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| Neuropsychopharmacology: The Fifth Generation of Progress |
Dopaminergic Mechanisms in Depression and Mania
Paul Willner
Traditional
accounts of the biochemical basis of depression have focussed largely on noradrenaline
(NA) and serotonin (5-HT), and although most of the evidence that coalesced
into the 'catecholamine hypothesis of depression'
does not distinguish clearly between NA and dopamine (DA), the potential
role of DA was at first overlooked. Following two influential reviews that drew
attention to this oversight [89, 114], there has been an upsurge of interest
in the possible involvement of DA in affective disorders. In fact, as will be
seen below, there is little in the recent clinical evidence to justify this
change of fashion; the pressure to reconsider the role of DA in depression arises
almost entirely from preclinical developments. One is the now substantial body
of work (reviewed below) demonstrating that antidepressant drugs enhance the
functioning of mesolimbic DA synapses. However, the major driving force has
undoubtedly been the massive research effort around the involvement of DA systems
in motivated behaviour (see Mesocorticolimbic
Dopaminergic Neurons: Functional and Regulatory Roles, this volume [Le Moal]).
DA turnover, measured post-mortem,
is also reduced in the caudate nucleus and nucleus accumbens of depressed suicides
[17]. As DA uptake is unchanged in depressed suicides [1,18], the decreased
turnover apparently reflects decreased DA release. There are also many reports
of decreased CSF HVA in depressed suicide attempters [20]. Consistent with these
findings, a decrease in 24-hour urinary excretion of HVA and DOPAC has been
reported in depressed suicide attempters [93]. As abnormalities of DA metabolism
are not observed in nondepressed suicide attempters [20], these data provide
further evidence that decreased DA turnover is a correlate of depression.
Nevertheless, the interpretation
of these data is far from straightforward. Although one study has reported that
CSF HVA was lower in melancholic than in non-melancholic patients [94], this
relationship is probably explained by the association between low CSF HVA and
psychomotor retardation [20, 114], which is a prominent feature of melancholia.
In fact, low CSF HVA has been associated with psychomotor slowing (bradyphrenia)
not only in depressed patients, but also in Parkinson's disease and Alzheimer's
disease [120]. In agitated patients, however, CSF HVA levels are normal or slightly
elevated [114]. CSF HVA levels (as well as plasma DA [96]) are also elevated
in delusional patients [114]. Again, this finding may reflect psychomotor change:
in a study of psychotic patients, CSF HVA levels were elevated in those with
delusions and agitation, but normal in those with delusions but no agitation
[113]. CSF HVA levels are usually found to be elevated in mania [54]. These
data suggest that CSF HVA levels may reflect motor activity rather than mood,
and further raise the problem of whether a reduction in HVA level is the primary
cause or a secondary reflection of psychomotor retardation. This latter problem
has lain dormant since an early study in which a group of depressed patients
were asked to simulate mania: the exercise did increase DA turnover, but also
elevated mood [84].
It is hardly surprising that
CSF HVA levels are associated with level of motor activity, since CSF HVA derives
largely from the caudate nucleus, on account of its large size and its periventricular
location. In schizophrenic patients, decreased CSF HVA concentrations are associated
with ventricular enlargement [26], which is equally common in major depressive
disorder [53]. Indeed, PET imaging studies have reported hypometabolism of the
head of the caudate nucleus in unipolar and bipolar depressed patients, which
may reflect a decreased DA activity in this structure [9]. However, the contribution
to CSF HVA of DA release in mesolimbic structures such as the nucleus accumbens
and frontal cortex is relatively minor. There is therefore no reason to expect
that changes in mesolimbic DA function would be apparent in studies measuring
HVA levels in lumbar CSF; it is far more likely that any such changes would
be obscured by alterations in nigrostriatal DA function associated with changes
in motor output. Thus, although most reviewers have tended to interpret the
HVA data as evidence for a DA dysfunction in depression [54, 89, 114], these
data are actually silent with respect to the important question of the state
of activity in the mesocorticolimbic DA system.
Neuroendocrine
studies
The tuberoinfundibular DA system
has neuroendocrine functions, inhibiting the release of prolactin and stimulating
the release of growth hormone (GH). Thus, basal levels of these hormones have
been examined as potential markers of DA function in affective disorders, and
their reponses to DA agonists have been used to evaluate DA receptor responsiveness.
