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The role of dopamine in mood disorders
The Role of Dopamine
in Mood Disorders
David J. Diehl and Samuel Gershon The findings on dopamine in mood disorders suggest that decreased dopamine activity is involved in depression, while increased dopamine function contributes
pression. We also discuss the importance of integrating these dopamine findings with dopamine brain circuitry and with other neurotransmitter theories of
to mania. This report reviews the considerable preclinical and clinical evidence supporting this hypothesis, with particular emphasis on specific subtypes of de-
affective disorders. Copyright 0 1992 by W.B. Saunders Company
M
theories of mood OST ETIOLOGICAL disorders have proposed functional increase or decrease in a given neurotransmitter system. Neurotransmitters invoked have included acetylcholine, y-aminobutyric acid (GABA), and, most frequently, the monoamines norepinephrine and serotonin. These neurotransmitter hypotheses have been of great heuristic importance, but have certainly not yielded “the answer” to the etiology of mood disorders. Dopamine has been cited less often than the other monoamines in the neurotransmitter hypotheses of mood disorders. However, dopamine has also been widely implicated in the pathophysiology of affective syndromes. In its simplest form, the dopamine hypothesis suggests that decreased dopamine neurotransmission is involved in the pathogenesis of depression, while increased functional dopamine activity contributes to the symptoms of mania.’ This report will review the evidence supporting dopamine’s role in depression with particular emphasis on different subtypes of depression. We will separately examine the evidence suggesting dopamine overactivity in mania. We will then address the need to integrate these dopamine “facts” with dopamine brain circuitry and with other neurotransmitter findings in mood disorders. DEPRESSION:
EVIDENCE FOR DOPAMINE HYPOTHESIS
There are several types of evidence suggesting dopamine activity is decreased in depression. In some instances, the data implicate specific subtypes of depression, and this will be discussed in detail in the next section. We will first briefly consider evidence from animal models of depression. In the “learned helplessness” model, rats are subjected to unpredictable electric shocks and are subsequently
found to have decreased learning of new behavioral tasks. Rats exposed to this paradigm have shown decreased levels of dopamine in subcortical brain regions. The learning deficits are exacerbated when the rats are given dopamine antagonists and lessened by dopamine agonists. The “behavioral despair” model involves forcing rats to swim in a confined space. The behavioral consequence is prolonged immobility. Dopamine antagonists increase this immobility, while dopamine agonists decrease it. Tricyclic antidepressants and electroconvulsive therapy also diminish the despair immobility.’ Conclusions from such studies are tenuous, since it is uncertain how well the rat paradigms model human depression. Another source of support for the dopamine hypothesis is the clinical effects of dopamine agonists and antagonists. Jimerson’ provides a good review of this literature. Four studies have reported that at least half of depressed subjects show temporary improvement in depressive symptoms following intravenous administration of methylamphetamine or methylphenidate.3” Of course, these psychomotor stimulants increase norepinephrine as well as dopamine activity. The relatively selective dopamine receptor agonist piribedil showed mild to moderate antidepressant effect in 12 of 16 depressed patients, with greater improvement in patients with lower baseline levels of the dopamine metabolite homovanillic acid (HVA) in their cerebrospinal fluid (CSF).’ Several investigators have demonstrated an antidepressant effect of the dopamine agonist bromocriptine, including From the Department of Psychiatry UrGersi& of Pittsburgh School of Medicine, Pittsburgh, PA. Address reprint requests to David J. Diehl, M.D., Department of Psychiatry, Universiryof Pittsburgh School of Medicine, 381 I O’Hara St, Pittsburgh, PA 15213. Copyright 0 1992 by W.B. Saunders Company OOlO-440X19213302-0007$03.00l0
Comprehensive Psychiatry, Vol. 33, No. 2 (March/April), 1992: pp 115-120
115
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two fairly large double-blind, controlled studies. Theohar et al’ found no statistically significant difference in antidepressant response between bromocriptine and amitriptyline in 83 endogenously depressed patients. The second study compared bromocriptine to imipramine in 33 endogenous depressives and showed no significant difference in therapeutic effect.’ Based on the dopamine hypothesis, one would predict that dopamine antagonists would result in or exacerbate depressive symptoms. There are indeed many reports of patients experiencing depressive states while receiving neuroleptics. However, there are also reports of neuroleptics having an antidepressant effect. For the interested reader, Randrup et al” provide a review of this body of literature. Another type of evidence for the dopamine hypothesis is the measurement of the dopamine metabolite HVA in the CSF of depressed patients. The prediction is that decreased functional dopamine activity will lead to reduced HVA levels in the CSF. Several studies have addressed this question with substantial variability in their findings. Jimerson’ points out that of the six studies with the soundest methodology (including at least a lo-day medication-free period), five show decreased CSF HVA in depressed patients compared with controls. Some studies have actually demonstrated increased HVA levels in the CSF, and these will be further discussed in the section on subtypes of depression. The presence of effective “dopamine-active” antidepressants also supports the role of dopamine in depression. Bupropion is a relatively selective dopamine reuptake inhibitor that also has some direct agonist action on dopamine receptors. This second-generation antidepressant has demonstrated superior efficacy to placebo and equal efficacy to amitriptyline in double-blind comparisons. Nomifensine is another proven antidepressant with potent dopamine reuptake blocking properties. However, nomifensine is also a strong inhibitor of norepinephrine reuptake. Selective monoamine oxidase (MAO)-B inhibitors (eg, L-deprenyl) have shown some antidepressant effect for certain subtypes of depression. These medications selectively inhibit the metabolism of dopamine while
