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The prolactin response to sulpiride in major depression: the role of the D2 receptor in depression
European Neuropsychopharmacology 11 (2001) 215–220 www.elsevier.com / locate / euroneuro
The prolactin response to sulpiride in major depression: the role of the D 2 q receptor in depression a d, b c W.J.C. Verbeeck , M. Berk *, J. Paiker , B. Jersky
b
a Department of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa Department of Chemical Pathology, University of the Witwatersrand, Johannesburg, South Africa c Department of Mathematics, University of Sonoma, Sonoma, CA, USA d Department of Psychiatry, University of Melbourne, Melbourne, Australia
Received 10 August 2000; accepted 27 February 2001
Abstract Multiple lines of investigations have implicated the role of the dopaminergic system in depression. The aim of the study was to characterise the Dopamine D 2 receptor sensitivity status in depressed patients versus controls by means of a novel neuro-endocrine challenge test, the prolactin response to sulpiride. In this intervention, ten patients and ten age matched male volunteers were studied. The patients were diagnosed according to DSM-IV criteria, and Montgomery Asberg and Zung scales were done. There was no significant difference in baseline levels of prolactin between the depressed and control groups. Significantly higher prolactin levels after sulpiride challenge were however found in depressed patients than controls at all time points after sulpiride administration. This neuroendocrine challenge paradigm suggests that the prolactin response to sulpiride, a D 2 receptor antagonist, is enhanced in depression, which suggests that this receptor might be supersensitive in depression compared to controls. This adds to the data implicating the dopaminergic system in the pathophysiology of depression, and suggests that dopaminergic mechanisms might be a target of therapeutic interest. 2001 Elsevier Science B.V. / ECNP. All rights reserved.
1. Introduction The behavioural functions reward and motivation, subserved by the mesolimbic dopamine system have prompted researchers to hypothesise that hypofunction of this system make it a candidate to mediate the anhedonia and loss of motivation, that are part of major depressive disorder (Willner, 1995). The role of dopamine in depression is evidenced by many preclinical and clinical studies, that have examined multiple facets of the dopaminergic system, ranging from in vitro molecular biological experiments to randomised controlled trials.
q
This study was undertaken by W.J.C. Verbeeck as part of the requirements of obtaining the MPharmMed degree in the Department of Pharmacology, Faculty of Medicine, University of Pretoria. *Corresponding author. Present address: Mental Health–Swanston Centre, P.O. Box 281, Geelong, Victoria 3200, Australia. Tel.: 161-35226-7410; fax: 161-3-5226-7436. E-mail address: [email protected] (M. Berk).
Results of several animal model studies of depression have been consistent with dopamine-deficiency in depression. Animal models demonstrating the behavioural equivalent of depression improved by administration of dopamine agonists or antidepressants. Conversely, dopamine antagonists aggravated their symptoms (Mann and Kapur, 1995). An association between low homovanillic acid levels (HVA) in cerebrospinal fluids (CSF) has been demonstrated, particularly in depressed patients with psychomotor retardation (Mann and Kapur, 1995). Studies in suicide attempters also found low HVA in CSF (Engstrom et al., 1999), whereas reduced dihydroxyphenyl–acetic concentrations were observed in the basal ganglia of depressed patients in completed suicide (Bowden et al., 1997). Higher HVA and dopamine levels in CSF and plasma of psychotically depressed patients have been reported in several, but not all, studies (Schatzberg et al., 1995). Decreased dopamine-beta-hydroxylase activity in unipolar psychotic depression further substantiates presynaptic
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. / ECNP. All rights reserved. PII: S0924-977X( 01 )00086-4
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dysregulation of the dopamine system in a subgroup of depressed patients (Meyers et al., 1999; Serrete et al., 1998). There is sufficient clinical evidence that rendering the dopaminergic system hypoactive, via presynaptic dopamine depletion (reserpine) or postsynaptic blockade (classical neuroleptics), is frequently associated with a depressive syndrome (Kapur and Mann, 1992). In a similar vein, the incidence of depression in Parkinson’s disease, characterised by degeneration of the nigrostriatal dopaminergic system and loss of dopaminergic mesolimbic projections, is higher than in healthy controls (Mayeux, 1990). Agents that enhance dopaminergic transmission (amphetamine, bromocriptine) are euphorogenic and can precipitate mania. Agents such as pergolide, dextroamphetamine, methylphenidate and pemoline have been studied as antidepressant adjuncts, although the evidence is limited by unsatisfactory study methodology (Fawcett et al., 1991). Their use as antidepressants or as augmentation strategies is mainly based on clinical experience rather than clinical trials. Controlled studies with dopamine re-uptake inhibitors, such as nomifensine (Grof et al., 1977), bupropion (Lineberry et al., 1990), minaprine and amineptine (Rampello et al., 1991) have demonstrated antidepressant activity. Venlafaxine,a serotonin and noradrenaline re-uptake inhibitor, inhibits dopamine re-uptake in high dosages (Stahl, 1996). There exists some evidence that other classes of antidepressants apart