These studies suffer two serious limitations: the inability to generalize any
conclusions to the forebrain DA systems, and the involvement of many other neurotransmitters
in neuroendocrine regulation; in particular, a stimulatory role of 5HT in prolactin
secretion and a stimulatory role of alpha-adrenergic receptors in GH secretion.
Abnormal prolactin levels have
frequently been reported in depressed patients, but there is no consistency
in the direction of change: low, normal and high values have been reported in
different studies [20, 54, 114]. Prolactin levels are reported to be normal
in mania [54, 67]. Prolactin responses were also normal in depressed patients
following DA agonist [20, 54] or antagonist [4] challenges. However, two studies
have reported a decrease in prolactin levels in seasonal affective disorder
(SAD), which was seen in both unipolar and bipolar patients, and was present
during both winter depression and summer euthymia [30, 31]. This apparent trait
abnormality in SAD patients is consistent either with increased DA function
or with decreased 5HT function. The former interpretation is supported by the
observation that SAD patients also showed a seasonally-independent increase
in spontaneous eye blinking: this behaviour is thought to be under dopaminergic
control, being increased by D2 agonists and suppressed by D2 antagonists [30,
31]. Blink rate has been reported to be unaltered in patients with major depression
[35]
Studies of GH are similarly
inconclusive. Basal GH levels have been reported to be decreased [19], normal
[6] or increased [68] in major depression; no changes were seen in mania [51].
One study reported a blunting of the GH response to apomorphine in major depression,
relative to patients with minor depression or normal controls [6], but no differences
were observed in many earlier studies, using either a slightly higher dose of
apomorphine (0.75 vs. 0.5 mg), or L-dopa [54, 114]. The group reporting blunted
GH responses to apomorphine have reported a difference between major and minor
depressives in two further studies [5, 80], and have also reported blunted responses
in manic patients [5] and in suicide attempters [81]. The same group also reported
that blunted apomorphine responses in depressed patients were associated with
low introversion and anxiety scores on the MMPI, but not with severity of depression
[82]; others have reported a negative correlation between GH response and severity
of delusions [67]. Together, these observations suggest that there may be some
subsensitivity to apomorphine in a subgroup of depressed patients. If these
findings are confirmed, the question remains of whether they reflect DA receptor
subsensitivity, or a more general decrease in GH responsivity (it is well established
that the GH response to alpha-adrenergic challenges is subsensitive in major
depression [104]). The relevance of GH changes for forebrain DA function also
remains to be determined.
MOOD
EFFECTS OF DA AGONISTS AND ANTAGONISTS
Psychostimulants
The psychostimulants amphetamine
and methylphenidate cause activation and euphoria in normal volunteers. Although
these drugs enhance activity at both DA and noradrenergic synapses, the psychostimulant
effects are mediated at DA synapses, since they are antagonized by DA receptor
blockers, but not by adrenergic receptor blockers [51, 76, 77]. The euphoric
effects of psychostimulants at low doses closely parallel the symptomatology
of hypomania, while high doses, particularly when taken repeatedly or chronically,
can cause grandiosity, delusions, dysphoria, and all the other symptoms of a
full-blown manic episode [51, 85].
Single doses of amphetamine
or methylphenidate also cause a transient mood elevation in a high proportion
(>50%) of depressed patients [61]; the response in depressed patients appears
similar, in size and in the proportion of subjects responding, to that seen
in nondepressed volunteers [23, 76]. Following an initial report by Fawcett
& Simonpoulous [39], a number of studies have used the acute mood response
to psychostimulants to predict the clinical response to chronic antidepressant
therapy. A review of this literature confirmed that the response to antidepressants
was well predicted by the result of an amphetamine challenge (85% improvement
in responders vs 43% in nonresponders), but questioned the predictive value
of a methylphenidate challenge (66% improvement in responders vs 68% in nonresponders)
[61]. However, the amphetamine and methylphenidate studies differ in that the
former involved mainly patients treated with imipramine and desipramine, while
the latter also included a high proportion of patients treated with 'serotonergic'
antidepressants. A reanalysis of the same literature showed that the acute response
to methylphenidate does predict antidepressant efficacy, provided that the analysis
is restricted to patients treated with 'noradrenergic' antidepressants [48].