DIEHL AND GERSHON
leaving norepinephrine and serotonin relatively unaffected. The more “traditional” somatic treatments of depression have also been shown to affect dopamine function.’ Tricyclic antidepressants block dopamine reuptake, although this effect is generally less potent than effects on other neurotransmitters. Chronic tricyclic antidepressant treatment has also been shown to decrease the sensitivity of dopamine autoreceptors and increase sensitivity of postsynaptic dopamine receptors. Investigators have reported that MAO inhibitors reduce dopamine autoreceptor sensitivity which could secondarily increase postsynaptic dopamine concentrations. In infrahuman studies, repeated electroconvulsive shocks have been shown to increase the response to dopamine agonists, suggesting an enhanced postsynaptic activity.’ Neuroendocrine studies have been performed to investigate possible dopaminergic dysfunction in depression. The assumption is that changes in the tuberoinfundibular dopamine pathway may reflect changes in the mesolimbic and mesocortical systems. Dopamine inhibits prolactin release and stimulates growth hormone release. Some investigators have predicted blunted neuroendocrine response to dopamine precursors in depressed patients consistent with the hypothesis of decreased presynaptic dopamine release in depression. These researchers predict increased neuroendocrine response to dopamine postsynaptic receptor agonists secondary to compensatory recepOthers hypothesize that tor upregulation. reduced dopaminergic transmission in depression results from a primary decrease in postsynaptic receptor function, and thus they predict a blunted neuroendocrine response to both dopamine precursors and receptor agonists. These neuroendocrine studies have been largely negative and, if taken alone, provide little support for dopamine dysfunction in depression. SUBTYPES OF DEPRESSION
Even proponents of the dopamine hypothesis of depression usually emphasize that dopamine dysfunction is probably only important for certain symptoms or subtypes of depression. We will first consider bipolar depression. Silberman et al6 administered intravenous amphet-
THE ROLE OF DOPAMINE
IN MOOD DISORDERS
amine to depressed subjects and found that seven of seven bipolar versus only five of 11 unipolar patients exhibited an elated response. Silverstone” demonstrated a more clear-cut antidepressant response to bromocriptine in five bipolar depressives as compared with five unipolar patients in an open study. Interestingly, two of the bipolar subjects developed manic symptoms. The catecholamine precursor L-dopa has also been shown to produce manic symptoms more often in bipolar than unipolar depressed patients.‘* These studies suggest a possible role of dopamine in bipolar depression, but conclusions are limited because of the nature and number of the investigations. Another understudied depressive subtype is depression with prominent psychomotor retardation. Retarded depression is of theoretical importance because of the known role of basal ganglion dopamine function in motor activity, including the established link between decreased dopamine activity and pathological hypokinesia (ie, Parkinson’s disease). Van Praag and Korf13 treated five retarded and five nonretarded depressives with L-dopa for 2 weeks and found that motor retardation markedly improved, while mood scores did not change significantly in either group. The retarded subgroup had lower CSF HVA levels which increased following L-dopa treatment. Two other studies have shown a positive correlation between psychomotor activity and CSF HVA level in medication-free depressed patients’4X’s;however, there have also been two negative studies exploring this question.lO,” The small body of literature addressing endogenous versus nonendogenous depression has yielded conflicting results. Asberg et al’* found significantly lower concentrations of CSF HVA in 83 melancholic depressives as compared with 66 healthy controls. Roy et all9 compared 15 patients with major depression with melancholia to 13 subjects with either major depression without melancholia or dysthymia. The melancholic depressives had significantly lower levels of CSF HVA. On the other hand, the small experience with the selective MAO-B inhibitor L-deprenyl in depressed patients suggests a preferential response in nonendogenous depressives.“’ Seasonal afective disorder (SAD) has recently
117
been investigated with respect to possible decreased dopaminergic function. This is theoretically appealing because SAD patients characteristically have significant psychomotor slowing. Arbisi et al” studied the thermoregulatory heat loss to an endogenous heat challenge, which dopamine is thought to mediate. They found heat loss significantly blunted in four SAD women with winter depression as compared with four healthy female controls. The SAD patients did not have blunted heat loss following a successful antidepressant response to phototherapy or during a summer euthymic state. The same researchers have reported similar findings using prolactin as a neuroendocrine measure of dopamine activity. This area of investigation is provocative, but clearly very preliminary. There is also preliminary evidence suggesting the transient depressive symptomatology often found in detoxifying alcoholic patients may be related to reduced dopaminergic activity. Miller et all2 studied 15 alcoholic patients during an 8-day detoxification period and found increased serum prolactin levels which were positively correlated to depression ratings. Since dopamine inhibits prolactin release, increased serum prolactin is a proposed neuroendocrine marker of decreased brain dopamine function. Geriattic depression is another depressive subtype worthy of discussion. There are two forms of MAO enzymes in humans. MAO-A selectively metabolizes norepinephrine and serotonin, whereas MAO-B primarily metabolizes dopamine. MAO-B is the predominant MAO enzyme in the brain and its activity has been shown to increase with age. In fact, the increase in MAO-B activity begins in middle age, which coincides with the increased incidence of depressive illness. This leads to the inference that late-life depression may be related to decreased brain dopamine. Unfortunately, there are no clinical studies investigating dopamine-active antidepressants (eg, selective MAO-B inhibitors) in geriatric depressives. Several investigators have hypothesized that the depression associated with Parkinson’s disease is a result of dopamine deficiency. This hypothesis follows from the established link between decreased basal ganglion dopamine activity and the neurological findings in Parkin-
