treatment of depression were the monoamine oxidase inhibitor (MAOI) iproniazid, and the tricyclic antidepressant (TCA)
imipramine. Both compounds were discovered fortuitously, with iproniazid being developed as a treatment for tuberculosis and imipramine as an antihistamine but tested for schizophrenia due to the success of chlorpromazine. The discovery of these compounds mechanisms of actions led to the catecholamine hypothesis of depression being developed in the mid-1960s. This theory stated that some, if not all, depressions are associated with an absolute or relative deciency of catecholamines, particularly noradrenaline (NA), at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines [4]. There is still a lack of understanding of the pathology of depression, which has hindered the development of novel therapies, and all present antidepressant therapies have a delayed onset of action with their primary action to increase the levels of monoamines in the brain. However, these therapies, which elevate central monoamines have proved very successful and remain the most widely prescribed drugs (e.g. TCAs, MAOIs and uptake inhibitors). Currently, a number of drug targets, which act independently, or indirectly increase monoamine are being examined as new antidepressants, with the hope of
2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121
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a more rapid onset of action and more universal effectiveness. The following review describes the evolution of the theories of antidepressant mechanisms and looks at a number of the emerging nonmonoamine approaches. MONOAMINE NEUROTRANSMITTER LEVEL THEORIES The rst catecholamine theory of depression was proposed by Schildkraut in 1965, based mainly on the actions of reserpine, iproniazid and imipramine [4]. It stated that a deciency of catecholamines, particularly NA, led to some forms of depression. Evidence for this came from reserpine, a drug used in the treatment of hypertension due to its ability to decrease sympathetic activity, was noted to cause sedation and in many instances evoke severe depression in patients. Tetrabenazine, a similar agent to reserpine, which both deplete catecholamine stores, and to a lesser degree 5-hydroxytryptamine (5-HT) was also shown to induce depression in many patients [5]. Contrastingly, iproniazid, an inhibitor of MAOI, was fortuitously noted to elevate mood in depressed patients in the early 1950s, and soon thereafter was shown to lead to an increase in NA and 5-HT. Initially, imipramine cast doubt on the catecholamine theory because it was shown not to inhibit MAO. However, Hertting et al. demonstrated that it inhibited cellular uptake of NA in peripheral tissues. This enabled imipramine to t into the hypothesis as it, like iproniazid, elevated both mood and NA [6]. Moreover, both antidepressant agents were demonstrated to prevent reserpine-induced sedation [79]. Similarly, administration of dihydrophenylalanine [DOPA; a precursor of dopamine (DA) and NA] to laboratory animals was shown to reverse reserpineinduced sedation [10]; a nding reproduced in humans [11]. Amphetamine, which releases NA from vesicles and prevents re-uptake was also used in the treatment of depression at the time with varying success and so added further support to the catecholamine theory of depression. The decreased levels of NA proposed by Schildkraut, suggested that there would be a compensatory upregulation of b-adrenoceptors. Despite inconsistent ndings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ECT) decrease b-adrenoceptor density in the rat forebrain [12,13]. This lead to the theory that b-adrenoceptor downregulation was
required for clinical antidepressant efcacy [14]; however, some of the newly developed antidepressants do not alter, or even increase b-adrenoceptor density [15]. Another adrenoceptor implicated in depression is the presynaptic a2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of a2-adrenoceptors, a nding supported by the fact that clonidine administration caused a signicant increase in growth hormone (an indirect measure of a2-adrenoceptor activity) although platelet studies proved inconsistent. This supersensitivity of a2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression [16,17]. The NA theory received a major boost with the arrival of new antidepressants in the 1990s, including mirtazapine (mainly an a2-adrenoceptor antagonist with 5-HT2 and 5-HT3 receptor binding properties), venlafaxine (inhibitor of 5-HT and NA reuptake) and in particular reboxetine (the most specic inhibitor of NA reuptake approved for treating depression). Indeed, reboxetine has been shown in clinical trials to be at least as effective as citalopram, the most specic inhibitor of 5-HT re-uptake currently available. This nding suggests that individual modulation of either NA or 5-HT neurotransmission is benecial in treating depression. However, there is substantial interplay between the two systems, as in addition to enhancing NA release, a2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of a2-adrenoceptors present on 5-HT nerve terminals [18] (Figure 1).
Locus coeruleus
Terminal regions
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Mirtazapine Mianserin
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ve
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Figure 1 Mechanism of NA reuptake inhibitors and a2-adrenoceptor antagonists. Schematic diagram showing the interaction of different antidepressants at the level of the NA neurone. Blockade of reuptake results in increased NA in the synaptic cleft, whilst blockade of a2-adrenoceptor results in inhibition of NA-mediated negative feedback.
The evolution of antidepressant mechanisms
Shortly after Schildkrauts catecholamine hypothesis was published, Coppen proposed that 5-HT, rather than NA, was the more important neurotransmitter in depression. This was based on similar evidence to that which produced the NA theory as reserpine, imipramine and iproniazid affect the 5-HT system, in addition to the noradrenergic system [19]. It was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-HT neurotransmission remained unaltered there was no sedation in animals [20]. Alongside this, the main observation promoting the 5-HT theory was that administration of a MAOI in conjunction with tryptophan (precursor of 5-HT) elevated mood in control patients and potentiated the antidepressant effect of MAOI [21]. Set against this, combination of an MAOI with DOPA did not produce a therapeutic benet [22]. Additionally, the therapeutic effect of MAOI and TCA drugs was later shown to be blocked by the administration of 5-HT synthesis inhibitors [23,24]. The 5-HT hypothesis gained signicant weight with the introduction of the selective serotonin reuptake inhibitors (SSRI) in the mid-1970s, which soon became the main prescribed antidepressant medication. Indeed the success of SSRIs led to the role of 5-HT in depression and antidepressant therapies dominating thinking in scientic and drug company research throughout the 1980s. However, these monoamine hypotheses do not address the fact that alterations of neurotransmitters occur after acute administration of the pharmacological agents, whereas the onset of therapeutic action requires 24 weeks. Indeed, although tolerance develops to the side-effects of SSRIs the opposite appears to be the case with their therapeutic effects continuing to grow over time [25]. Additionally, the fact that antidepressants do not elevate mood in healthy individuals does not t with the original hypothesis. The time lag in current SSRI antidepressant medications is believed, at least in part, to be due to desensitization of 5-HT1A autoreceptors, which occurs over a 4-week period [26,27]. The increase in 5-HT levels in response to reuptake block is partially offset initially by activation of these autoreceptors, which decreases cell ring [28]. In view of this, a number of 5-HT1A-receptor antagonist drugs have been used in attempts to augment and accelerate antidepressant drug actions. Despite animal studies demonstrating the clear efcacy of pindolol (a 5-HT1A-receptor partial agonist and b-adrenoceptor antagonist) in achieving this [29,30], clinical studies have been ambiguous (see Artigas et al. for review [31]).