Psychostimulants are not themselves
considered to be efficaceous as antidepressants. In early trials, the catecholamine
precursor l-DOPA produced a modest global improvement, primarily in retarded
patients, but the effect was largely one of psychomotor activation with little
effect on mood; in bipolar patients, DOPA frequently caused a switch into hypomania
[46]. These data have been interpreted as evidence against a prominent role
for DA in depression. However, the effects of DOPA were greatest in patients
with the lowest pretreatment CSF HVA levels [112]. This suggests that the effect
of DOPA might primarily be to increase DA release in the caudate nucleus, perhaps
causing motor side effects that could mask any potentially therapeutic effects
of an increase in mesolimbic DA release. It is now known that low doses of amphetamine
preferentially release DA within the nucleus accumbens [33]. Despite the absence
of clinical trial data, amphetamine continues to find widespread, if little
publicized, use in the treatment of depression [8].
DA-active
antidepressants
More convincing antidepressant
effects have been reported with the directly acting DA agonists piribedil and
bromocriptine. These were largely open trials, but there are also controlled
studies, including a double-blind trial showing piribedil to be superior to
placebo, particularly in patients with low pre-treatment CSF HVA, and two large
trials which found no difference in antidepressant efficacy between bromocriptine
and imipramine [114]. The antidepressant response to bromocriptine may be greater
in bipolar patients [105], and one study suggests a preferential effect of bromocriptine
on emotional blunting [3]. Hypomanic responses during bromocriptine therapy
have been reported [55, 105]. In a particularly interesting development, Mouret
and colleagues have described striking and rapid therapeutic effects of piribedil
in previously non-responsive patients whose sleep EEG showed signs characteristic
for Parkinson's disease; in patients not showing these signs, piribedil was
ineffective [70].
Trials of DA agonists in depression
are not currently fashionable, but a recent double-blind study found effects
superior to placebo and comparable to fluoxetine for pramipexole, a very selective
D3-preferring D2/D3 receptor agonist [13]. It is also notable that DA uptake
inhibition is a prominent feature of a number of newer antidepressants, including
nomifensine, buproprion, and amineptine [21]. The mechanism of action of bupropion,
which is widely used both as monotherapy for depression and in combination with
SSRIs, appears to involve both dopaminergic and noradrenergic components [2].
Bupropion is also used for smoking cessation, but this effect appears to be
independent of its antidepressant properties [50], and may involve direct nicotinic
antagonist actions [41]. Amineptine, which is a relatively selective DA uptake
inhibitor, was more efficaceous than clomipramine, and had a faster onset of
antidepressant action, in a double-blind trial in retarded patients; another
dopaminomimetic agent, minaprine, was also more effective than clomipramine
in retarded patients [88].
Contrary to expectations, given
the antidepressant effects of DA agonists, there is also clear evidence that
under certain circumstances, neuroleptics, which are DA receptor antagonists,
are also active as antidepressants [73, 92]. One potential resolution of this
apparent paradox (which will be discussed further below) is that neuroleptics
may be antidepressant only at low doses, which act preferentially as DA autoreceptor
antagonists and so increase DA turnover. This hypothesis has been advanced in
particular in relation to certain atypical antidepressants, such as sulpiride,
which are said to have 'activating' properties [59]. Antidepressant effects
of sulpiride are seen in a dose range of 50-150mg/day, which is considerably
lower than the typical antipsychotic dose of 800-1000mg/day. A DA-activating
effect of sulpiride at low doses is supported by the finding that low doses
of sulpiride antagonized the sedative actions of apomorphine in human subjects
[99].
Antidepressant effects have
also been reported for roxindole, a putatively selective DA autoreceptor agonist.
In an open trial, roxindole caused rapid improvements in 8 of 12 patients suffering
from a major depressive episode, as well as reducing depression and anergia
in schizophrenic patients [12]. Roxindole possesses 5HT uptake-inhibiting and
5HT agonist actions, both of which could contribute to an antidepressant effect,
but neuroendocrine data (suppression of prolactin secretion [12]) suggest that
DA agonism is the predominant action of this drug. If, as claimed, roxindole
is a selective autoreceptor agonist, the effect should be to decrease DA
function. However, it is questionable whether roxindole is antidepressant
by virtue of decreasing DA function: the drug also appears to be effective in
negative schizophrenia [12], which is compatible with a DA-activating effect.