118
son’s disease. Surprisingly, there is little empirical work addressing the question of dopamine’s role in depression occurring with Parkinson’s disease. An interesting study by Cantello et a123 compared 18 L-dopa-treated Parkinson’s patients who manifested typical “end-of-dose” deterioration with increased disability and immobility versus 12 controls with chronic rheumatoid arthritis who exhibited similar fluctuations in disability and immobility. They found that the temporary immobility was accompanied by adverse changes in mood that were significantly more marked in the Parkinson’s patients than in the controls. Psychotic (delusional) depression is the only depressive subtype for which the evidence points to increased dopamine activity. Four studies have demonstrated increased levels of CSF HVA in psychotic depressives as compared with depressed patients without psychotic features.’ Neuroleptics (which are potent dopamine antagonists) have an undisputed therapeutic role in psychotic depression. These findings are consistent with the dopamine hypothesis of schizophrenia, which argues that increased dopamine activity contributes to psychotic symptoms. Perhaps psychotic depression exemplifies dopamine having different roles depending on the dopamine pathway involved.
DIEHL AND GERSHON
affect several neurotransmitter systems in addition to being potent dopamine antagonists. The importance of dopamine antagonism per se is substantiated by two controlled studies which found that the relatively selective dopamine antagonist pimozide was as effective as typical neuroleptics in treating manic patients.30331 Other evidence is derived from the measurement of HVA in the CSF of manic patients. The prediction is that increased dopamine activity will lead to higher CSF HVA levels. The majority of such studies have indeed reported increased CSF HVA concentrations in manic patients as compared with controls.’ Another source of support is the dopamine effects of antimanic drugs other than the previously discussed neuroleptics. Waldmeier3* provides an excellent review of the neurotransmitter effects of lithium, carbamazepine, and valproate. He surveyed the major mood-implicated neurotransmitter systems in search of a “common denominator” of these medications and concluded that similarities of these drugs are most evident with respect to reduced dopaminergic transmission. There is considerable literature demonstrating that lithium attenuates dopamine activity. However, the evidence is equivocal regarding how and where lithium interacts with the dopamine system (presynaptic v postsynaptic). CarMANIA: EVIDENCE FOR DOPAMINE bamazepine and valproate are not as extensively HYPOTHESIS studied, but the dopamine effects appear to be mediated by GABA. One source of support for a role of increased Neuroendocrine studies have also been condopamine function in the pathogenesis of mania ducted to investigate possible dopaminergic is the clinical effects of dopamine agonists and dysfunction in manic patients. Researchers have antagonists. It is well established that psychomopredicted decreased baseline levels of prolactin, tor stimulants such as amphetamine cause a increased baseline growth hormone levels, and euphoric response that has some behavioral altered neuroendocrine responses to dopamine similarities to mania. Several studies have demagonists. These studies have mostly been negaonstrated the elated response to stimulants can tive. be blocked by dopamine antagonists.“-27 L-dopa, We have presented evidence of dopamine piribedil and bromocriptine have all been shown dysfunction for both bipolar depression and to precipitate manic symptoms in small studies mania. This raises the question of how dopaor case reports of depressed patients.11X”Z28.29 mine might be involved in the switch from This effect has been most prominent in bipolar depression to mania and vice versa in manicdepressives. depressive illness. One switch hypothesis argues There is clear evidence that neuroleptics are that decreased presynaptic dopamine release in effective drugs in mania. However, inferences depression leads to compensatory postsynaptic from this regarding dopamine hyperactivity in receptor upregulation, which sets the stage for a mania are limited, since typical neuroleptics
THE ROLE OF DOPAMINE
119
IN MOOD DISORDERS
subsequent mania. When the presynaptic dopamine release “normalizes,” the upregulated postsynaptic receptors result in increased dopaminergic neurotransmission. Of course, the above reasoning could be equally well applied to other neurotransmitter systems implicated in mood disorders. TOWARD AN INTEGRATED
MODEL
Two types of integration will be addressed in this section. We will first consider the need to integrate the above dopamine “facts” with what is known of brain anatomy and pharmacology. Investigators often view the brain as a sort of soup in which too much of one neurotransmitter or too little of another results in pathological states. This simple approach has been of tremendous heuristic importance, but may now have outlived its usefulness. Swerdlow and Koob’ have offered a highly speculative hypothesis of depression and mania, which exemplifies this integrative approach. They propose that dopamine underactivity and overactivity may be related to depression and mania, respectively, through its effects on cortico-striato-pallidothalamic function. The challenge is to develop ways to empirically test such hypotheses. There is also a need to integrate the above dopamine facts with other neurotransmitter findings in mood disorders. It seems highly unlikely that any single neurotransmitter system will fully explain the pathophysiology of affective disorders. Indeed, many investigators have reported relationships between the various neurotransmitters implicated in mood disorders.
