Dopamine agonist-responsive depression

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1 bs_bs_banner doi: /psyg PSYCHOGERIATRICS 2013; 13: REVIEW ARTICLE Dopamine agonist-responsive depression Hiroaki HORI and Hiroshi KUNUGI Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan Correspondence: Dr Hiroshi Kunugi MD, PhD, Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo, , Japan. Received 4 September 2012; accepted 18 March This review article was presented by the authors in Symposium of the 26th annual meeting of Japanese Psychogeriatrics Society in Tokyo, June 16, Key words: augmentation therapy, depression, dopamine agonist, nucleus accumbens, pramipexole. Abstract Dopaminergic dysfunction is implicated in the pathophysiology of treatmentresistant depression. In this review, we describe the putative role of dopamine in depression, summarize the evidence for the efficacy of dopamine receptor agonists in the treatment of treatment-resistant depression, and discuss the underlying mechanisms by which these medications work. Both preclinical and clinical data suggest that adjunctive dopamine agonists could be a promising option for the treatment of such a condition, indicating that there is a dopamine agonist-responsive subgroup of depression. Future clinical studies are warranted to clarify unresolved issues regarding dopamine agonists such as long-term efficacy, efficacy as a monotherapy, and efficacy for juvenile and senile depression. Further basic research is also necessary to fully understand how dopamine acts in the brain of depressed patients. INTRODUCTION Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) are medications currently used as first-line treatments for depression. However, large-scale clinical trials in Western countries, such as the Sequenced Treatment Alternatives to Relieve Depression, 1 have revealed that a significant proportion of patients fail to respond to or achieve remission with these medications. In these patients, symptoms such as avolition, psychomotor retardation, poor concentration and anhedonia are likely to persist even after mood symptoms including depressed mood and anxiety have resolved. Because dopamine, particularly mesolimbic dopamine system, regulates motivation, psychomotor speed, concentration and emotions like pleasure, it has been postulated that at least some treatmentresistant patients are in a hypodopaminergic state in which medications such as dopamine reuptake inhibitors, monoamine oxidase inhibitors and dopamine receptor agonists, rather than serotonergic or noradrenergic agents, could be effective. 2 There are six dopamine agonists currently used in clinical practice, mainly for Parkinson s disease: bromocriptine, cabergoline, pergolide, talipexole, ropinirole and pramipexole. Ergot alkaloids (bromocriptine, cabergoline and pergolide) can cause serious, albeit rare, adverse events including valvular heart diseases, whereas non-ergot dopamine agonists (talipexole, ropinirole and pramipexole) do not have such an effect on cardiac valves. Although these dopamine agonists have not been approved for the treatment of depression, a number of studies have suggested that augmentation with dopamine agonists can be effective, especially for treatmentresistant depression. In this review, we first briefly describe the putative role of dopamine in depression, then summarize the evidence for the efficacy of dopamine receptor agonists in the treatment of refractory depression, and lastly discuss the underlying mechanisms by which these medications work. INVOLVEMENT OF DOPAMINE IN THE PATHOPHYSIOLOGY OF DEPRESSION The monoamine hypothesis is one of the best-known aetiological hypotheses for depression. Although there are different classes of antidepressants with different mechanisms of action, they generally inhibit the 189