There are a number of possible reasons for this, such as sample population, and the fact that pindolol is a partial agonist. Additionally, it is believed that the therapeutic effects of increasing 5-HT levels are due to action on 5-HT1A postsynaptic receptors as buspirone (a 5-HT1A agonist) displays some antidepressant properties [32,33]. Therefore, the postsynaptic actions of pindolol may offset the presynaptic ones. A more specic compound that only blocked presynaptic 5-HT1A-receptors may be more successful in accelerating the clinical onset of current medications. Other approaches Post-mortem studies also remain equivocal about the levels of neurotransmitters in depression and their receptors and transporters. There are numerous reports showing elevated, no alteration, or decreases in monoamine metabolite levels, monoamine receptors and uptake sites, in the studies examining them (see Cheetham et al. [34] for review). One of the more consistent ndings from postmortem brains are elevated levels of 5-HT2 receptor levels in the frontal cortex of suicide victims [3537]; a group which contains a signicant proportion of depressed patients [38]. Additionally, the antidepressants mirtazapine, mianserin, trazodone and nefazodone all have 5-HT2 antagonistic properties, which are believed to suppress the serotonergic inhibition of noradrenergic neurones and decrease serotonergic side-effects [3942]. Depletion studies have been performed over the course of the last 20 years in a further attempt to elucidate the role of NA and 5-HT in depression. In the 1970s administration of parachlorophenylalanine (an inhibitor of tryptophan hydroxylase) produced a relapse in depressive symptoms of treated patients [24], but it is considered too toxic for use today. Therefore, tryptophan depletion paradigms have been used to reduce 5-HT levels in the brain, and are performed by giving a drink loaded with amino acids, except tryptophan. In animals, such depletion is known to increase pain sensitivity, motor activity, aggression and decrease rapid eye movement (REM) sleep, all behaviours used to measure 5-HT function [4345]. Control patients subjected to tryptophan depletion, do not demonstrate a lowering of mood [4648]. Similarly, untreated depressives subjected to this paradigm do not demonstrate any worsening of symptoms, which was a surprise as it was hypothesized that there would be a further decline in mood in response to lowering of 5-HT levels [4951]. This could be due to the fact that the 5-HT system is already diminished and
Raphe SRIs
Forebrain
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5-HT1B 5-HT1D 5-HT2C 5-HT2A 5-HT3
5-HT neuron
ve
5-HT1A
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5-HT 5-HT
ve
Pindolol
Figure 2 Mechanism of action of serotonergic antidepressants and pindolol. Schematic diagram showing the interaction of different antidepressants at the level of the 5-HT neurone. Blockade of reuptake results in increased NA concentration in the synaptic cleft, whilst blockade of presynaptic 5-HT1A-receptors by pindolol results in inhibition of 5-HT-mediataed negative feedback. Blockade of 5-HT reuptake increases 5-HT concentration in the synaptic cleft and pindolol prevents negative feedback of 5-HT on presynaptic 5-HT1A receptors.
that a further decline has no effect, or that downstream responses to 5-HT function are the main component of depression. However, in an SSRI treated group, tryptophan depletion causes a relapse in depressive symptoms and especially in those whose symptoms had remitted for under 2 weeks while having little effect on patients treated with mainly noradrenergic drugs [5254]. The opposite holds true for catecholamine depletion studies using a-methyl-p-tyrosine (an inhibitor of tyrosine hydroxylase). Patients treated with noradrenergic drugs relapse more frequently than those treated with serotonergic antidepressants [55] (Figure 2). Dopamine With discrepancies emerging regarding the NA and 5-HT theories of depression, the 1970s saw DA postulated to play a critical role in depression and antidepressant action. It had been known that drugs such as amphetamine and cocaine elevated mood and DA release. This knowledge, coupled with the knowledge that reserpine depleted DA, in addition to NA and 5-HT, to produce sedation and severe depression in some patients provided evidence for DA playing a signicant role in depression. Additionally, Serra et al. [56] examined the role of antidepressants on dopaminergic neurotransmission, demonstrating that chronic imipramine, amitriptypline and mianserin treatment prevented or reversed the sedative effect of low doses of apomorphine. This nding
has since been replicated for other antidepressants, ECT treatment and REM sleep deprivation [5759]. This is believed to reect an increased sensitivity of postsynaptic DA receptors induced by chronic antidepressant treatment, as opposed to the initial belief that it was due to a subsensitivity of D1-autoreceptors [57]. Early autoradiographical studies utilizing DA agonists provided inconsistent ndings, but the advent of selective DA antagonists provided ndings consistent with DA postsynaptic modulation by antidepressants. These antagonists revealed an increased D2/D3-receptor number following chronic antidepressant treatment, particularly in the nucleus accumbens, but also in the striatum [6064], and increased D2 mRNA expression [6567]. This may relate to part of the therapeutic prole of the antidepressants, given the role of the nucleus accumbens in pleasure, which is impaired in depressed patients. A recent animal study by Lammers et al. [68] reported that a common effect of chronic antidepressant treatment was a selective increase in D3 receptor gene expression in the shell of the nucleus accumbens. Desipramine, imipramine, amitriptyline and tranylcypromine all elevated D3 mRNA in this region after 21-day treatment. Interestingly, uoxetine following 42-day administration, despite signicantly decreasing D3 mRNA levels, prevented the downregulation of D3-receptors caused by handling stress, as did imipramine. ECT produced the largest increase of the treatments, both mRNA and D3 receptor number, which is in accordance with clinical efcacy [68]. Lending weight to the DA theory of depression are a number of dopaminergic compounds, which have been successful in treating depression; bupropion [69], nomifensine (also a potent inhibitor of NA-uptake; [70,71]) and amineptine [72]. Pramipexole, a primarily D3-agonist has been approved for use in Parkinsons disease but has also been shown in two animal models, the forced swim test (FST) and exposure to chronic stress, to be antidepressant-like [7375]. Although no largescale clinical trials have been performed, a small-scale trial by Ostow with 22 patients, demonstrated not only that pramipexole augmented previously ineffectual antidepressant treatments, but that it signicantly improved mood alone with relatively few side-effects [76]. However, it is clear that a larger trial will have to be performed to validate these ndings. Another line of evidence supporting a role of DA in depression comes from Keck et al. [77], who successfully demonstrated that repetitive transcranial magnetic stimulation (rTMS) elevated DA in the hippocampus,