For example, Janowsky et al” hypothesize that depression and mania may be determined by a balance between central cholinergic and adrenergic neurotransmitter activity. Antelman and Caggiula34 argue that the reduced norepinephrine associated with bipolar depression could produce increased activity of the dopamine system, which in turn might lead to a switch into mania. CONCLUSIONS/FUTURE
DIRECTIONS
There is considerable evidence that dopamine dysfunction plays some role in mania and at least certain subtypes of depression. The depressive subtypes most strongly implicated are bipolar and retarded depressions. The question of whether dopamine dysfunction is primary to the pathogenesis of these mood disorders or simply a secondary phenomenon is far from answered. Even if it is a secondary process, this does not preclude the possibility that treatments affecting dopamine neurotransmission will ameliorate affective symptoms. In fact, there is good evidence that dopamine-active treatments have some therapeutic efficacy in mood disorders. We conclude by suggesting future research directions. In the preclinical arena, the integrative approaches described previously should be emphasized. Clinical studies are needed to investigate the efficacy of dopamine-active antidepressants in specific subtypes of depression. Depressive subtypes that should be emphasized include bipolar, retarded, and geriatric depressions.
REFERENCES 1. Jimerson DC. Role of dopamine mechanisms in the affective disorders. In: Meltzer HY (ed): Psychopharmacology: The Third Generation of Progress. New York, NY, Raven, 1987:505-511. 2. Swerdlow NR, Koob GF. Dopamine, schizophrenia, mania, and depression: toward a unified hypothesis of cortico-striato-pallido-thalamic function. Behav Brain Sci 1987;10:197-245. 3. Janowsky DS, El-Yousef MK. Davis JM, Sekerke HJ. Provocation of schizophrenic symptoms by intravenous administration of methylphenidate. Arch Gen Psychiatry 1973;28:185-191. 4. Kiloh LG, Neilson M. Andrews depressed patients to methylamphetamine. 19743125-496-499.
G.
Response of Br J Psychiatry
5. Roberts JM. Prognostic factors in the electroshock treatment of depressive states. J Ment Sci 1959;105:703-713. 6. Silberman EK, Reus VI, Jimerson DC. Lynott AM, Post RM. Heterogeneity of amphetamine response in depressed patients. Am J Psychiatry 1981;138:1302-1307. 7. Post RM, Gerner RH, Carman JS, Gillin JC. Jimerson DC, Goodwin FK, et al. Effects of a dopamine agonist piribedil in depressed patients. Arch Gen Psychiatry 1978;35: 609-615. 8. Theohar C, Fischer-Cornelssen K. Brosch H, Fischer EK, Petrovic D. A comparative, multicenter trial between bromocriptine and amitriptyline in the treatment of endogenous depression. Arzneimittelforsch 1982;32:783-789. 9. Waehrens J, Gerlach J. Bromocriptine and imipramine in endogenous depression. J Affect Disord 19X1:3:193202.
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10. Randrup A, Munkvad I, Fog R, Gerlach J, Molander L, Kjellberg B, et al. Mania, depression, and brain dopamine. Current Dev Psychopharmacol1975;2:205-248. 11. Silverstone T. Response to bromocriptine distinguishes bipolar from unipolar depression. Lancet 1984;1:903904. 12. Murphy DL, Brodie HKH, Goodwin FK, Bunney WE. Regular induction of hypomania by L-dopa in “bipolar” manic-depressive patients. Nature 1971;229:135-136. 13. van Praag HM, Korf J: Central monoamine deficiency in depressions: causative or secondary phenomenon? Pharmakopsychiatrie 1975;8:322-326. 14. Banki CM. Correlation between cerebrospinal fluid amine metabolites and psychomotor activity in affective disorders. J Neurochem 1977;28:255-257. 1.5. van Praag HM, Korf J: Retarded depression and the dopamine metabolism. Psychopharmacologia 1971;19:199203. 16. Goodwin FK, Post RM, Dunner DL, Gordon EK. Cerebrospinal fluid amine metabolites in affective illness: the probenecid technique. Am J Psychiatry 1973;130:73-79. 17. Vestergaard P, Sorensen T, Hoppe E, Rafaelsen OJ, Yates CM, Nicolaou N. Biogenic amine metabolites in cerebrospinal fluid of patients with affective disorders. Acta Psychiatr Stand 1978;58:88-96. 18. Asberg M, Bertilsson L, MBrtensson B, Scalia-Tomba GP, Thoren P, Traskman-Bendz L. CSF monoamine metabolites in melancholia. Acta Psychiatr Stand 1984;69:201219. 19. Roy A, Pickar D, Linolla A, Doran AR, Ninan P, Paul SM. Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia. Psychiatry Res 1985;15:281-292. 20. Kabins D, Gershon S. Potential applications for MAO-B inhibitors. Dementia 1990;1:323-349. 21. Arbisi PA, Depue RA, Spoont MR, Leon A, Ainsworth B. Thermoregulatory response to thermal challenge in seasonal affective disorder: preliminary report. Psychiatry Res 1989;28:323-334.