from dopamine re-uptake inhibitors have effects on dopaminergic neurotransmission (Klimek and Maj, 1989). These include the classical MAO inhibitors. The decrease in D 2 and D 3 receptor numbers in chronic mild stress in animals is completely reversed by long term treatment with imipramine (Papp et al., 1994), implying this agent causes an increase in the responsiveness of D 2 –D 3 receptors in the nucleus accumbens. A recent study using a behavioural model of depression in rats, concluded that an increased dopaminergic activity is a neurochemical effect common to amineptine, desipramine and imipramine (Besson et al., 1999). Although an increase in D 2 and D 3 responsiveness or increased dopamine in the prefrontal cortex (Carlson et al., 1996), may be responsible for the therapeutic actions of some antidepressants, the data remain preclinical and are often demonstrated in animal models of depression, which compromises extrapolation. Several experiments hypothesise that SSRI’s exert their antidepressant actions by increasing dopaminergic transmissions in the mesolimbic system. Fluoxetine initially inhibits the mesolimbic dopamine pathway by enhancing the extracellular level of serotonin, probably mediated via 5-HT2b / 2c receptors (Prisco et al., 1994). This short-term inhibitory effect of fluoxetine on the mesolimbic dopamine system is followed by restoration of the dopaminergic neurotransmission, after long term fluoxetine treatment. There is a subsequent increase of D 2 receptors in the
limbic system, which could result from a compensatory reaction to offset fluoxetine induced inhibition of dopaminergic neurons. Thus repeated administration of fluoxetine might elicit an increased function of the mesolimbic dopamine system (Bonhomme and Esposito, 1998). It is suggested that drugs acting on the serotonergic system, such as serotonin selective re-uptake inhibitors and 5-HT 2b / 2c receptor antagonists such as mianserin, would exert their antidepressant actions by enhancing dopaminergic transmission in the mesolimbic pathway (Bonhomme and Esposito, 1998, Tiihohen et al., 1996). There are however negative studies. A microdialysis study in monkeys administered fluoxetine did not find any increase in dopamine with chronic administration (Smith et al., 2000). Similarly, a PET study failed to find any effect of fluvoxamine on D 2 binding in the basal ganglia (Moresco et al., 2000). Klimke et al. (1999) also found no difference in D 2 binding between depressed patients and controls using SPECT, although interestingly he found a correlation between higher binding and a poor response to SSRI’s. Healy and McKeon (2000) also found using a neuroendocrine challenge, that there was an association between higher dopamine sensitivity and poor response to SSRI’s. There is provisional evidence that sulpiride may have antidepressant effects, which may be hypothetically mediated via presynaptic blockade (at low dosage), thereby increasing dopamine turnover (Standish-Barry et al., 1983). Both experimental animal models (Vergoni et al., ¨ 1995) and controlled trials (Ruther et al., 1999) support the notion that low dose sulpiride may have antidepressant-like activity. Similar antidepressant properties have been published in controlled trials with flupenthixol (Tam et al., 1982). Amisulpiride, a selective D 2 and D 3 antagonist, acts preferentially on presynaptic receptors, increasing dopaminergic transmission at low dosages. The results of a controlled study showed amisulpiride to be effective in the treatment of dysthymia (Boyer et al., 1999; Lecrubier et al., 1997). The antidepressant amoxapine has the capacity to antagonise D 2 receptors, and is equally effective to that of an antidepressant plus an antipsychotic in systematic double-blind trials of psychotic depression (Kapur et al., 1999). Dopaminergic transmission is also enhanced by electroconvulsive therapy (Costain et al., 1982). Both single photon emission computerised tomography (SPECT) (D’Haenen and Bossuyt, 1994) and single photon emission tomography (SPET) studies (Shah et al., 1997; Larisch et al., 1997) of depressed patients reported a bilateral increase in D 2 -receptor binding in the basal ganglia, this finding being compatible with a decrease in DA turnover. An increase in D 2 receptor binding in bipolar disorder was also found by Pearlson et al. (1995). A small controlled SPECT study measuring striatal dopamine transporter density in patients with depression, found the radioligand uptake reflecting dopamine transporter density to be significantly higher amongst depressed patients. This finding is unexpected, since it is generally believed that
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monoaminergic neurotransmission is lower in depression, and therefore it could be assumed that a reduction in dopamine transmission would lead to secondary downregulation of dopamine transporter density. However, the authors conclude, it is possible that up-regulation of the dopamine transporter may be the primary alteration, which leads to lower intrasynaptic (DA) and to lower dopamine neural transmission (Laasonen-Balk et al., 1999). Sulpiride is a D 2 antagonist that causes a robust increase in prolactin levels. This property was used to characterise the dopamine D 2 receptor sensitivity status in depressed patients versus healthy controls by measure of a neuroendocrine challenge test. We hypothesised that if the pathophysiology of depressive disorders involves a dysregulation in the dopamine system, the prolactin response to a dopamine D 2 antagonist will be altered in patients who are suffering from a major depression as opposed to controls.