Neuroleptic-induced
depression
Depression is frequently encountered
as a side effect of neuroleptic therapy in schizophrenia [89, 106]. This is
a complex issue, with debates about whether ‘neuroleptic-induced depression’
is a side effect of treatment, a part of schizophrenia, a secondary effect of
having schizophrenia, or the unmasking of a pre-existing depression when psychotic
symptoms are brought under control. However, schizophrenic patients on neurolepics
are more likely to show full depressive syndromes than those not on neuroleptics,
with a strong association between neuroleptic use and anhedonia, and this relationship
holds up after controlling for level of psychosis [49]. This suggests that ‘neuroleptic-induced
depression’ is genuine, and there are strong grounds for believing that the
effect is caused by antagonism of DA receptors. Conversely, neuroleptic drugs
also decrease manic symptomatology. Although classical neuroleptics act at a
variety of receptor sites, antimanic effects are also observed with drugs that
act relatively specifically as DA receptor antagonists [54]. In normal volunteers
neuroleptics induce feelings of dysphoria, paralysis of volition and fatigue
[10].
Parkinson's
Disease
It is now recognized that Parkinson's disease can not be considered as a pure DA deficiency syndrome: NA, 5HT, ACh, somatostatin and neurotensin are also abnormal [79]. Nevertheless, there are good reasons to relate the symptoms of Parkinsonian depression to DA depletion. In one well-designed study, depressed Parkinsonian patients showed profound attenuation of the euphoric response to methylphenidate, relative to non-depressed Parkinsonian patients, depressed non-Parkinsonian patients, and normal controls [23]. The antidepressant effect of DOPA in Parkinson's disease [3, 46, 89] also points towards a dopaminergic substrate of Parkinsonian depression. In some cases there is clear evidence that mood improvement precedes the improvement in physical symptoms [71], suggesting that the antidepressant effect cannot be simply explained away as secondary to an improvement in physical symptoms. Antidepressant effects of bupropion [43] and bromocriptine [55] have also been reported in Parkinsonian patients.
Neuroleptics
as antidepressants
The clinical pharmacology literature
reviewed in this section is broadly consistent with the hypothesis that increases
in DA function elevate mood and decreases in DA function induce symptoms of
depression. However, not all of the data are compatible with this formulation.
In particular, the fact that neuroleptics are used to treat depression [73,
92] strikes at the heart of the dopamine/anhedonia/depression hypotheses. This
phenomenon therefore requires careful consideration.
It is also questionable whether
neuroleptics are truly antidepressant, and examination of the pattern of symptomatic
improvement may provide the clearest resolution to the paradox of the antidepressant
action of neuroleptics: in brief, there is no evidence that neuroleptics can
improve either psychomotor retardation or anhedonia, the core symptom of depression
most closely associated with the DA hypothesis. The antidepressant potential
of neuroleptics is most firmly established in delusional depression, which responds
well to combined therapy with a neuroleptic/tricyclic mixture, but responds
poorly if at all to tricylics alone. However, neuroleptics alone are also ineffective
in delusional depression: they produce a substantial global improvement, but
this arises almost entirely from a decrease in agitation and delusional thinking;
motor retardation, lack of energy and anhedonia do not respond to neuroleptic
treatment, and indeed, may become worse [73]. In endogenous depressions, while
neuroleptics have been claimed to be as effective as tricyclics, or nearly so,
this appearance may be spurious, insofar as the studies in question may have
seriously underestimated the true effectiveness of tricyclics (owing to a failure
to attain adequate plasma drug levels, and other factors) [73]. On the basis
of the findings in delusional depression, it seems likely that the global improvement
seen in endogenous depressives treated with neuroleptics results from the preponderance
in these studies of agitated and delusional patients [73, 92]. This analysis
of the place of neuroleptics in the treatment of depression implies that retardation
and delusions are mediated by different sets of DA terminals, which may be activated
independently [40]. In support of this assumption, it is well established that
different components of the mesocorticolimbic DA projection are differentially
regulated (see Dopamine
Receptor Transcript Localization in Human Brain, this volume [Le Moal])
DOPAMINERGIC
MECHANISMS OF ANTIDEPRESSANT ACTION
DA
autoreceptor desensitization
Most antidepressant drugs have
little effect on DA function following acute administration; in particular,
tricyclic antidepressants do not act as potent DA uptake inhibitors [114], in
contrast to their well known effects at adrenergic and serotonergic synapses
(though some data suggest that antidepressants may cause significant inhibition
of DA uptake within the nucleus accumbens and frontal cortex [24, 27]). Nevertheless,
there is now considerable evidence that antidepressants do enhance dopaminergic
function following chronic administration.