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22. Miller F, Barasch A, Sacks M, Levitan J, Ashcroft L. Serum prolactin correlates with depressed mood during alcohol withdrawal. Drug Alcohol Depend 1986;17:331-338. 23. Cantello R, Gilli M, Riccio A, Bergamasco B. Mood changes associated with “end-of-dose deterioration” in Parkinson’s disease: a controlled study. J Neurol Neurosurg Psychiatry 1986;49:1182-1190. 24. Gunne LM, Anggard E. Pharmacokinetic studies with amphetamine-relationship to neuropsychiatric disorders. J Pharmacokinet Biopharmaceut 1973;1:481-495. 25. Jonsson LE, Anggard E, Gunne LM. Blockade of intravenous amphetamine euphoria in man. Clin Pharmacol Therapeut 1971;12:889-896. 26. Nurnberger JI, Gershon ES, Simmons S, Ebert M, Kessler LR, Dibble ED, et al. Behavioral, biochemical and neuroendocrine responses to amphetamine in normal twins and “well-state” bipolar patients. Psychoneuroendocrinology 1982;7:163-176. 27. Wald D, Ebstein RP, Belmaker RH. Haloperidol and lithium blocking of the mood response to intravenous methylphenidate. Psychopharmacology 1978;57:83-87. 28. Gerner RH, Post RM, Bunney WE. Dopaminergic mechanism in mania. Am J Psychiatry 1976;133:1177-1180. 29. Johnson JM. Treated mania exacerbated by bromocriptine. Am J Psychiatry 1981;138:980-982. 30. Cookson J, Silverstone T, Wells B. Double-blind comparative clinical trial of pimozide and chlorpromazine in mania. Acta Psychiatr Stand 1981;64:381-397. 31. Post RM, Jimerson DC, Bunney WE, Goodwin FK. Dopamine and mania: behavioral and biochemical effects of the dopamine receptor blocker pimozide. Psychopharmacology 1980;67:297-305. 32. Waldmeier PC. Is there a common determinator for the antimanic effect of lithium and anticonvulsants? Pharmacopsychiatry 1987;20:37-47. 33. Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ. A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972;2:6732-6735. 34. Antelman SM, Caggiula AR. Norepinephrine-dopamine interactions and behavior. Science 1977;195:646-653.
in Mood Disorders
David J. Diehl and Samuel Gershon The findings on dopamine in mood disorders suggest that decreased dopamine activity is involved in depression, while increased dopamine function contributes
pression. We also discuss the importance of integrating these dopamine findings with dopamine brain circuitry and with other neurotransmitter theories of
to mania. This report reviews the considerable preclinical and clinical evidence supporting this hypothesis, with particular emphasis on specific subtypes of de-
affective disorders. Copyright 0 1992 by W.B. Saunders Company
M
theories of mood OST ETIOLOGICAL disorders have proposed functional increase or decrease in a given neurotransmitter system. Neurotransmitters invoked have included acetylcholine, y-aminobutyric acid (GABA), and, most frequently, the monoamines norepinephrine and serotonin. These neurotransmitter hypotheses have been of great heuristic importance, but have certainly not yielded “the answer” to the etiology of mood disorders. Dopamine has been cited less often than the other monoamines in the neurotransmitter hypotheses of mood disorders. However, dopamine has also been widely implicated in the pathophysiology of affective syndromes. In its simplest form, the dopamine hypothesis suggests that decreased dopamine neurotransmission is involved in the pathogenesis of depression, while increased functional dopamine activity contributes to the symptoms of mania.’ This report will review the evidence supporting dopamine’s role in depression with particular emphasis on different subtypes of depression. We will separately examine the evidence suggesting dopamine overactivity in mania. We will then address the need to integrate these dopamine “facts” with dopamine brain circuitry and with other neurotransmitter findings in mood disorders. DEPRESSION:
EVIDENCE FOR DOPAMINE HYPOTHESIS
There are several types of evidence suggesting dopamine activity is decreased in depression. In some instances, the data implicate specific subtypes of depression, and this will be discussed in detail in the next section. We will first briefly consider evidence from animal models of depression. In the “learned helplessness” model, rats are subjected to unpredictable electric shocks and are subsequently
found to have decreased learning of new behavioral tasks. Rats exposed to this paradigm have shown decreased levels of dopamine in subcortical brain regions. The learning deficits are exacerbated when the rats are given dopamine antagonists and lessened by dopamine agonists. The “behavioral despair” model involves forcing rats to swim in a confined space. The behavioral consequence is prolonged immobility. Dopamine antagonists increase this immobility, while dopamine agonists decrease it. Tricyclic antidepressants and electroconvulsive therapy also diminish the despair immobility.’ Conclusions from such studies are tenuous, since it is uncertain how well the rat paradigms model human depression. Another source of support for the dopamine hypothesis is the clinical effects of dopamine agonists and antagonists. Jimerson’ provides a good review of this literature. Four studies have reported that at least half of depressed subjects show temporary improvement in depressive symptoms following intravenous administration of methylamphetamine or methylphenidate.3” Of course, these psychomotor stimulants increase norepinephrine as well as dopamine activity. The relatively selective dopamine receptor agonist piribedil showed mild to moderate antidepressant effect in 12 of 16 depressed patients, with greater improvement in patients with lower baseline levels of the dopamine metabolite homovanillic acid (HVA) in their cerebrospinal fluid (CSF).’ Several investigators have demonstrated an antidepressant effect of the dopamine agonist bromocriptine, including From the Department of Psychiatry UrGersi& of Pittsburgh School of Medicine, Pittsburgh, PA. Address reprint requests to David J. Diehl, M.D., Department of Psychiatry, Universiryof Pittsburgh School of Medicine, 381 I O’Hara St, Pittsburgh, PA 15213. Copyright 0 1992 by W.B. Saunders Company OOlO-440X19213302-0007$03.00l0