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sulpiride was injected intravenously. Sulpiride is a benzamide derivative of which the dissociation constants (Ki ) values of D 2 and D 3 are almost the same and 6100-fold more potent than D 4. This D 2 –D 3 antagonistic selectivity is 3000-fold more potent than that at D 1 . Prolactin concentrations were accurately determined at the following time intervals: 220, 210, 0, 15, 30, 45, 60, 90, and 120 min. Prolactin levels were measured using the Chiron Diagnostics ACS: Centaur Prolactin assay, which is a two site sandwich immunoassay using direct chemiluminometric technology, which uses constant amounts of two antibodies. Statistical analysis of the data involved testing for normality using normal quantile plots, which confirmed the normality of the data. For all comparisons between groups, ANOVA was used, and a Scheffe post hoc analysis was also performed.
3. Results 2. Methods This cross-sectional study utilised a neuroendocrine challenge, which measured sequential plasma prolactin after intravenous administration of 25 mg sulpiride (Eglonyl, Sanofi-Synthelabo) to a group of ten depressed patients and 10 controls. Controls were all volunteers, mainly staff members. All 20 subjects were male. Except for one, all depressed patients were inpatients. All patients met diagnostic criteria for major depression (DSM-4) on a structured interview, the Mini International Neuropsychiatric Interview (MINI), and rated according to the Mon˚ tgomery-Asberg and Zung depression scales. The minimum age was 18 years. No treatment with agents that could affect prolactin levels was permitted. Exclusion criteria included the following: All patients were drug free for at least a month and no patients had been on fluoxetine or neuroleptics. No patients had received antidepressant treatment for the current episode. No significant medical illnesses were permitted, as were patients with substance abuse or dependence. For seven of the patients, this was their first episode of depression. No patient had a family or past history of bipolar disorder. No patients had psychotic features. Patients with another axis one diagnosis were excluded from the study. The study was approved by the Ethics Committee of the University of the Witwatersrand, Johannesburg, South Africa, and informed written consent was obtained from all subjects prior to the study (M 95116). The 20 subjects were asked to present at 07.00 h, having fasted from midnight the previous night. They relaxed for 15 min after insertion of a heparinised cannula in a forearm vein. Two baseline prolactin samples were obtained before zero time. This allowed for the calculations of a mean basal prolactin value, taking into account the pulsatile nature of the secretions. At zero time, 25 mg of
The experimental and control group both consisted of ten males. The groups were matched in terms of ethnicity and age, with the mean age of the depressed group 37.4 and that of the controls being 33.6 (P50.479, F50.52). The mean MADRS and Zung scores were 41.4 and 64.7 in the depressed group respectively, and were 7.3 and 32 respectively in the control group. These differences were highly significant (P,0.0001 for both the MADRS and Zung). In order to analyse these data, a repeated measures ANOVA was performed. There are two missing data points (two subjects at 120 min), so there are two slightly different ways to do this. One is to use a MANOVA framework for the repeated measures design, making all the points missing for the appropriate subjects, and the other is to use a univariate ANOVA with subjects nested within group. Since both these analyses provided essentially the same conclusions, we have chosen to present the latter design. There are significant differences in overall means between the experimental and the control groups (F58.4215; P50.0095), as well as significant differences in overall means between the times at which the prolactin was measured (F5125.42; P50.0001). The key point is that this significant effect differs for the two groups of patients over the various times (F57.6227; P50.0001). As a result, we did Scheffe post hoc tests to see for which of the times the two groups differed. In all cases where there was a significant difference (15, 30, 45, 60 and 90 min), the depressed group had higher means than the control group. One interesting observation is that there is an unusually high prolactin level (26) in one of the depressed patients. With this observation included, the depressed baseline mean was 8.24 (S.D.56.40). Removal of this outlier reduced the depressed group’s baseline mean to 6.27
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Table 1 Prolactin levels (mg / l) in depressed and control groups (mean6S.D., n510) Time (min)
Depressed group (n510)
Controls (n510)
ANOVA
Baseline 15 30 45 60 90 120
8.2466.40 90.88620 110.78631.25 100.94631.36 87.83627.73 72.01625.78 60.12621.42
10.6163.57 65619.76 71.79620.42 65.4617.87 59.98616.18 48.6614.08 41.29612.79
P50.320, P50.009, P50.004, P50.006, P50.013, P50.022, P50.038,
(S.D.51.51). For comparison, the control group’s baseline mean was 10.61 (S.D.53.57). Removal of this unusual observation makes virtually no difference to the repeated measures ANOVA or the Scheffe post hoc tests, so it was left in for completeness (Table 1).
