Dopamine in depression

Randrup et al. (55) first postulated a role for dopamine in depressive disorders. More recently, a reanalysis of the data from several groups has found evidence for a bimodal distribution of CSF homovanillic acid (HVA) levels in depressed patients, with one group comparable with normal control subjects and the other with decreased levels (56). Roy and colleagues (57) also reported on the potential predictive value of lower urinary HVA output in depressed patients who attempted suicide versus those who did not. Both reports indicate a decreased turnover in dopamine. 

Consistent with earlier studies, Muscat et al. ( 58) reported on chronic exposure to mild unpredictable stress in rats as a model to study the antidepressant-reversible decreases in the consumption of palatable sweets. Using this model, they found that certain dopamine agonists (i.e., quinpirole, bromocriptine) administered intermittently had the same positive effects as TCAs. They further postulated that the infrequent, intermittent administration of dopamine agonists (e.g., psychostimulants) may avoid problems with tolerance and abuse while providing a clinically relevant antidepressant strategy. A report by Kapur and Mann ( 59) comprehensively reviews the role of dopamine in depressive disorders. They discuss several lines of evidence, including the following ... 

The principal groups of antidepressants available today are all presumed to exert their action via alteration of brain monoamine metabolism. These amines include norepinephrine, dopamine, and serotonin. The involvement of catecholamines in the pathogenesis of depression was invoked as early as 1965. A deficiency in brain serotonin was theorized in 1967, while a role for dopamine in depression was formally proposed in 1975. The drugs that are used to treat depression basically act to increase neurotransmitter concentration in the synaptic cleft either by (1) decreasing neurotransmitter degradation or (2) inhibiting neurotransmitter reuptake. 

The monoamine hypothesis proposes that depression results from a deficiency in 5-HT and/or NE (8,9) and that antidepressant therapy aims to correct these deficiencies. The role of dopamine in depression remains... 

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

Neurotransmitter depletion has been attempted in at least 90 studies and has been the subject of a number of systematic reviews, the most recent and comprehensive of which is a metaanalysis conducted by a research team at the University of Amsterdam.24 The hypotheses of these studies were based on the premise that lowered monoamine levels cause depression, in which case depletion of these neurotransmitters ought to trigger depression in people who are not depressed. Here is what actually happens. Experimentally lowering the level of available serotonin, or of norepinephrine and dopamine, in healthy volunteers who have never been depressed does not affect their mood in the slightest. 

Numerous reports of altered neurotransmitter and hormone functions which have been associated with the affective disorders are reviewed by Levell [142]. It was originally proposed that one or more of the neurotransmitter amines in the brain (norepinephrine, dopamine, serotonin) may be functionally elevated in manic patients and reduced in depressed patients [143]. For instance, an increase in the production of dopamine, observed in a number of case reports, is thought to be the cause of the switch into the manic phase in bipolar patients. For example, Bunney et al. reported an increase in the level of homovanillic acid (HVA), a... 

Triple reuptake inhibitors (TRIs), which inhibit reuptake at all three transporters, have attracted considerable interest in recent years [77]. The involvement of dopamine reuptake in the etiology of depression and other CNS disorders has been recognized [29,30]. As a result, TRIs have been proposed to offer a faster onset of action and improved efficacy for depression over currently prescribed single or dual action monoamine reuptake inhibitors. Historically, the mesocorticolimbic dopamine pathway is thought to mediate the anhedonia and lack of motivation observed in depressed patients [78,79]. In addition, methylphenidate, both immediate release and extended release formula, has been found to be effective as an augmenting agent in treatment-resistant depression [4]. Furthermore, clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone [5,80,81]. 

Balfour DJK, Ridley DL (2000) The effects of nicotine on neural pathways implicated in depression a factor in nicotine addiction Pharmacol Biochem Behav 66 79-85 Balfour DJK, Birrell CE, Moran RJ, Benwell MEM (1996) Effects of acute D-CPPene on mesoac-cumbens dopamine responses to nicotine in the rat. Eur J Pharmacol 316 153-156 Balfour DJK, Wright AE, Benwell MEM, BirreU CE (2000) The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence. Behav Brain Res 113 73-83... 

Third is the presence of other psychiatric or medical disorders. This can help gnide antidepressant selection in several ways. In some cases, an antidepressant may be preferred becanse it can treat both disorders. For example, the extensive evidence that flnoxetine is an effective treatment for bnlimia nervosa makes it preferable for patients with depression and bnlimia. Similarly, the depressed Parkinson s disease patient whose nenrological illness results from a lack of dopamine in a particular area of the brain may have both her depression and her Parkinson s disease improved by bnpropion, which increases brain dopamine activity. In other cases, an antidepressant shonld be avoided if it worsens the other illness or interacts adversely with a medication needed to treat the other illness. For example, TCAs and MAOIs can complicate glncose control in diabetics and shonld not rontinely be used by depressed diabetics. (See Table 3.11.)... 

Both clinical and experimental studies have provided evidence that 5-HT can also regulate dopamine turnover. Thus several investigators have shown that a positive correlation exists in depressed patients between the homovaniUic acid (HVA), a major metabolite of dopamine, and 5-HIAA concentrations in the CSF. In experimental studies, stimulation of the 5-HT cell bodies in the median raphe causes reduced firing of the substantia nigra where dopamine is the main neurotransmitter. There is thus convincing evidence that 5-HT plays an important role in modulating dopaminergic... 

None of the TCAs seem to have an effect on dopaminergic neurotransmission in the central nervous system (CNS). This has been supported by the lack of alterations in dopamine receptor sensitivity in chronically treated patients who have shown response to treatment (Sugrue, 1983). More recent investigations have also shown that administration of DMI to depressed subjects had no effect on levels of homovanillic acid, the principal metabolite of dopamine, in a measure of brain neurotransmitter production. In this investigation, DMI administration did increase norepinephrine production and overall cerebral metabolism (Lambert, 2000). 

Borsini F, Meli A Is the forced swimming test a suitable model for revealing antidepressant activity Psychopharmacology 94 147-160, 1988 Borsini F, Lecci A, Mancinelli A, et al Stimulation of dopamine D2 but not Dj receptors reduces immobility time of rats in the forced swimming test implication for antidepressant activity. Eur J Pharmacol 148 301-307, 1988 Bouchard JM, Delaunay J, Delisle J-P, et al Citalopram versus maprotiline a controlled clinical multicenter trial in depressed patients. Acta Psychiatr Scand 76 583-592, 1987... 

Bowden CL, Huang LG, Javors MA, et al Calcium function in affective disorders and healthy controls. Biol Psychiatry 23 367-376, 1988 Bowden C, Cheetham SC, Crompton MR, et al Dopamine and its metabolites in depressed suicide victims (abstract). Can J Physiol Pharmacol 72 (suppl 1) 386,... 

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