2 H. Hori and H. Kunugi reuptake of neurotransmitters (released into the synaptic cleft), including serotonin, noradrenaline and dopamine, into the neurons via transporters. They also inhibit the breakdown of these neurotransmitters with monoamine oxidase, thereby increasing these monoamines in the synaptic cleft. Given the findings from in vitro studies that SSRI and SNRI inhibit the reuptake of serotonin, the simple conclusion seems to be that serotonin is the most important monoamine in the treatment of depression. Nonetheless, evidence on the reduction of brain extracellular serotonin levels in depressed patients is not conclusive. For example, post-mortem brain studies have not consistently observed a reduction in serotonin (or its metabolites). The finding that 5-hydroxyindoleacetic acid, a serotonin metabolite in cerebrospinal fluid (CSF), is reduced in depressed patients is also controversial. 3 Indeed, a number of studies have reported reduced CSF 5-hydroxyindoleacetic acid in individuals who have a history of impulsive behaviours, such as suicidal attempts and violent acts, 4,5 irrespective of their diagnosis (i.e. schizophrenia, personality disorder). Therefore, it is conceivable that reduced serotonin is associated with impulsivity in general rather than depression per se. This idea corresponds well to the fact that SSRI are effective at reducing anxiety, agitation and depressed mood but not necessarily at ameliorating other symptoms such as avolition, psychomotor retardation, poor concentration and anhedonia. With regard to other catecholamines such as noradrenaline and dopamine, findings from post-mortem brain studies and CSF studies in depressed patients have not been uniform. However, there has been one relatively consistent finding: reduced homovanillic acid (a primary dopamine metabolite) in CSF, 6 which suggests an important role of dopamine in the pathophysiology of depression. Although in vitro studies show that SSRI do not inhibit the reuptake of dopamine, in vivo animal studies using microdialysis have demonstrated that many SSRI increase extracellular dopamine in the prefrontal cortex. Because tricyclic antidepressants also increase prefrontal dopamine (Fig. 1), some investigators argue that this process could be central to the effects of antidepressants. 7 It should be noted, however, that tricyclic antidepressants do not increase dopamine in the nucleus accumbens, a brain region known as the pleasure centre, according to the study of Tanda et al. (Fig. 1). 7 One of the potential mechanisms by which SSRI and SNRI increase prefrontal dopamine is by stimulating dopamine release via 5-hydroxytryptamine (5-HT)1A receptors as a result of elevated serotonin levels. Another one is that the inhibition of dopamine reuptake via the noradrenaline transporter by SNRI leads to an increase in extracellular dopamine levels because the noradrenaline transporter, but not the dopamine transporter, is mainly responsible for the dopamine reuptake in the prefrontal cortex. DOPAMINE AGONISTS: EVIDENCE FOR THEIR EFFICACY IN TREATMENT-RESISTANT DEPRESSION Table 1 summarizes the receptor binding affinity and pharmacokinetics of dopamine agonists that are approved for the treatment of Parkinson s disease and/or hyperprolactinemia. 8 Dopamine receptors comprise five subtypes, D1, D2, D3, D4 and D5 receptors, which are classified into D1-like (D1 and D5) and D2-like (D2, D3 and D4) receptors. 9 All the dopamine agonists used to treat Parkinson s disease have high affinity for the D2-like receptors and low affinity for Table 1 Receptor binding affinity and pharmacokinetics of dopamine agonists (adapted from Kvernmo et al. 8 ) Receptor affinity (inhibitor constants: nm) Bromocriptine Cabergoline Pergolide Pramipexole Ropinirole D > D D D D > HT2B 56.2 <partial agonist> 1.2 <agonist> 7.1 <agonist> > > Oral bioavailability (%) >90 50 Half-life (hour) HT,5-hydroxytryptamine. 190

3 Dopamine and depression Figure 1 Effect of tricyclic antidepressants on dopamine output (expressed as a percentage of basal) (a) from the prefrontal cortex, (b) from the nucleus accumbens and (c) on 5-HT output from the prefrontal cortex. Error bars represent standard errors of the mean. (Adapted from Tanda et al. 7 )*P < 0.05 compared with basal in post-hoc test. 5-HT, 5-hydroxytryptamine. the D1-like receptors. Ergot alkaloids (bromocriptine, cabergoline and pergolide) have high affinity for the 5-HT2B receptor and therefore can cause serious, albeit rare, adverse events including valvular heart diseases. In contrast, non-ergot dopamine agonists (talipexole, ropinirole and pramipexole) do not have such an effect on cardiac valves because of their low affinity for the 5-HT2B receptor, although these three agents can potentially cause sleep attack. Table 2 lists the studies that have examined the possible effect of dopamine agonists on treatment-resistant depression and/or bipolar depression In the 1990s, several studies, mostly from Japan (particularly from a research group at Hokkaido University in Sapporo), reported the efficacy of the ergot alkaloids bromocriptine and pergolide in the treatment of (treatment-resistant) depression More recently, attention has shifted to the efficacy of non-ergot dopamine agonists pramipexole and ropinirole In treatment-resistant bipolar depression, two randomized controlled trials demonstrated that the addition of pramipexole, a D2/D3 receptor agonist approved for the treatment of Parkinson s disease and restless legs syndrome, to existing mood stabilizers resulted in a significant improvement in depressive symptoms. 22,23 The Canadian Network for Mood and Anxiety Treatment lists the combination of lithium and pramipexole as a third-line option for bipolar depression