4. Discussion In this study, we demonstrated that the prolactin response to sulpiride is significantly increased in males with major depression compared to healthy controls. This was expected, given the body of pharmacological and neuroimaging data documenting dysreguation of central dopaminergic function in depression. This study therefore suggests that central dopamine D 2 receptors may be supersensitive in depression. The role of the D 2 receptor in this model is implied as dopamine D 3 receptors appear not to be involved in the prolactin response (Durham et al., 1997). Although studies of basal prolactin levels have revealed no consistent change associated with depression, there is evidence of a decrease of prolactin levels in seasonal affective disorder. Some of the neurotransmitters that are implicated in the pathophysiology of depression, serotonin and dopamine, are closely involved in regulating the release of prolactin. Prolactin release is inhibited by the tubero-infundibular DA system. Numerous neuroendocrine provocation tests, challenging the hypothalamo-pituitary axis, have been published. Depending on the challenging agent, these studies reveal alterations with regard to the serotonergic, dopaminergic systems and adrenergic systems. The basal levels of prolactin, and its response to dopamine agonists or antagonists have been examined as potential markers of mood disorder (Anderson and Cowen, 1991; Joyce et al., 1987; Judd et al., 1982). A small study found that depressed patients who responded to the therapeutic actions of total sleep deprivation (TSD) showed a relative enhancement of prolactin response to 25 mg intramuscular sulpiride, and non-responders showing a relative blunting of prolactin response to sulpiride after
Scheffe F51.05 F58.47 F510.91 F59.69 F57.54 F56.34 F55.13
P50.9997 P50.0003 P50.0001 P50.0001 P50.0001 P50.0019 P50.1515
TSD. Although these findings were the opposite of their postulated hypothesis, they still indicate a possible role of dopamine in the therapeutic action of TSD (Ebert et al., 1993). The difference between these finding and the results of the current study are difficult to explain, but may be due to the intervention used (TSD) and the lack of a normal control group. There are a number of limitations to this study. Firstly fluctuations in prolactin levels occur, particularly with diurnal rhythms. This was controlled for by doing all assays at 7.00 a.m. There is in addition a seasonal variation in prolactin. Because prolactin is significantly influenced by a myriad of intra- and extra-ceptive stimuli (i.e., gender, age, menstrual status, stress, nutrition, posture, drugs including corticosteroids, obesity, medical illness and alcoholism) (Hell and Wernze, 1988) the prolactin probe as a research tool should be used in experimental conditions that control as many of these co-variables. This study controlled for gender, posture, medical illness and alcohol abuse. Inconsistent results in the literature may be related to study design that did not adequately control for the above co-variables as well as the assay used, time of sampling, neuroleptic type, and neuroleptic dose (Green and Brown, 1988). Prolactin release from pituitary lactotrophs is tonically inhibited by dopamine. The prolactin response to sulpiride therefore provides a measure of the status of dopamine receptors on pituitary lactotrophs. It is however unclear if these findings in the tuberoinfindibular pathways are generalisable to the mesolimbic pathways which are more likely to subserve the pathopysiology of affective illness. Many issues for further study are raised by these results. It needs to be established if other subtypes of depression would show a similar pattern, such as atypical or bipolar depression. The state or trait marker status of this neuroendocrine probe remains to be established. Therapeutic implications of this finding such as the use of dopaminergic agents are raised. Nevertheless this study confirms, using a novel neuroendocrine marker, that there is dopamine D 2 receptor supersensitivity in depression. This adds to the body of literature suggesting dysregulation of dopaminergic systems in depression.
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Acknowledgements This study was financially supported in part by the Department of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa. We gratefully acknowledge Dr M. van Wyk, Department of Pharmacology, University of Pretoria, for her helpful comments on the manuscript. The sulpiride was made available to us by courtesy of Sanafi–Synthelabo, South Africa.