Enzyme inhibitors
1950s MAOIs
Uptake blockers TCAs
Receptor blockers
1960s Subtypeselective MAOIs NA selective 5-HT selective Mianserin
1970s
Trazodone SSRIs Nefazodone Mirtazapine
1980s 1990s RIMAs NARIs SNRIs
Figure 3 Summary of monoamine drug treatment evolution.
nucleus accumbens and striatum; the rst in vivo evidence that rTMS acutely increases DA concentration. A previous study by Keck et al. [78] revealed an increase in DA but not in 5-HT and NA in the hippocampus, providing evidence that DA may play a role in the use of rTMS in affective disorders. These ndings have also been supported by a clinical study showing that rTMS decreased [11C]-raclopride binding [79]. This evidence is suggestive of alterations in the dopaminergic system in depression, which, at least partially, are redressed by antidepressant treatments. However, it is unknown whether this is secondary to changes in other monoaminergic systems given the interaction between DA and these. Taken as a whole, the body of literature dealing with monoamine decits in depression does not satisfactorily provide clear evidence for one neurotransmitter being central to the aetiology. Both serotonergic and noradrenergic compounds are equally useful in treating patients, and there are also a number of dopaminergic drugs that are successful in treating depression. This may also reect different underlying heterogeneity of depressive disorders. It is clear that these drugs, which raise monoamine levels in the synapse, have been very successful in the treatment of depression. What still remains unclear is whether disruption of these systems results in depressive disorders (Figure 3). HYPOTHALAMICPITUITARY ADRENAL (HPA)-AXIS Due to the incomplete nature of the monoamine theories of depression research has attempted to determine other systems that may be involved in depression, and therefore, potentially benecial treatment options. One
of the most consistent ndings in depressed patients is hyperactivity of the HPA-axis, as demonstrated by increased cortisol levels, enlargement of the pituitary and adrenal glands and decreased glucocorticoid receptor (GR) sensitivity [8084]. These alterations are believed to be secondary to hypersecretion of corticotrophin-releasing factor (CRF), as highlighted by increased concentrations in cerebrospinal uid (CSF) of major depressive disorder (MDD) patients, increased CRF protein and mRNA levels in the paraventricular nucleus of the hypothalamus and a blunted adrenocorticotrophic hormone (ACTH) response to CRF challenge [83,85,86]. Dexamethasone challenges in depressed patients consistently reveal an impaired feedback of the glucocorticoid system on CRF levels, which suggests altered GR function [87]. Therefore, extensive research into HPAaxis abnormalities has been performed in attempts to understand their role in the aetiology of depression and to design potential antidepressants. There are two main receptors for CRF; CRFR1, which is located mainly in the CNS, and CRFR2, which is more abundant in peripheral tissues. Mice, lacking a functional CRFR1, display an impaired stress response, as indicated by steady-state levels of ACTH and corticosterone following exposure to stressful stimuli [88]. Chronic amitriptyline has been shown to decrease CRF1 mRNA levels in the amygdala [89]. Additionally, the nonpeptide CRF antagonist, CP-154, 526, reversed escape decits in rats with learned helplessness and also prevented the development of learned helplessness [90]. Increased CRF binding sites in the dorsal raphe nucleus, which is the major origin of serotonin activation of the forebrain, have been demonstrated in depressed patients [91]. CRF has also been immuno-localized in the raphe nuclei and the locus coeruleus implying a possible role in its modulation of monoamine pathways [92]. The CRF has been proposed to mediate the physiological and behavioural responses to stress, and it is the principal component of the HPA-axis therefore, co-ordinates the hormonal response to stress [93]. When CRF is applied to patients with depression a dull ACTH response is observed [94]. Moreover, Holsboer et al. demonstrated that depressed patients, pretreated with dexamethasone, displayed higher ACTH and cortisol responses to CRF compared with controls [86]. Indeed, this last test seemed to be an accurate measure for diagnosing depression. Interestingly, pretreatment of depressed patients with metyrapone (a glucocorticoid synthesis inhibitor) normalized ACTH activity following injection of CRF [94]. Substantial decreases in CRF
concentration in 15 depressed women who had remained depression-free for 6 months have been reported [95]. However, CRF concentrations do not correlate with depression severity but the results from these studies implicate the requirement of normalization of CRF concentrations following antidepressant treatment to prevent a relapse [92]. A number of clinical trials are ongoing to provide more conclusive evidence of CRF antagonists antidepressant efcacy and represent a nonmonoamine treatment of depression (see Holsboer for a review of the rational for CRF antagonists use in depression [96]). Antidepressants, both individually, and in conjunction with anti-glucocorticoid agents, reverse a number of the HPA-axis abnormalities displayed by depressed patients. Ketoconazole and metyrapone, inhibitors of steroid production, is believed to alleviate depression in some individuals by decreasing cortisol levels, as there is a close relationship between cortisol levels and scores on the Hamilton Depression Rating System (HDRS) [97]. This nding, coupled with similar studies, has given rise to the glucocorticoid hypothesis of depression. This theory states that alterations to the HPA-axis are necessary for the development of depression and restoration of the HPA-axis to normal glucocorticoid function will have a therapeutic effect [98]. Stressful events activate the HPA-axis and thereby glucocorticoid synthesis via CRF and ACTH. Long-term increases of these substances are believed by some to be the cause of the anatomical and psychological alterations in patients with depression or any stress-related illness [99]. Animal studies revealed that metyrapone and glucocorticoid antagonists reduced the immobility time in the FST. Antidepressant activity of metyrapone is abolished by corticosterone administration, providing further evidence of an HPA-axis mechanism of action [100]. In one small-scale clinical study, metyrapone was shown to have antidepressant activity in eight depressed patients; however, constant monitoring of plasma cortisol was required for safety purposes, therefore it is obviously not a viable antidepressant [101]. Olfactory bulbectomized (OB) rats, which are used as an animal model of depression, display HPA-axis abnormalities, including increased nocturnal secretion of corticosterone and a hypersecretion of cortisol which is not suppressed by the administration of dexamethasone, and heightened responses to stress which can be normalized by antidepressant administration (for review of OB rats see Kelly et al. [102]). Metyrapone, in a