4 H. Hori and H. Kunugi Table 2 Evidence for efficacy of dopamine agonists in treatment-resistant depression Study Year Design Sample characteristics n Efficacy (%) Bromocriptine Kishimoto Open-label trial Not specified 9 0 Inoue et al Open-label trial UP patients who did not respond to 6 67 Inoue et al Retrospective chart review UP/BP patients who did not respond to two or more antidepressants Hirayama et al Case report A BP patient who did not respond to 1 (effective) two antidepressants Pergolide Bouckoms and 1993 Open-label trial UP/BP patients Mangini 14 Izumi et al Case report A UP patient who did not respond to 1 (effective) two antidepressants Izumi et al Open-label trial UP patients who did not respond to Pramipexole Sporn et al Retrospective chart review UP/BP patients who did not respond to Perugi et al Open case series BPII patients who did not respond to mood stabilizers or antidepressants Lattanzi et al Open-label trial UP/BP patients who did not respond to Takahashi et al Case report UP patients who did not respond to 2 (effective) one antidepressant Cassano et al Prospective naturalistic UP/BP patients who did not respond to study Zarate et al Placebo-controlled RCT BPII patients who did not respond to 10 (placebo: 11) 60 (placebo: 9) Goldberg et al Placebo-controlled RCT BP patients who did not respond to 12 (placebo: 10) 67 (placebo: 20) two or more antidepressants Tanaka et al Retrospective chart review BP patients who did not respond to 8 63 Inoue et al Open-label trial UP/BP patients who did not respond to two or more antidepressants El-Mallakh et al Retrospective chart review BP patients Hori and Kunugi Open-label trial UP/BP patients who did not respond to Ropinirole Perugi et al Open case series BPII patients who did not respond to 8 50 mood stabilizers or antidepressants Cassano et al Open-label trial UP/BP patients who did not respond to BP, bipolar disorder; RCT, randomized control trial; UP, unipolar major depressive disorder. However, data on the efficacy of dopamine agonists in treating treatment-resistant unipolar major depressive disorder (MDD) is scarce. To our knowledge, six openlabel studies (excluding case reports and naturalistic studies), including ours, have investigated the possible effect of adjunctive dopamine agonists in the treatment of treatment-resistant MDD (Table 2). 11,16,19,25,27,28 These studies overall showed substantial efficacy of dopamine agonist augmentation therapy, with the strongest evidence obtained for pramipexole. Therefore, it has been suggested that pramipexole augmentation, among various dopamine agonists, may be a worthwhile option for treatmentresistant depressed patients. In our open-label trial, patients with DSM-IV major depressive episode who failed to respond to previous treatment with a SSRI were enrolled. Five patients were diagnosed as having bipolar II disorder and 12 as having unipolar MDD. Patients were monitored at an ambulatory care facility every 2 weeks for 12 weeks, and pramipexole was added to existing medication. Depression severity was assessed with the Hamilton Depression Rating 192

5 Dopamine and depression Mean HDRS-21 scores Weeks Figure 2 The sample s (n = 17) mean scores over time on the Hamilton Depression Rating Scale 21-item version (HDRS-21), based on the intent-to-treat analysis. Error bars represent standard errors of the mean. (Adapted from Hori and Kunugi. 27 ) Scale 21-item version (HDRS-21). The mean 1 SD maximum dosage of pramipexole was mg. As shown in Figure 2, the HDRS-21 total score decreased from at baseline to at endpoint (P < ). Twelve patients (71%) responded based on a reduction of 50% or more in the HDRS-21 score. Ten patients (59%) remitted (HDRS-21 total score at endpoint <8). These results were almost unchanged when the sample was confined to patients with MDD. No serious adverse events were observed. Our study confirmed previous findings and indicated that pramipexole augmentation therapy might be effective and well tolerated in treatmentresistant depressed patients. With respect to cognitive function, a recent randomized placebo-controlled study found greater improvements on measures of processing speed and working memory in euthymic bipolar patients taking pramipexole than those taking placebo. 30 Potential cognitive enhancement effects of dopamine agonists in mood disorder patients deserve further investigations. OUR PRECLINICAL STUDY ON THE EFFICACY OF PRAMIPEXOLE MONOTHERAPY While there have been a number of studies in which dopamine agonists were added on to other medications such as antidepressants and/or mood stabilizers (see Table 2), few clinical or preclinical studies have examined the efficacy of dopamine agonists as a monotherapy in depression. We therefore conducted a preclinical study to investigate the possible antidepressant-like effect of cabergoline monotherapy. 31 In this study we administered cabergoline repeatedly and found that immobility in the forced swimming test and latency of feeding in the noveltysuppressed feeding test were significantly reduced and that the time spent in closed arms tended to decrease in the elevated-plus maze test. Furthermore, based on the brain-derived neurotrophic factor (BDNF) hypothesis of depression, 32,33 the hippocampus was removed 24 h after the last injection of cabergoline, and Western blotting was used to examine the protein levels of BDNF and the activation of intracellular signalling molecules, which revealed that the expression of BDNF and activation of extracellular signal-regulated kinase 1 were upregulated (Fig. 3). These results indicated that potentiation of intracellular signalling of BDNF in the hippocampus may be involved in the antidepressant- and anxiolytic-like effects of cabergoline. POTENTIAL MECHANISM(S) UNDERLYING THE EFFICACY OF DOPAMINE AGONISTS FOR THE TREATMENT OF REFRACTORY DEPRESSION Although the mechanisms enabling dopamine agonists to exert an antidepressant effect have not been elucidated, several possibilities have been suggested. First, as dopamine regulates motivation, psychomotor speed, concentration and pleasure, these emotional circuits in the brain can be activated and reinforced through the stimulation of dopamine receptors. Activity-dependent BDNF release and its signals may be involved in the process of the transition from activation to reinforcement. Second, SSRI and tricyclic antidepressants also increase dopamine in the prefrontal cortex, but they do not increase dopamine in the nucleus accumbens (Fig. 1). Thus, it is possible that the stimulation of the dopaminergic system of the nucleus accumbens could be a mechanism of action of dopamine agonists. 34 Third, the selective stimulation of D2-like receptors by dopamine agonists is fundamentally different from the indirect increase of extracellular dopamine caused by SSRI, SNRI and tricyclic antidepressants and from the dopamine reuptake inhibition caused by norepinephrinedopamine reuptake inhibitors such as bupropion. 193