Comprehensive Psychiatry, Vol. 33, No. 2 (March/April), 1992: pp 115-120
115
116
two fairly large double-blind, controlled studies. Theohar et al’ found no statistically significant difference in antidepressant response between bromocriptine and amitriptyline in 83 endogenously depressed patients. The second study compared bromocriptine to imipramine in 33 endogenous depressives and showed no significant difference in therapeutic effect.’ Based on the dopamine hypothesis, one would predict that dopamine antagonists would result in or exacerbate depressive symptoms. There are indeed many reports of patients experiencing depressive states while receiving neuroleptics. However, there are also reports of neuroleptics having an antidepressant effect. For the interested reader, Randrup et al” provide a review of this body of literature. Another type of evidence for the dopamine hypothesis is the measurement of the dopamine metabolite HVA in the CSF of depressed patients. The prediction is that decreased functional dopamine activity will lead to reduced HVA levels in the CSF. Several studies have addressed this question with substantial variability in their findings. Jimerson’ points out that of the six studies with the soundest methodology (including at least a lo-day medication-free period), five show decreased CSF HVA in depressed patients compared with controls. Some studies have actually demonstrated increased HVA levels in the CSF, and these will be further discussed in the section on subtypes of depression. The presence of effective “dopamine-active” antidepressants also supports the role of dopamine in depression. Bupropion is a relatively selective dopamine reuptake inhibitor that also has some direct agonist action on dopamine receptors. This second-generation antidepressant has demonstrated superior efficacy to placebo and equal efficacy to amitriptyline in double-blind comparisons. Nomifensine is another proven antidepressant with potent dopamine reuptake blocking properties. However, nomifensine is also a strong inhibitor of norepinephrine reuptake. Selective monoamine oxidase (MAO)-B inhibitors (eg, L-deprenyl) have shown some antidepressant effect for certain subtypes of depression. These medications selectively inhibit the metabolism of dopamine while
DIEHL AND GERSHON
leaving norepinephrine and serotonin relatively unaffected. The more “traditional” somatic treatments of depression have also been shown to affect dopamine function.’ Tricyclic antidepressants block dopamine reuptake, although this effect is generally less potent than effects on other neurotransmitters. Chronic tricyclic antidepressant treatment has also been shown to decrease the sensitivity of dopamine autoreceptors and increase sensitivity of postsynaptic dopamine receptors. Investigators have reported that MAO inhibitors reduce dopamine autoreceptor sensitivity which could secondarily increase postsynaptic dopamine concentrations. In infrahuman studies, repeated electroconvulsive shocks have been shown to increase the response to dopamine agonists, suggesting an enhanced postsynaptic activity.’ Neuroendocrine studies have been performed to investigate possible dopaminergic dysfunction in depression. The assumption is that changes in the tuberoinfundibular dopamine pathway may reflect changes in the mesolimbic and mesocortical systems. Dopamine inhibits prolactin release and stimulates growth hormone release. Some investigators have predicted blunted neuroendocrine response to dopamine precursors in depressed patients consistent with the hypothesis of decreased presynaptic dopamine release in depression. These researchers predict increased neuroendocrine response to dopamine postsynaptic receptor agonists secondary to compensatory recepOthers hypothesize that tor upregulation. reduced dopaminergic transmission in depression results from a primary decrease in postsynaptic receptor function, and thus they predict a blunted neuroendocrine response to both dopamine precursors and receptor agonists. These neuroendocrine studies have been largely negative and, if taken alone, provide little support for dopamine dysfunction in depression. SUBTYPES OF DEPRESSION
Even proponents of the dopamine hypothesis of depression usually emphasize that dopamine dysfunction is probably only important for certain symptoms or subtypes of depression. We will first consider bipolar depression. Silberman et al6 administered intravenous amphet-
THE ROLE OF DOPAMINE
IN MOOD DISORDERS