dose-related manner, decreased the immobility time of OB rats subjected to the FST [98]. The fact that metyrapone and established antidepressants reduce the immobility time in OB rats provides further evidence of an HPA-axis involvement in depression. Tronche et al. [99] created adult mice, lacking GR activity in specic regions, which demonstrated resultant increases in glucocorticoid levels due to the loss of HPA-axis feedback regulation. Furthermore, these mice could not adapt to stress as shown by the Porsolt FST. These alterations in glucocorticoid levels present in depression may be secondary to changes in CRF activity. Finally, the majority of animal studies examining the effect of chronic antidepressant administration on GR mRNA and protein levels demonstrate an upregulation, except from SSRIs, mianserin and oxaprotaline (see Pariante et al. for a review [87]). However, the mechanism by which antidepressants achieve this upregulation remains unclear, as does the reason why SSRIs, which are currently the most prescribed drugs, do not alter GR levels. Further understanding of HPA-axis abnormalities in depression are required before such questions can be answered but drugs which modulate this system are currently, alongside the traditional monoamine approach, the most likely candidates for new antidepressants. NEWER APPROACHES TO THE TREATMENT OF DEPRESSION A number of novel research approaches to the treatment of depression have emerged over the course of last decade. These have arisen due to the lack of universal success of monoamine antidepressants and the lack of suitable HPA-axis modulators. The novel targets are being pursued in attempts to design antidepressants with faster onsets of action and more universal efcacy. Many of these targets directly, as in the case for H3 compounds, or indirectly, such as cytokines, increase monoamine levels. Therefore, although the target system may be novel, it may be as a consequence of an alteration of monoamine levels, which leads to their antidepressantlike properties. Additionally, cigarette smoking and the herb Hypericum perforatum are medications, which are commonly used by depressed patients, while only Hypericum of the two is a prescribed antidepressant; and that only in Germany. The remainder of the review examines a number of these novel approaches briey describing the rational behind their study, then outlining preclinical data and any instances were clinical data are available.
Cytokines It is widely accepted that there are a number of alterations of the immune system observed in major depression; particularly increased levels of pro-inammatory cytokines [103]. However, it is unclear whether this is as a result of depression, or a causal effect. In argument for the latter, interleukin (IL)-2 and interferon (IFN)-a have been used to treat patients with hepatitis C and some cancers but both frequently produce depressive symptoms, within a few days in the case of IL-2 and 34 weeks for IFN-a [104]. There are also a number of interesting coincidences between depression and the immune system, for example women have been reported to have a higher level of immune activation than men [105] and depression is twice as common in women, while childbirth provokes secretion of cytokines, which has been postulated to contribute to postnatal depression [106]. Furthermore, cytokines can alter many of the systems known to be altered in depression, such as monoamines and the HPAaxis, and therefore potentially may be able to address the discrepancies in a number of abnormal systems in depression. This evidence prompted the macrophage theory of depression, which states that oversecretion of pro-inammatory cytokines, such as (IL-1, tumour necrosis factor-a and IFN-c are responsible for at least some cases of major depression [107]. A number of the overactive immune responses, which occur in depressed patients, including monocyte phagocytosis, serum IL-b concentration and serum IL-6 are normalized by antidepressant treatment [108]. Perhaps most interestingly, in view of the monoamine hypotheses are reports that have found increased serum antiserotonin antibody titres and increased serum antibodies against gangliosides, which are part of the serotonin receptor in depressed patients [109,110]. These ndings may be indicative of an autoimmune reaction against certain elements of the serotonergic system in patients with depression. Further research is required before the signicance of these ndings can be ratied [109,110]. Studies on the effect of overactive immune systems, such as seen in depressed patients, have found that agents, which activate the immune system of rats, cause signicant alterations in the release and turnover of monoaminergic transmitters in various parts of the brain [111,112]. Increased 5-HT transporter activity following IL-1 administration has been shown, which would effectively reduce the concentration of 5-HT in the synapse [113]. The fact that the immune system can interfere with monoaminergic pathways in the brain has
led some researchers to hypothesize that immune changes cause the abnormalities in transmitter function in the brains of at least some depressed patients [106]. It is feasible therefore that antidepressants may alter immune function, which then contributes to the alterations in neurotransmitter function found in depression. Pro-inammatory cytokines are also well documented to cause HPA-axis activation and therefore, it is possible that the oversecretion of CRF in depression may be to some extent due to cytokine activation. In one study, chronic treatment with different classes of antidepressant, e.g. imipramine, uvoxamine and maprotiline signicantly increased the production of IL-1 receptor antagonist (IL-1ra) mRNA in specic regions of the rat brain. These included the hippocampus, frontal cortex, hypothalamus and brainstem by up to 100-fold [114], but these ndings have been difcult to reproduce. However, they raise the possibility that one mechanism by which antidepressants act is to cause an inhibition of the IL-1 receptor thereby counteracting the increased production of IL-1. This hypothesis is strengthened by a study, which demonstrated that treatment with IL-1ra prevented the development of learned helplessness in rats [115]. Interleukin-1ra may therefore provide a novel therapeutic strategy for the treatment of depression and clinical trials are required to determine this possibility. Small nonpeptide molecules, which are more general antagonists of pro-inammatory cytokines may be more viable as treatments, as although IL-1ra may normalize a number of the immune system abnormalities displayed in depression, it may also produce more side-effects. Neurokinins Non-peptide antagonists have been synthesized for the substance P preferring neurokinin-1 (NK1) receptor and promised a breakthrough in the treatment of many diseases. However, this appeared unfounded as trials failed to prove efcacy of substance P antagonists in pain, which was believed to be their most likely use. The breakthrough came when several trials demonstrated that NK1 antagonists were effective in treating emesis and surprisingly depression given the preclinical data [116,117]. The NK1-receptor antagonists were shown to possess antidepressant-like properties in inhibiting stress-induced vocalizations in guinea-pigs, and recently a selective NK2-receptor antagonist, SR48968, was also shown to display antidepressant-like properties in both the FST and in maternal separation of guinea-pig pups [118].
Table I Antidepressant properties of neurokinin antagonists.