6 H. Hori and H. Kunugi a Cabergoline b Relative expressin levels (Mean value of vehicle =1) c d Cabergoline BDNF Phosphorylation Total Relative phosphorylation levels (Mean value of vehicle =1) Vehicle Cabergoline * p75 TrkB BDNF p75 TrkB * perk ERK1/2 perk2 Akt Vehicle Cabergoline pakt Figure 3 Effects of chronic administration of cabergoline on the expression and activation of BDNF-related signals. (a) Representative blotting of BDNF (left), p75 (centre), and TrkB (right). (b) Densitometry quantified values of BDNF and its receptors. (c) Representative blotting of perk1/2 (left) and pakt (right). (d) Densitometry quantified values of BDNF-related signals. Columns and bars represent mean 1 SEM. n = 6 for each group. (Adapted from Chiba et al. 31 )*P < 0.05, #P < 0.1 versus vehicle. BDNF, brainderived neurotrophic factor; pakt, phosphorylated protein kinase B; perk, phosphorylated extracellular signal-regulated kinase; TrkB, tyrosine receptor kinase B. With regard to functional brain systems affected by dopamine agonists, a recent neuroimaging study showed that clinical improvement with pramipexole augmentation in bipolar depression was associated # with a reduction in regional metabolism in orbitofrontal cortex, ventrolateral prefrontal cortex and anteromedial prefrontal cortex. 35 This finding provides support for a role of the central dopaminergic system in the pathophysiology of depression, as cerebral metabolic activity in these regions has been found to be elevated in depression. 36 CONCLUSION In this review, we have described the role of dopamine in depression and the efficacy of dopamine receptor agonists in (treatment-resistant) patients with depression, with some discussion on the mechanisms. Evidence suggests that there may be a subgroup of depression that is responsive to the dopamine agonists but not to the current first-line antidepressants such as SSRI, SNRI, or tricyclics. Further randomized controlled trials in a large sample would be needed to prove the efficacy and safety of dopamine agonists for treatment-resistant major depression. In addition, many issues regarding the efficacy of dopamine agonists remain to be resolved, including long-term efficacy, efficacy as a monotherapy, and efficacy for juvenile and senile depression. Basic research, including cell biology and animal model studies, is also necessary to understand where and how dopamine is involved in the brain of depressed patients and to determine which receptor is of more importance than others. Such attempts may ultimately lead to the elucidation of the pathophysiology of depression as well as the development of new drugs with greater efficacy and less side effects. REFERENCES 1 Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, sertraline, or venlafaxine-xr after failure of SSRIs for depression. N Engl J Med 2006; 354: Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 2007; 64: Cowen PJ, Harmer CJ. Is it all monoamines? In: Pariante CM, Nesse RM, Nutt D, Wolpert L, eds. Understanding Depression: A Translational Approach. New York: Oxford University Press, 2009; Brown GL, Ebert MH, Goyer PF et al. Aggression, suicide, and serotonin: relationships to CSF amine metabolites. Am J Psychiatry 1982; 139: Virkkunen M, Goldman D, Nielsen DA, Linnoila M. Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence. J Psychiatry Neurosci 1995; 20:

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