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The prolactin response to sulpiride in major depression: the role of the D 2 q receptor in depression a d, b c W.J.C. Verbeeck , M. Berk *, J. Paiker , B. Jersky
b
a Department of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa Department of Chemical Pathology, University of the Witwatersrand, Johannesburg, South Africa c Department of Mathematics, University of Sonoma, Sonoma, CA, USA d Department of Psychiatry, University of Melbourne, Melbourne, Australia
Received 10 August 2000; accepted 27 February 2001
Abstract Multiple lines of investigations have implicated the role of the dopaminergic system in depression. The aim of the study was to characterise the Dopamine D 2 receptor sensitivity status in depressed patients versus controls by means of a novel neuro-endocrine challenge test, the prolactin response to sulpiride. In this intervention, ten patients and ten age matched male volunteers were studied. The patients were diagnosed according to DSM-IV criteria, and Montgomery Asberg and Zung scales were done. There was no significant difference in baseline levels of prolactin between the depressed and control groups. Significantly higher prolactin levels after sulpiride challenge were however found in depressed patients than controls at all time points after sulpiride administration. This neuroendocrine challenge paradigm suggests that the prolactin response to sulpiride, a D 2 receptor antagonist, is enhanced in depression, which suggests that this receptor might be supersensitive in depression compared to controls. This adds to the data implicating the dopaminergic system in the pathophysiology of depression, and suggests that dopaminergic mechanisms might be a target of therapeutic interest. 2001 Elsevier Science B.V. / ECNP. All rights reserved.
1. Introduction The behavioural functions reward and motivation, subserved by the mesolimbic dopamine system have prompted researchers to hypothesise that hypofunction of this system make it a candidate to mediate the anhedonia and loss of motivation, that are part of major depressive disorder (Willner, 1995). The role of dopamine in depression is evidenced by many preclinical and clinical studies, that have examined multiple facets of the dopaminergic system, ranging from in vitro molecular biological experiments to randomised controlled trials.
q
This study was undertaken by W.J.C. Verbeeck as part of the requirements of obtaining the MPharmMed degree in the Department of Pharmacology, Faculty of Medicine, University of Pretoria. *Corresponding author. Present address: Mental Health–Swanston Centre, P.O. Box 281, Geelong, Victoria 3200, Australia. Tel.: 161-35226-7410; fax: 161-3-5226-7436. E-mail address: [email protected] (M. Berk).
Results of several animal model studies of depression have been consistent with dopamine-deficiency in depression. Animal models demonstrating the behavioural equivalent of depression improved by administration of dopamine agonists or antidepressants. Conversely, dopamine antagonists aggravated their symptoms (Mann and Kapur, 1995). An association between low homovanillic acid levels (HVA) in cerebrospinal fluids (CSF) has been demonstrated, particularly in depressed patients with psychomotor retardation (Mann and Kapur, 1995). Studies in suicide attempters also found low HVA in CSF (Engstrom et al., 1999), whereas reduced dihydroxyphenyl–acetic concentrations were observed in the basal ganglia of depressed patients in completed suicide (Bowden et al., 1997). Higher HVA and dopamine levels in CSF and plasma of psychotically depressed patients have been reported in several, but not all, studies (Schatzberg et al., 1995). Decreased dopamine-beta-hydroxylase activity in unipolar psychotic depression further substantiates presynaptic
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. / ECNP. All rights reserved. PII: S0924-977X( 01 )00086-4
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dysregulation of the dopamine system in a subgroup of depressed patients (Meyers et al., 1999; Serrete et al., 1998). There is sufficient clinical evidence that rendering the dopaminergic system hypoactive, via presynaptic dopamine depletion (reserpine) or postsynaptic blockade (classical neuroleptics), is frequently associated with a depressive syndrome (Kapur and Mann, 1992). In a similar vein, the incidence of depression in Parkinson’s disease, characterised by degeneration of the nigrostriatal dopaminergic system and loss of dopaminergic mesolimbic projections, is higher than in healthy controls (Mayeux, 1990). Agents that enhance dopaminergic transmission (amphetamine, bromocriptine) are euphorogenic and can precipitate mania. Agents such as pergolide, dextroamphetamine, methylphenidate and pemoline have been studied as antidepressant adjuncts, although the evidence is limited by unsatisfactory study methodology (Fawcett et al., 1991). Their use as antidepressants or as augmentation strategies is mainly based on clinical experience rather than clinical trials. Controlled studies with dopamine re-uptake inhibitors, such as nomifensine (Grof et al., 1977), bupropion (Lineberry et al., 1990), minaprine and amineptine (Rampello et al., 1991) have demonstrated antidepressant activity. Venlafaxine,a serotonin and noradrenaline re-uptake inhibitor, inhibits dopamine re-uptake in high dosages (Stahl, 1996). There exists some evidence that other classes of antidepressants apart from dopamine re-uptake inhibitors have effects on dopaminergic neurotransmission (Klimek and