In one of the earliest studies
to demonstrate an antidepressant-induced increase in DA function, Serra et al
reported that imipramine, amitriptyline and mianserin all decreased the sedative
effect of a low dose of apomorphine. Since this latter effect was assumed to
be mediated by stimulation of DA autoreceptors, the results were interpreted
as a decrease in autoreceptor sensitivity [97]. However, the evidence that antidepressants
desensitize DA autoreceptors is equivocal. There are a number of supportive
studies, using a variety of techniques, but equally, there have been failures to replicate
all of these data [114]. Some studies have reported that clear evidence of DA
autoreceptor subsensitivity was not present until 3-7 days following withdrawal
from chronic antidepressant treatment [95, 111]. Another reason to question
the relevance of DA autoreceptor desensitization for the clinical action of
antidepressants is that these data were obtained in 'normal' rats; rats exposed
to chronic mild stress, which has been proposed as an animal model of depression,
show evidence of DA autoreceptor desensitization similar to that sometimes seen
following chronic antidepressant treatment in 'normal' animals [117]. Finally,
changes in apomorphine-induced sedation do not necessarily imply changes in
DA autoreceptor function. High doses of apomorphine cause locomotor stimulation,
so a decrease in apomorphine-induced sedation might equally well indicate an
increase in postsynaptic responsiveness rather than autoreceptor subsensitivity.
Sensitization
of D2/D3 receptors
In fact, a substantial body
of literature now demonstrates that following chronic treatment, antidepressants
do increase the responsiveness of postsynaptic D2/D3 receptors in the mesolimbic
system; these effects are seen irrespective of the primary neurochemical action
of the drug [62, 115]. The majority of studies have examined the locomotor stimulant
response to moderate doses of apomorphine or amphetamine; these responses are
consistently elevated following chronic administration of antidepressants. Similar
effects were observed using the specific D2/D3 agonist quinpirole [62]. There
are well known pharmacokinetic interactions between antidepressants and amphetamine.
However, antidepressants also increased the psychomotor stimulant effect when
amphetamine, or DA itself, was administered directly to the nucleus accumbens
[62], confirming a true pharmacodynamic interaction. Furthermore, these effects
were present within a short time (2h) of the final antidepressant treatment,
confirming that, unlike DA autoreceptor desensitization, the increase in responsiveness
of postsynaptic D2/D3 receptors is not simply a withdrawal effect. The potentiation
of D2/D3 receptor function by chronic antidepressant treatment is confined to
mesolimbic terminal regions: antidepressants do not increase the intensity of
stereotyped behaviours caused by high doses of amphetamine, which are mediated
by DA release within the dorsal striatum [115]. Neither did chronic antidepressant
treatment potentiate a DA-mediated neuroendocrine response [86].
Receptor binding studies have
usually failed to detect any alterations in the binding parameters of D2/D3
receptors that would explain the increased functional responses. The majority
of these studies are of limited relevance, as they assayed DA receptors in samples
of dorsal striatum. Nevertheless, negative findings have also been reported
in nucleus accumbens. However, D2/D3 receptors in limbic forebrain (but not
dorsal striatum) have an increased affinity for the agonist ligand, quinpirole,
following chronic antidepressant administration to rats, and an increase in
receptor number has recently been reported, in ventral but not dorsal striatum,
using an agonist ligand [64]. Consistent with these observations, a recent study
using a conventional antagonist ligand found that a decrease in D2/D3 receptor
numbers in limbic forebrain of rats subjected to chronic mild stress was completely
reversed by chronic treatment with imipramine [117]. Increased D3-receptor binding
in ventral striatal regions, following chronic antidepressant treatment, has
also been recently reported [65].
In addition to increasing the
responsiveness of D2/D3 receptors, antidepressants also decrease the number
of D1 receptors, following chronic treatment [62]. This effect is associated
with a decrease in the ability of DA to stimulate adenyl cyclase [62], and a
decreased behavioural response (grooming) to D1 receptor stimulation [63], consistent
with the binding data. A role for D1 receptor changes in the sensitization of
D2/D3 receptors has been proposed [98], but this seems unlikely, as the downregulation
of D1 receptors is species specific: D1 receptors were downregulated by chronic
imipramine in rats but not in mice [75]. Furthermore, D1 receptors were not
downregulated by chronic imipramine in chronically stressed rats, which did
show D2/D3 receptor upregulation [78]. In both of these studies, functionally-relevant
behavioural effects of chronic antidepressant treatment were seen in the absence
of D1-receptor changes [75, 78]
Role
of mesolimbic DA in animal models of depression
published 2000