amine to depressed subjects and found that seven of seven bipolar versus only five of 11 unipolar patients exhibited an elated response. Silverstone” demonstrated a more clear-cut antidepressant response to bromocriptine in five bipolar depressives as compared with five unipolar patients in an open study. Interestingly, two of the bipolar subjects developed manic symptoms. The catecholamine precursor L-dopa has also been shown to produce manic symptoms more often in bipolar than unipolar depressed patients.‘* These studies suggest a possible role of dopamine in bipolar depression, but conclusions are limited because of the nature and number of the investigations. Another understudied depressive subtype is depression with prominent psychomotor retardation. Retarded depression is of theoretical importance because of the known role of basal ganglion dopamine function in motor activity, including the established link between decreased dopamine activity and pathological hypokinesia (ie, Parkinson’s disease). Van Praag and Korf13 treated five retarded and five nonretarded depressives with L-dopa for 2 weeks and found that motor retardation markedly improved, while mood scores did not change significantly in either group. The retarded subgroup had lower CSF HVA levels which increased following L-dopa treatment. Two other studies have shown a positive correlation between psychomotor activity and CSF HVA level in medication-free depressed patients’4X’s;however, there have also been two negative studies exploring this question.lO,” The small body of literature addressing endogenous versus nonendogenous depression has yielded conflicting results. Asberg et al’* found significantly lower concentrations of CSF HVA in 83 melancholic depressives as compared with 66 healthy controls. Roy et all9 compared 15 patients with major depression with melancholia to 13 subjects with either major depression without melancholia or dysthymia. The melancholic depressives had significantly lower levels of CSF HVA. On the other hand, the small experience with the selective MAO-B inhibitor L-deprenyl in depressed patients suggests a preferential response in nonendogenous depressives.“’ Seasonal afective disorder (SAD) has recently
117
been investigated with respect to possible decreased dopaminergic function. This is theoretically appealing because SAD patients characteristically have significant psychomotor slowing. Arbisi et al” studied the thermoregulatory heat loss to an endogenous heat challenge, which dopamine is thought to mediate. They found heat loss significantly blunted in four SAD women with winter depression as compared with four healthy female controls. The SAD patients did not have blunted heat loss following a successful antidepressant response to phototherapy or during a summer euthymic state. The same researchers have reported similar findings using prolactin as a neuroendocrine measure of dopamine activity. This area of investigation is provocative, but clearly very preliminary. There is also preliminary evidence suggesting the transient depressive symptomatology often found in detoxifying alcoholic patients may be related to reduced dopaminergic activity. Miller et all2 studied 15 alcoholic patients during an 8-day detoxification period and found increased serum prolactin levels which were positively correlated to depression ratings. Since dopamine inhibits prolactin release, increased serum prolactin is a proposed neuroendocrine marker of decreased brain dopamine function. Geriattic depression is another depressive subtype worthy of discussion. There are two forms of MAO enzymes in humans. MAO-A selectively metabolizes norepinephrine and serotonin, whereas MAO-B primarily metabolizes dopamine. MAO-B is the predominant MAO enzyme in the brain and its activity has been shown to increase with age. In fact, the increase in MAO-B activity begins in middle age, which coincides with the increased incidence of depressive illness. This leads to the inference that late-life depression may be related to decreased brain dopamine. Unfortunately, there are no clinical studies investigating dopamine-active antidepressants (eg, selective MAO-B inhibitors) in geriatric depressives. Several investigators have hypothesized that the depression associated with Parkinson’s disease is a result of dopamine deficiency. This hypothesis follows from the established link between decreased basal ganglion dopamine activity and the neurological findings in Parkin-
118
son’s disease. Surprisingly, there is little empirical work addressing the question of dopamine’s role in depression occurring with Parkinson’s disease. An interesting study by Cantello et a123 compared 18 L-dopa-treated Parkinson’s patients who manifested typical “end-of-dose” deterioration with increased disability and immobility versus 12 controls with chronic rheumatoid arthritis who exhibited similar fluctuations in disability and immobility. They found that the temporary immobility was accompanied by adverse changes in mood that were significantly more marked in the Parkinson’s patients than in the controls. Psychotic (delusional) depression is the only depressive subtype for which the evidence points to increased dopamine activity. Four studies have demonstrated increased levels of CSF HVA in psychotic depressives as compared with depressed patients without psychotic features.’ Neuroleptics (which are potent dopamine antagonists) have an undisputed therapeutic role in psychotic depression. These findings are consistent with the dopamine hypothesis of schizophrenia, which argues that increased dopamine activity contributes to psychotic symptoms. Perhaps psychotic depression exemplifies dopamine having different roles depending on the dopamine pathway involved.