Maj, 1989). These include the classical MAO inhibitors. The decrease in D 2 and D 3 receptor numbers in chronic mild stress in animals is completely reversed by long term treatment with imipramine (Papp et al., 1994), implying this agent causes an increase in the responsiveness of D 2 –D 3 receptors in the nucleus accumbens. A recent study using a behavioural model of depression in rats, concluded that an increased dopaminergic activity is a neurochemical effect common to amineptine, desipramine and imipramine (Besson et al., 1999). Although an increase in D 2 and D 3 responsiveness or increased dopamine in the prefrontal cortex (Carlson et al., 1996), may be responsible for the therapeutic actions of some antidepressants, the data remain preclinical and are often demonstrated in animal models of depression, which compromises extrapolation. Several experiments hypothesise that SSRI’s exert their antidepressant actions by increasing dopaminergic transmissions in the mesolimbic system. Fluoxetine initially inhibits the mesolimbic dopamine pathway by enhancing the extracellular level of serotonin, probably mediated via 5-HT2b / 2c receptors (Prisco et al., 1994). This short-term inhibitory effect of fluoxetine on the mesolimbic dopamine system is followed by restoration of the dopaminergic neurotransmission, after long term fluoxetine treatment. There is a subsequent increase of D 2 receptors in the
limbic system, which could result from a compensatory reaction to offset fluoxetine induced inhibition of dopaminergic neurons. Thus repeated administration of fluoxetine might elicit an increased function of the mesolimbic dopamine system (Bonhomme and Esposito, 1998). It is suggested that drugs acting on the serotonergic system, such as serotonin selective re-uptake inhibitors and 5-HT 2b / 2c receptor antagonists such as mianserin, would exert their antidepressant actions by enhancing dopaminergic transmission in the mesolimbic pathway (Bonhomme and Esposito, 1998, Tiihohen et al., 1996). There are however negative studies. A microdialysis study in monkeys administered fluoxetine did not find any increase in dopamine with chronic administration (Smith et al., 2000). Similarly, a PET study failed to find any effect of fluvoxamine on D 2 binding in the basal ganglia (Moresco et al., 2000). Klimke et al. (1999) also found no difference in D 2 binding between depressed patients and controls using SPECT, although interestingly he found a correlation between higher binding and a poor response to SSRI’s. Healy and McKeon (2000) also found using a neuroendocrine challenge, that there was an association between higher dopamine sensitivity and poor response to SSRI’s. There is provisional evidence that sulpiride may have antidepressant effects, which may be hypothetically mediated via presynaptic blockade (at low dosage), thereby increasing dopamine turnover (Standish-Barry et al., 1983). Both experimental animal models (Vergoni et al., ¨ 1995) and controlled trials (Ruther et al., 1999) support the notion that low dose sulpiride may have antidepressant-like activity. Similar antidepressant properties have been published in controlled trials with flupenthixol (Tam et al., 1982). Amisulpiride, a selective D 2 and D 3 antagonist, acts preferentially on presynaptic receptors, increasing dopaminergic transmission at low dosages. The results of a controlled study showed amisulpiride to be effective in the treatment of dysthymia (Boyer et al., 1999; Lecrubier et al., 1997). The antidepressant amoxapine has the capacity to antagonise D 2 receptors, and is equally effective to that of an antidepressant plus an antipsychotic in systematic double-blind trials of psychotic depression (Kapur et al., 1999). Dopaminergic transmission is also enhanced by electroconvulsive therapy (Costain et al., 1982). Both single photon emission computerised tomography (SPECT) (D’Haenen and Bossuyt, 1994) and single photon emission tomography (SPET) studies (Shah et al., 1997; Larisch et al., 1997) of depressed patients reported a bilateral increase in D 2 -receptor binding in the basal ganglia, this finding being compatible with a decrease in DA turnover. An increase in D 2 receptor binding in bipolar disorder was also found by Pearlson et al. (1995). A small controlled SPECT study measuring striatal dopamine transporter density in patients with depression, found the radioligand uptake reflecting dopamine transporter density to be significantly higher amongst depressed patients. This finding is unexpected, since it is generally believed that
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monoaminergic neurotransmission is lower in depression, and therefore it could be assumed that a reduction in dopamine transmission would lead to secondary downregulation of dopamine transporter density. However, the authors conclude, it is possible that up-regulation of the dopamine transporter may be the primary alteration, which leads to lower intrasynaptic (DA) and to lower dopamine neural transmission (Laasonen-Balk et al., 1999). Sulpiride is a D 2 antagonist that causes a robust increase in prolactin levels. This property was used to characterise the dopamine D 2 receptor sensitivity status in depressed patients versus healthy controls by measure of a neuroendocrine challenge test. We hypothesised that if the pathophysiology of depressive disorders involves a dysregulation in the dopamine system, the prolactin response to a dopamine D 2 antagonist will be altered in patients who are suffering from a major depression as opposed to controls.