Similar antidepressant activity of NK1-receptor antagonist as paroxetine in clinical trial Inhibition of stress-induced vocalizations in guinea-pigs by NK1-receptor antagonist NK2-receptor antagonist active in forced swim and maternal separation models of depression Recent synthesis of a dual NK1-receptor antagonist and 5-HT uptake inhibitor
In a randomized double blind trial MK-0869 (a nonpeptide substance P antagonist; 300 mg) showed similar antidepressant activity as that of paroxetine (20 mg) on the HDRS, moreover there was a very low incidence of sexual dysfunction reported [119], which is one of the major reasons for noncompliance with SSRI antidepressants. A major benet of MK-0869 is its safety and it also has less side-effects than paroxetine but it produced more irritability, which may be as MK-0869 does not increase serotonin activity [119,120]. It also appears that MK-0869 does not enhance NA function, as 14 days of administration did not downregulate the number of b-adrenoceptors in rats (Table I). This substance P approach received a setback with the high placebo response rate in a subsequent trial and more studies will be required to verify whether substance P antagonists can be used to treat depression, and to that end more selective NK1-receptor antagonists may be helpful (see Stout et al. (117) for a review of NK1 antagonists). Ryckmans et al. [121] reported the synthesis of a dual NK1-receptor antagonist and 5-HT reuptake inhibitor, which may offer added therapeutic advantages by coupling the known antidepressant benet of SSRIs with that of the potential antidepressant properties of NK1-receptor antagonism. cAMP response element binding protein (CREB) and brain derived neurotrophic factor (BDNF) A common nding in animal studies is that, when administered chronically, almost every antidepressant elevates CREB, and its active form pCREB in the hippocampus and cerebral cortex [122125]. CREB is a downstream component in the cAMP cascade system, which in its phosphorylated form pCREB, induces BDNF expression and this in turn leads to neurogenesis, neuronal survival and neuronal plasticity [126]. Therefore, it is conceivable that increased CREB and BNDF levels may contribute to the therapeutic role of antidepressants. Moreover, cell loss and decreased hippocampal volume and increased ventricle size, indicative of
decreased volume of the cortex, have been reported in depressed patients [127129]. Preclinical studies using CREB mutant mice lacking two of the three CREB isoforms, demonstrated that these animals display less baseline immobility in the FST than controls. Additionally, antidepressant administration prevents the increased corticosterone levels due to swim-stress [130]. However, antidepressant administration in these mice does not lead to elevated BDNF levels, suggestive that CREB is necessary for the long-term neuro-adaptive responses to antidepressants but not the acute responses in animal models of depression. In agreement with the ndings from laboratory animals, Dowlatshahi et al. [131] reported increased CREB levels in postmortem brains of antidepressanttreated subjects compared with antidepressant drug-free patients. In the contrary, Odagaki et al. [132] found increases in CREB and pCREB immunoreactivity in depressed patients compared with controls, specically in the antidepressant drug-free group. Therefore, similar to postmortem monoamine metabolite and receptor density studies CREB postmortem ndings remain equivocal. However, the results from animal studies support the idea that CREB activating agents may be potentially antidepressant in humans. The BDNF is the most widespread growth factor in the brain and is responsible for neuronal survival and is activated by a number of stimuli including pCREB [133]. Both chronic antidepressant and ECS therapies have been demonstrated to increase BDNF levels in rats and its transmembrane receptor tyrosine kinase B [133135]. Moreover, infusions of BDNF into the adult rat neocortex resulted in 5-HT nerve terminal growth and regrowth after destruction by para-chloroamphetamine, especially in the CA3 region of the hippocampus [136]. Administration of BDNF has been demonstrated to display antidepressant-like properties in two animal models of depression; the FST and learned helplessness. One study utilized osmotic minipumps to continually infuse BDNF for 7 days into the midbrain [137]. A more recent study has demonstrated that a single injection of BDNF into the dentate gyrus or CA3 region of the hippocampus is antidepressant-like in these two models, moreover this effect lasted for 10 days [138]. In a recent study a decrease in serum levels of BDNF in major depressed patients was reported [139] and in a separate study postmortem brains of antidepressanttreated patients were shown to display an increase in BDNF-immunoreactivity in the hippocampus and cerebral cortex [140]. Stress has also been demonstrated to
BDNF
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BDNF
Figure 4 Current antidepressants proposed action via CREB and BDNF. Adapted from Skolnick [142].
decrease BDNF mRNA expression in rat brain, and it is well established that stressful events often precede the development of depression in susceptible individuals [141]. Taken together these ndings support an alteration in BDNF levels in depression, which can be normalized by antidepressant administration and drugs that mimic the actions of BDNF may therefore be successful treatment options (Figure 4). Drugs which can lead to the upregulation of any of the factors in the CREB and BDNF cascade have the potential to have antidepressant activity. At present a number of researchers are attempting to nd novel small nonpeptide molecules, which mimic the action of BDNF with the goal of treating a wide variety of neurodegenerative diseases and depression. NMDA N-methyl-D-aspartate (NMDA) receptors have in the past decade been implicated in depression as a result of preclinical studies, postmortem studies and clinical trials. This body of research has lead to the hypothesis that NMDA receptor antagonists may be therapeutically effective antidepressants. Animal studies have shown some NMDA modulators, 2-aminophosphonoheptanoic acid (a competitive NMDA antagonist), 1-aminocyclopropanecarboxylic acid (ACPC, a glycine partial agonist) and dizocilpine (a use-dependent channel blocker) all reduce immobility time in the FST [143]. Additionally, competitive NMDA antagonists display antidepressant-like activity in the Willner chronic mild stress model [144]. Furthermore, the ACPC effect was reversed by glycine, indicative of a
specic action on the glycine site of NMDA receptors. Further research conrmed these ndings (see Skolnick and Petrie et al. [142,145] for reviews) and represents a signicant body of evidence supporting a role for NMDA receptors in depression. However, acute and repeated administration of ACPC (400 mg/kg; 14 days) followed by the same dose 24 h or 4 days later did not signicantly reduce immobility time in the FST, which implies a tolerance to the antidepressant-like property of ACPC [146]. In addition to these ndings, in animal models, it has been demonstrated that chronic antidepressant administration can alter NMDA receptor function. Chronic imipramine (15 mg/kg i.p. for 14 days) was shown to decrease basal [3H]-MK-801 binding and also decrease the proportion of high afnity glycine sites in the cerebral cortex but not other brain areas [147]. Subsequent radioligand binding studies support the original ndings of Nowak (see Skolnick [142] for review). There appears to be a more widespread alteration in mRNA levels encoding NMDA receptor subunits following chronic antidepressant treatment. Skolnick reviewed the currently available research utilizing in situ hybridization to show the changes in NMDA receptor subunit mRNA. Additionally, the loss of glial cells in major depression could potentially lead to an increase in glutamatergic activity as they express glutamate transporters, which provide the main mechanism for removing glutamate from the synapse [148,149]. There has also been a postmortem study of suicide victims revealing a decrease in the number of glycine binding sites on the NMDA receptor in the frontal cortex [150], which acts as a co-agonist at NMDA-receptors (Table II). One small clinical trial studied the effects of ketamine (a use-dependent NMDA channel blocker) in patients who were unresponsive to available antidepressants. Those who received 0.5 mg/kg ketamine for 40 min had improved symptoms for up to 72 h [151].