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affect several neurotransmitter systems in addition to being potent dopamine antagonists. The importance of dopamine antagonism per se is substantiated by two controlled studies which found that the relatively selective dopamine antagonist pimozide was as effective as typical neuroleptics in treating manic patients.30331 Other evidence is derived from the measurement of HVA in the CSF of manic patients. The prediction is that increased dopamine activity will lead to higher CSF HVA levels. The majority of such studies have indeed reported increased CSF HVA concentrations in manic patients as compared with controls.’ Another source of support is the dopamine effects of antimanic drugs other than the previously discussed neuroleptics. Waldmeier3* provides an excellent review of the neurotransmitter effects of lithium, carbamazepine, and valproate. He surveyed the major mood-implicated neurotransmitter systems in search of a “common denominator” of these medications and concluded that similarities of these drugs are most evident with respect to reduced dopaminergic transmission. There is considerable literature demonstrating that lithium attenuates dopamine activity. However, the evidence is equivocal regarding how and where lithium interacts with the dopamine system (presynaptic v postsynaptic). CarMANIA: EVIDENCE FOR DOPAMINE bamazepine and valproate are not as extensively HYPOTHESIS studied, but the dopamine effects appear to be mediated by GABA. One source of support for a role of increased Neuroendocrine studies have also been condopamine function in the pathogenesis of mania ducted to investigate possible dopaminergic is the clinical effects of dopamine agonists and dysfunction in manic patients. Researchers have antagonists. It is well established that psychomopredicted decreased baseline levels of prolactin, tor stimulants such as amphetamine cause a increased baseline growth hormone levels, and euphoric response that has some behavioral altered neuroendocrine responses to dopamine similarities to mania. Several studies have demagonists. These studies have mostly been negaonstrated the elated response to stimulants can tive. be blocked by dopamine antagonists.“-27 L-dopa, We have presented evidence of dopamine piribedil and bromocriptine have all been shown dysfunction for both bipolar depression and to precipitate manic symptoms in small studies mania. This raises the question of how dopaor case reports of depressed patients.11X”Z28.29 mine might be involved in the switch from This effect has been most prominent in bipolar depression to mania and vice versa in manicdepressives. depressive illness. One switch hypothesis argues There is clear evidence that neuroleptics are that decreased presynaptic dopamine release in effective drugs in mania. However, inferences depression leads to compensatory postsynaptic from this regarding dopamine hyperactivity in receptor upregulation, which sets the stage for a mania are limited, since typical neuroleptics
THE ROLE OF DOPAMINE
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IN MOOD DISORDERS
subsequent mania. When the presynaptic dopamine release “normalizes,” the upregulated postsynaptic receptors result in increased dopaminergic neurotransmission. Of course, the above reasoning could be equally well applied to other neurotransmitter systems implicated in mood disorders. TOWARD AN INTEGRATED
MODEL
Two types of integration will be addressed in this section. We will first consider the need to integrate the above dopamine “facts” with what is known of brain anatomy and pharmacology. Investigators often view the brain as a sort of soup in which too much of one neurotransmitter or too little of another results in pathological states. This simple approach has been of tremendous heuristic importance, but may now have outlived its usefulness. Swerdlow and Koob’ have offered a highly speculative hypothesis of depression and mania, which exemplifies this integrative approach. They propose that dopamine underactivity and overactivity may be related to depression and mania, respectively, through its effects on cortico-striato-pallidothalamic function. The challenge is to develop ways to empirically test such hypotheses. There is also a need to integrate the above dopamine facts with other neurotransmitter findings in mood disorders. It seems highly unlikely that any single neurotransmitter system will fully explain the pathophysiology of affective disorders. Indeed, many investigators have reported relationships between the various neurotransmitters implicated in mood disorders.
For example, Janowsky et al” hypothesize that depression and mania may be determined by a balance between central cholinergic and adrenergic neurotransmitter activity. Antelman and Caggiula34 argue that the reduced norepinephrine associated with bipolar depression could produce increased activity of the dopamine system, which in turn might lead to a switch into mania. CONCLUSIONS/FUTURE
DIRECTIONS
There is considerable evidence that dopamine dysfunction plays some role in mania and at least certain subtypes of depression. The depressive subtypes most strongly implicated are bipolar and retarded depressions. The question of whether dopamine dysfunction is primary to the pathogenesis of these mood disorders or simply a secondary phenomenon is far from answered. Even if it is a secondary process, this does not preclude the possibility that treatments affecting dopamine neurotransmission will ameliorate affective symptoms. In fact, there is good evidence that dopamine-active treatments have some therapeutic efficacy in mood disorders. We conclude by suggesting future research directions. In the preclinical arena, the integrative approaches described previously should be emphasized. Clinical studies are needed to investigate the efficacy of dopamine-active antidepressants in specific subtypes of depression. Depressive subtypes that should be emphasized include bipolar, retarded, and geriatric depressions.
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