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sulpiride was injected intravenously. Sulpiride is a benzamide derivative of which the dissociation constants (Ki ) values of D 2 and D 3 are almost the same and 6100-fold more potent than D 4. This D 2 –D 3 antagonistic selectivity is 3000-fold more potent than that at D 1 . Prolactin concentrations were accurately determined at the following time intervals: 220, 210, 0, 15, 30, 45, 60, 90, and 120 min. Prolactin levels were measured using the Chiron Diagnostics ACS: Centaur Prolactin assay, which is a two site sandwich immunoassay using direct chemiluminometric technology, which uses constant amounts of two antibodies. Statistical analysis of the data involved testing for normality using normal quantile plots, which confirmed the normality of the data. For all comparisons between groups, ANOVA was used, and a Scheffe post hoc analysis was also performed.
3. Results 2. Methods This cross-sectional study utilised a neuroendocrine challenge, which measured sequential plasma prolactin after intravenous administration of 25 mg sulpiride (Eglonyl, Sanofi-Synthelabo) to a group of ten depressed patients and 10 controls. Controls were all volunteers, mainly staff members. All 20 subjects were male. Except for one, all depressed patients were inpatients. All patients met diagnostic criteria for major depression (DSM-4) on a structured interview, the Mini International Neuropsychiatric Interview (MINI), and rated according to the Mon˚ tgomery-Asberg and Zung depression scales. The minimum age was 18 years. No treatment with agents that could affect prolactin levels was permitted. Exclusion criteria included the following: All patients were drug free for at least a month and no patients had been on fluoxetine or neuroleptics. No patients had received antidepressant treatment for the current episode. No significant medical illnesses were permitted, as were patients with substance abuse or dependence. For seven of the patients, this was their first episode of depression. No patient had a family or past history of bipolar disorder. No patients had psychotic features. Patients with another axis one diagnosis were excluded from the study. The study was approved by the Ethics Committee of the University of the Witwatersrand, Johannesburg, South Africa, and informed written consent was obtained from all subjects prior to the study (M 95116). The 20 subjects were asked to present at 07.00 h, having fasted from midnight the previous night. They relaxed for 15 min after insertion of a heparinised cannula in a forearm vein. Two baseline prolactin samples were obtained before zero time. This allowed for the calculations of a mean basal prolactin value, taking into account the pulsatile nature of the secretions. At zero time, 25 mg of
The experimental and control group both consisted of ten males. The groups were matched in terms of ethnicity and age, with the mean age of the depressed group 37.4 and that of the controls being 33.6 (P50.479, F50.52). The mean MADRS and Zung scores were 41.4 and 64.7 in the depressed group respectively, and were 7.3 and 32 respectively in the control group. These differences were highly significant (P,0.0001 for both the MADRS and Zung). In order to analyse these data, a repeated measures ANOVA was performed. There are two missing data points (two subjects at 120 min), so there are two slightly different ways to do this. One is to use a MANOVA framework for the repeated measures design, making all the points missing for the appropriate subjects, and the other is to use a univariate ANOVA with subjects nested within group. Since both these analyses provided essentially the same conclusions, we have chosen to present the latter design. There are significant differences in overall means between the experimental and the control groups (F58.4215; P50.0095), as well as significant differences in overall means between the times at which the prolactin was measured (F5125.42; P50.0001). The key point is that this significant effect differs for the two groups of patients over the various times (F57.6227; P50.0001). As a result, we did Scheffe post hoc tests to see for which of the times the two groups differed. In all cases where there was a significant difference (15, 30, 45, 60 and 90 min), the depressed group had higher means than the control group. One interesting observation is that there is an unusually high prolactin level (26) in one of the depressed patients. With this observation included, the depressed baseline mean was 8.24 (S.D.56.40). Removal of this outlier reduced the depressed group’s baseline mean to 6.27
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Table 1 Prolactin levels (mg / l) in depressed and control groups (mean6S.D., n510) Time (min)
Depressed group (n510)
Controls (n510)
ANOVA
Baseline 15 30 45 60 90 120
8.2466.40 90.88620 110.78631.25 100.94631.36 87.83627.73 72.01625.78 60.12621.42
10.6163.57 65619.76 71.79620.42 65.4617.87 59.98616.18 48.6614.08 41.29612.79
P50.320, P50.009, P50.004, P50.006, P50.013, P50.022, P50.038,
(S.D.51.51). For comparison, the control group’s baseline mean was 10.61 (S.D.53.57). Removal of this unusual observation makes virtually no difference to the repeated measures ANOVA or the Scheffe post hoc tests, so it was left in for completeness (Table 1).