Table II Evidence that NMDA antagonists display antidepressantlike properties.
NMDA antagonists, glycine partial agonist and channel blocker display antidepressant-like properties in FST Chronic imipramine decreases basal [3H]-MK-801 binding Alteration of mRNA levels encoding NMDA-receptor subunits is observed following chronic antidepressant treatment Glial cell loss could lead to increased glutamatergic activity due to decreased glutamate transporters Ketamine acutely improved symptoms for up to 72 h in depressed patients
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Taken together the preclinical and clinical evidence supports a possible role for drugs which downregulate NMDA receptor function and is a further example of a nonmonoamine approach to the treatment of depression. GABA and neuroactive steroids Because of the reciprocal links between the c-aminobutyric acid (GABA) and glutamate systems if NMDA antagonists are potential antidepressants then GABA agonists might also be therapeutic. Injection of bicuculline (a GABAA receptor antagonist) into the hippocampus produces learned helplessness, an animal model of depression, whereas injection of GABA into the hippocampus prevented and reversed learned helplessness [152]. Additionally, Lloyd et al. [153] demonstrated that GABAB receptors are downregulated in the frontal cortex in the animal models learned helplessness and OB rats, and are normalized following chronic TCA administration [154]. CGP36742 (a GABAB agonist) improves learned helplessness to a similar degree as imipramine, all data suggests that GABAA and GABAB agonists display antidepressant-like properties in animal models of depression. The rst clinical evidence demonstrating that an (indirect) GABA agonist (valproate) was effective in treating bipolar depression was performed by Emrich et al. [155]. Fengabine, a GABA agonist pro-drug has also shown clinical efcacy in treating depression [156] and was demonstrated to have a faster onset than clomipramine [157]. Numerous clinical studies have found that GABA concentrations are reduced in the CSF, blood and postmortem brains of depressed patients in comparison with controls (see Shiah [158] for review). Two studies have shown that antidepressant treatment decreases [3H]-unitrazepam binding to the benzodiazepine recognition sites but antidepressants appear to have no effect on the GABAA receptor binding sites. Desipramine, maprotiline and amitriptyline inhibit GABA transporters [159], which may explain the sedative effects of some antidepressants if not their antidepressant action. The preclinical and clinical data support the hypothesis that GABA function is altered in depression and both GABAA and GABAB agonists represent a novel therapeutic target for its treatment. Further support of a GABA involvement in depression comes from research into neuroactive steroids (for a review on neuroactive steroids see Baulieu [160]). There is convincing evidence that the neuroactive steroids 3a, 5a-tetrahydroproges-
terone (THP) and 3a, 5a-tetrahydrodeoxycorticosterone (THDOC) are both positive allosteric modulators of GABAA receptors at concentrations ranging from 10)810)5 M [161]. In addition, levels of neuroactive steroids are increased in response to stress and it has been suggested that this is to restore the GABAergic tone. Following antidepressant administration the concentrations of 3a, 5a-THP and 3a, 5a-THDOC in the rat brain were increased, particularly in the OB, but there was no alteration in plasma levels [162]. A recent human study supports the view that these agents may be of relevance; an imbalance in the concentrations of 3a, 5a-THP and 3a, 5a-THDOC in depression was rectied by uoxetine and uvoxamine administration. Interestingly, the small group of control patients in the study had higher levels of neuroactive steroids than patients with major depression [163]. It is conceivable that such an imbalance in neuroactive steroids represents a risk factor in depression or is one result of depression and that a possible therapeutic action of current antidepressants is to redress this [164]. Direct administration of 3a, 5a-THP and 3a, 5a-THDOC, other yet unidentied neuroactive steroids, or synthetic ligands therefore represent a potential class of antidepressant drugs with a novel nonmonoaminergic mechanism of action. Opioids and cholecystokinin (CCK) Opioids at one time were rst-line antidepressants but due to the severity of their adverse they are no longer clinically acceptable [165]. However, substantial research has been performed to separate the clinically benecial properties of opiates and their side-effects. If achieved this could lead to the use of opioids in a number of diseases including depression. The SSRIs and TCAs cause an increase in the concentration of enkephalins, and uoxetine increases l-opioid receptor levels in the rat forebrain [166]. Opioids have a basal inhibitory effect on the HPA-axis, which is hyperactive in patients with depression, and naloxone (a nonselective opioid antagonist) in high doses blocks this action and precipitates a rise in ACTH and cortisol [167]. Injection of naloxone in 13 depressed patients revealed a signicantly lower mean cortisol response compared with the controls, although there was no signicant difference in basal cortisol levels. Despite the small size of this study, it suggests that the basal opioid level in the HPA-axis is decreased in patients with depression and adds further evidence to an opioid inuence in depression [167].
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Cholecystokinin, a neuropeptide which is co-localized with opioids in a number of brain regions, can modulate the antidepressant-like activity of opioids as CCKBreceptor but not CCKA-receptor antagonists enhance the antidepressant-like activity of opioids [168,169]. Co-administration of RB 101 (an inhibitor of enkephalin catabolism) and a noneffective dose of PD-134,308 a CCKB receptor antagonist) potentiated the antidepressant-like ability of RB 101 to decrease the conditioned suppression of motility, to similar levels as imipramine and amitriptyline [169]. In summary, administration of an enkephalin inhibitor alone, or in conjunction with a CCKB receptor antagonist may represent potential antidepressant targets but more research is required. Histamine The release of monoamine and acetylcholine transmitter can be directly modulated by the H3 receptor, which acts as a heteroreceptor [170]. Therefore, compounds that affect H3-receptors may display similar characteristics to the known monoaminergic antidepressants. Additionally, stress has been shown to decrease H3 receptor number in the rat cortex, while amitriptyline not only reverses this but increases the receptor density in control rats [171]. This knowledge, coupled with the widespread distribution of H3 receptors in the CNS, provides the possibility that ligands for the receptors could be benecial in the treatment of depression and a number of animal trials have been performed to examine this possibility. Thioperamide, a H3-receptor antagonist, has been shown to have antidepressant-like activity in the FST [170,172]. Thioperamide also contains some activity at 5-HT3 receptors that may contribute to the antidepressant-like effect [173] but clobenpropit, which is a more selective H3 receptor antagonist, has an antidepressantlike action in the FST [170], suggesting antagonism of H3-receptors alone provides an antidepressant-like effect. The animal studies to date, coupled with the knowledge that H3 heteroreceptors alter monoamine release, indicate a possible therapeutic effect of H3 antagonists in the treatment of depression but more research is required to validate the current evidence. This is especially with regard to utilizing additional animal models to further the evidence from the FST. Potassium channel blockade Another novel target for the treatment of depression, which has been discovered largely due to ndings from
Table III Potassium channel modulators and depression.

Fluoxetine blocks mKv1.1 and mKv1.3 channels at therapeutic concentrations K+ channel openers increase immobility time in the FST K+ channel blockers display antidepressant-like properties in the forced swim
the FST, is potassium channel blockade. Pre-treatment with subactive doses of glyburide (an ATP-sensitive K+ channel blocker) potentiated the reduction in immobility time of mice treated with a number of classes of antidepressant [174]. Furthermore, ATP-sensitive K+ channel activators (cromakalim, minoxidil and pinacidil) have been demonstrated to increase time that mice remain immobile while tetraethylammonium, apamin, charybdotoxin and gliquidone, which block a variety of K+ channels, show antidepressant-like properties in this model [175,176]. Taken together, these studies provide evidence that K+ channels may play an important role in depression, with K+ blockers being potential antidepressants (Table III). Further evidence for K+ channel involvement in depression comes from the knowledge that uoxetine inhibits voltage-activated potassium channels with an IC50 at mKv1.3 channels of 5.9 mM [177] and 55 mM for mKv1.1 channels [178]. The IC50 value suggests that potassium channel blockade may be an effect of uoxetine that occurs at therapeutic values and represents a novel approach that could be pursued. Potassium channel blockade therefore represents a novel therapeutic target for the treatment of depression and warrants further research. Obviously, much more preclinical research is required, especially with regard to different animal models being utilized. Nitric oxide synthase (NOS) inhibitors The activation of ligand-gated NMDA receptor results in an inux of Ca2+ into the cell, which can lead to the formation of nitric oxide (NO) by activation of NOS. As stated earlier NMDA receptor antagonists possess antidepressant-like properties and it is conceivable that this may be due in some part to preventing NO formation. There have been a small number of preclinical reports regarding NOS inhibitors exhibiting antidepressant-like properties. The NOS inhibitors guanidino nitrogen (NG)-nitroG L-arginine (L-NNA), N -nitro-L-arginine methyl ester G (L-NAME) and N -monomethyl-L-arginine (L-NMMA) dose-dependently alter immobility time in the mouse
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FST in a U-shaped response. Lower doses of the NOS inhibitors reduced the immobility time but higher doses resulted in immobility times comparable with saline only. These reductions were not accounted for by an increase in locomotor activity. It has been hypothesized that this is due to NO regulating NMDA receptor function bi-phasically; positive modulation via guanylate cyclase and negative modulation by feedback mechanisms on NMDA receptors [179]. It was also suggested that higher concentrations of NOS inhibitors impair cerebrovascular circulation or cause a loss of coordination and locomotor activity. Prior administration of L-arginine, which is a precursor and therefore increases NO concentrations, did not signicantly inuence the immobility time but it did prevent the reduction seen by L-NNA. Similarly and perhaps more importantly L-arginine pretreatment reversed the ability of imipramine to decrease immobility time [179]. Glycine pretreatment, however, has been shown not to alter the immobility time of imipramine [143]. This implies that imipramine alters NO levels but not via the NMDA receptor. L-NNA in chronic doses also downregulates the b-adrenoceptor density to a level comparable with that caused by imipramine [180]. Taken together these ndings provide evidence that NOS inhibitors possess antidepressant-like activity and constitute a novel therapeutic target for the treatment of depression. Imidazoline receptor ligands The a2-adrenoceptor agonists clonidine and idazoxan were noted in the early 1980s to label a further distinct binding site, which has been termed imidazoline binding sites, due to the selective ligands containing imidazoline moieties. The two main subtypes of imidazoline binding sites, I1 and I2, based on their preference for clonidine and idazoxan, respectively [181]. Utilizing more selective ligands than the original two compounds I1 and I2-sites have been demonstrated throughout the brain and both these sites have been hypothesized to play an important role in depression. The I2-sites present on MAO are located at a ligand binding domain distinct from the catalytic binding domain of the enzyme [182,183], which might explain why I2-selective compounds elevate 5-HT and NA [184]. With the success of MAOIs at treating depression I2-selective compounds may represent a novel class of drug to modulate monoamine levels in the brain and therefore display antidepressant potential. Furthermore, the I2-ligands, 2-BFI and BU224, have been demonstra-
ted to reduce the immobility time in the Porsolt FST at lower doses to the antidepressant effect caused by desipramine [185,186]. Studies linking I1-sites with depression have shown increased sites in platelets of untreated depressed patients [187,188], which can be normalized following chronic treatment with uoxetine or desipramine [189]. Similar ndings have been demonstrated in rat brain, where chronic imipramine treatment downregulate I1-site binding in the brainstem [190]. Contrary to the I1-site ndings, a downregulation of I2-sites have been reported in the frontal cortex of suicide victims using both radioligand binding and Western blotting despite no signicant alteration of [3H]-RX821002 (a selective a2-receptor antagonist) binding [191,192]. Additionally, chronic imipramine has been demonstrated to upregulate I2-sites in rat midbrain [193]. Therefore, agents that alter I1- or I2-sites may treat depressive symptoms, in some individuals, and I1-selective compounds may represent a novel treatment strategy. Nicotine Nicotine shows that not all novel approaches to depression have come from preclinical research. Smoking has a number of intriguing links with major depression and depressive episodes. For instance, depression in some individuals is a symptom of quitting smoking [194], which can be reversed by either recommencing smoking [195] or antidepressant administration [196]. Patients with major depression, or with depressive symptoms also have a higher occurrence of cigarette smoking [195,197], and show a higher tendency to smoke than the general population [198]. These ndings explain the rational behind research into nicotine, or a similar agent, as a possible antidepressant. It has been hypothesized that the reason for the elevated smoking levels among patients with major depression is an attempt at self-medication using nicotine, the major psychoactive component of cigarettes [199]. Nicotine increases the concentration of the monoamines 5-HT and NA, as well as DA [200,201] and may induce its putative antidepressant efcacy via these two neurotransmitters. Behavioural studies in animal models of depression have also revealed potential antidepressant effects of nicotine. Rats with learned helplessness, implanted with subcutaneous nicotine, released at 1.5 mg/kg/day (which correlates to plasma levels of one pack of cigarettes a day) produced a signicant reversal of escape decits [202]. However, nicotine may be acting by improvements in memory