4. Discussion In this study, we demonstrated that the prolactin response to sulpiride is significantly increased in males with major depression compared to healthy controls. This was expected, given the body of pharmacological and neuroimaging data documenting dysreguation of central dopaminergic function in depression. This study therefore suggests that central dopamine D 2 receptors may be supersensitive in depression. The role of the D 2 receptor in this model is implied as dopamine D 3 receptors appear not to be involved in the prolactin response (Durham et al., 1997). Although studies of basal prolactin levels have revealed no consistent change associated with depression, there is evidence of a decrease of prolactin levels in seasonal affective disorder. Some of the neurotransmitters that are implicated in the pathophysiology of depression, serotonin and dopamine, are closely involved in regulating the release of prolactin. Prolactin release is inhibited by the tubero-infundibular DA system. Numerous neuroendocrine provocation tests, challenging the hypothalamo-pituitary axis, have been published. Depending on the challenging agent, these studies reveal alterations with regard to the serotonergic, dopaminergic systems and adrenergic systems. The basal levels of prolactin, and its response to dopamine agonists or antagonists have been examined as potential markers of mood disorder (Anderson and Cowen, 1991; Joyce et al., 1987; Judd et al., 1982). A small study found that depressed patients who responded to the therapeutic actions of total sleep deprivation (TSD) showed a relative enhancement of prolactin response to 25 mg intramuscular sulpiride, and non-responders showing a relative blunting of prolactin response to sulpiride after
Scheffe F51.05 F58.47 F510.91 F59.69 F57.54 F56.34 F55.13
P50.9997 P50.0003 P50.0001 P50.0001 P50.0001 P50.0019 P50.1515
TSD. Although these findings were the opposite of their postulated hypothesis, they still indicate a possible role of dopamine in the therapeutic action of TSD (Ebert et al., 1993). The difference between these finding and the results of the current study are difficult to explain, but may be due to the intervention used (TSD) and the lack of a normal control group. There are a number of limitations to this study. Firstly fluctuations in prolactin levels occur, particularly with diurnal rhythms. This was controlled for by doing all assays at 7.00 a.m. There is in addition a seasonal variation in prolactin. Because prolactin is significantly influenced by a myriad of intra- and extra-ceptive stimuli (i.e., gender, age, menstrual status, stress, nutrition, posture, drugs including corticosteroids, obesity, medical illness and alcoholism) (Hell and Wernze, 1988) the prolactin probe as a research tool should be used in experimental conditions that control as many of these co-variables. This study controlled for gender, posture, medical illness and alcohol abuse. Inconsistent results in the literature may be related to study design that did not adequately control for the above co-variables as well as the assay used, time of sampling, neuroleptic type, and neuroleptic dose (Green and Brown, 1988). Prolactin release from pituitary lactotrophs is tonically inhibited by dopamine. The prolactin response to sulpiride therefore provides a measure of the status of dopamine receptors on pituitary lactotrophs. It is however unclear if these findings in the tuberoinfindibular pathways are generalisable to the mesolimbic pathways which are more likely to subserve the pathopysiology of affective illness. Many issues for further study are raised by these results. It needs to be established if other subtypes of depression would show a similar pattern, such as atypical or bipolar depression. The state or trait marker status of this neuroendocrine probe remains to be established. Therapeutic implications of this finding such as the use of dopaminergic agents are raised. Nevertheless this study confirms, using a novel neuroendocrine marker, that there is dopamine D 2 receptor supersensitivity in depression. This adds to the body of literature suggesting dysregulation of dopaminergic systems in depression.
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Acknowledgements This study was financially supported in part by the Department of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa. We gratefully acknowledge Dr M. van Wyk, Department of Pharmacology, University of Pretoria, for her helpful comments on the manuscript. The sulpiride was made available to us by courtesy of Sanafi–Synthelabo, South Africa.
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