13
and/or learning [203] and not an antidepressant-like mechanism. Flinders Sensitive Line (FSL) rats display a higher sensitivity to certain anticholinesterases and muscarinic agonists than Flinders Resistant Line [204] and this fact has been utilized to test nicotine in a number of antidepressant trials. An exaggerated immobility in the FST is present in FSL rats when compared with controls and can be reversed with antidepressant drugs [205]. The present body of evidence suggests that nicotine, acting via nicotinic receptors, is strongly linked to depression and therefore may represent a novel therapeutic target for the treatment of the illness. Before nicotine could be considered a better understanding of the dose required and the likelihood of dependence would be a prerequisite. Hypericum perforatum St Johns wort, the folk name for Hypericum perforatum, has been used for centuries in the treatment of many illnesses including the symptoms of depression before depression was diagnosed as an illness. Hypericum was ofcially sanctioned as an antidepressant medication in Germany in 1988 and much of the literature has come from there [206]. Hypericum extracts contain many active ingredients but recent research has focused on hypericin, hyperforin and avonoids. Binding studies reveal that Hypericum extracts do not have high afnity for receptors; the exception being the GABAB receptor but the concentration required for binding would not be reached with oral doses [207]. Inhibition of monoamine oxidase, catechol-o-methyltransferase has often been quoted as the mechanism of action but it is unknown whether these actions occur at clinically relevant concentrations. However, there have been a number of interactions reported between SSRIs and Hypericum, which resulted in 5-HT syndrome, possibly as a consequence of synergistic 5-HT uptake inhibition. Acute administration of large doses of two Hypericum extracts with different concentrations of avonoids (6 and 50%) caused an increased level of transmitters in various rat brain regions but the 50% avonoid extract had a more widespread effect [208]. Hyperforin has been reported to be a potent uptake inhibitor of 5-HT, DA, NA, GABA with an IC50 of 0.050.1 mg/mL in synaptosomal preparations [209]. Hyperforin (10 mg/kg, i.p.) alone increased the level of DA, NA, 5-HT and glutamate which implies that the potential antidepressant affect of
Hypericum extracts is due to increasing transmitter release in the CNS via the phloroglucinol hyperforin [210]. When combined the studies evaluating Hypericum extracts antidepressant ability the gures appear encouraging but they cannot be taken at face value as there are a number of problems with the majority of the trials [207]. Two meta-analyses have demonstrated that Hypericum extracts display antidepressant efcacy signicantly higher than placebo and similar to standard antidepressants for mild to moderate depression [211]. But the authors concluded that although there was evidence of an antidepressant action of Hypericum further and more organized studies were required to verify the ndings [211]. Earlier this year a large double-blind, placebo-controlled trial demonstrated that a Hypericum extract (WS 5570) produced a signicantly greater decrease of the HDRS than the placebo and a greater number of responders (52.7 c.f. 42.3%) [212]. However, there are a number of negative clinical trials concerning Hypericum, showing no signicant improvement in depression rating scale over placebo. Much more research is required to dene which of the many active components of the extracts contain the putative antidepressant efcacy. CONCLUSIONS From the serendipitous ndings in the 1950s that the iproniazid and imipramine were effective in treating depressed patients and both raised levels of monoamines in the CNS much of the work on antidepressants over the next four decades focused on monoamine levels, receptors and transporters. This research has provided a number of effective therapeutic compounds, which have proved very successful in treating depression. However, there remains a number of sufferers who do not benet from any of the currently approved medications, and the initial monoamine theories are now being modied to look at downstream alterations caused by antidepressant administration with a view to provide newer drugs with a faster onset of action and more universal efcacy. There are presently a number of different therapeutic approaches to novel mechanisms of action provided by animal studies and research into common properties of current antidepressants, such as their ability to alter CREB and BDNF levels and are summarized in Figure 5.
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Figure 5 Summary of current and novel antidepressant targets. A diagram summarizing the target systems discussed throughout the review. In the presynaptic terminal are shown the current antidepressant medications, 5-HT and NA reuptake inhibition, MAO inhibition, blockade of a2 and 5-HT1A receptors, as well as novel approaches including antagonism of NOS and enhancement of the pCREB, BDNF and tyrosine kinase B (trkB) pathway. Postsynaptic blockade of receptors in black text and agonists to those in red text are all novel targets for the treatment of depression. Also shown is a glial cell, which is required to remove glutamate from the synapse and are reduced in number in depression. A blood vessel is shown to carry neuroactive steroids and drugs, which enhance or mimic this group of compounds are antidepressant targets. Also shown are pro-inammatory cytokines, which are elevated in depressed patients and therefore represent a possible treatment target.
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Evolution of Antidepressant

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Evolution of Antidepressant

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REVIEW ARTICLE

Invited review: the evolution of antidepressant mechanisms

Received 24 February 2003; revised 4 June 2003; accepted 16 June 2003

*Correspondence and reprints: a.l.hudson@bristol.ac.uk

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

5-HT1B 5-HT1D 5-HT2C 5-HT2A 5-HT3

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

Uptake blockers TCAs

1960s Subtypeselective MAOIs NA selective 5-HT selective Mianserin

Trazodone SSRIs Nefazodone Mirtazapine

1980s 1990s RIMAs NARIs SNRIs

Figure 3 Summary of monoamine drug treatment evolution.

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

Table I Antidepressant properties of neurokinin antagonists.

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

MAP kinase pathway activated

Regulation of neuronal function

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

Table III Potassium channel modulators and depression.

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

195 196 197

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

The evolution of antidepressant mechanisms

2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 121

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