Hormonal responses to zimelidine and desipramine in depressed patients

Psychiatry

Reseawh,

231

13, 23 l-242

Elsevier

Hormonal Responses Depressed Patients

to Zimelidine

Helena M. Calil, Philippe Lesieur, Anthony P. Zavadil III, and William Received

March

30. 19X4; reipised version

and

Philip W.Gold, 2. Potter

receri,ed August

Desipramine

Gregory

M.

6, 1984; ac,cepted Augus/

in

Brown,

23, 1984.

Abstract. Plasma prolactin (PRL). growth hormone (GH), luteinizing hormone (LH). and cortisol were repeatedly measured during the morning over a 4-hour period in patients who received single or chronic doses of desipramine (DMI) or rimelidine(ZlM). Preclinical studies had suggested that DMI, an uptake inhibitor specific for norepinephrine, would have different effects than ZIM, a selective serotinin uptake inhibitor. The GH response to DMI was blunted in thedepressed patients. Neither DM I nor ZI M produced changes in LH or cortisol. DM I acutely increased plasma PRL. whereas ZIM had an effect only after chronic pretreatment. Chronic DMI but not ZIM increased baseline PRL. The patterns and magnitude of responses raise questions concerning the role of serotonin and norepinephrine in PRL release in man and the applicability of current preclinical models. Key

Words.

Desipramine.

limelidine.

prolactin.

growth

hormone,

affective

disorders. Biogenic amines thought to play an important role in primary affective disorder are also potential modulators of the hypothalamic-pituitary axis and may act to regulate anterior pituitary secretion (Weiner and Ganong, 1978). Investigators have studied the secretion of those anterior pituitary hormones which can be readily detected in blood both before and after treatment with various antidepressants in the hope of identifying biochemical changes reflecting the activity of central biogenic amine systems. Findings have been extremely variable and do not convincingly implicate specific biogenic amines (for review. see Meltzer et al., 1982). The present study was designed to examine the effects of two biochemically distinct antidepressants in the same patients with primary affective disorderPdesmethylimipramine (DM I) and zimelidine (ZIM). These drugs were chosen because they have relatively specific in vitro effects: DMI is a selective norepinephrine uptake inhibitor (Glowinski and Axelrod, 1964; Carlsson et al.. 1969). whereas ZIM is a selective serotonin uptake inhibitor (Ross et al.. 1976). By measuring the effects of the acute and chronic administration of these

Helena M. Calil. M.D.. Ph.D.. IS Asociate Professor. Department of Ps)choblolop!. Escola Paullstn de Medictne. Sao Paula. Brazil. Philtppe Lesteur. M.D.. and Anthon!, P. Zabadil III. M.D.. are In the Laboratory of Clinical Science. National lnatttute of Mental Health (NIMH). Bethesda. MD. Phillp W. Gold. M.D.. is Chief. Section on Neuroendocrinolog!. Biological Psychiatry Branch. NIMH. Gregcr! M. Brown. M.D.. is Professor and Chairman. Department of Neurosciencea. McMaster Untbersit! School of Medicine. Hamilton. Ont.. Canada. William Z. Potter. M.D.. Ph.D.. 1s Chief, Section on Clinical Psgchopharmacolog!,. ILahorator! of Clinical Science. NIM H. Bldg. IO. Rm. 4S239. Bethesda. MD 20205. USA. (Reprint requests to Dr. W.Z. Potter.) OlhS-1781

x4 502.00 * 19X4 Elsekier Science

Publishers

B.\‘.

232 drugs on neuroendocrine function some interindividual heterogeneity l l

l

using a full crossover design, and examine the following:

we hoped to avoid

Do ZIM and DMI have any and/ or different effects on neuroendocrine function? Do any effects of the drugs which might occur change over time: i.e., do compensatory changes in biogenic amine metabolism and associated neuroendocrine secretion occur after chronic administration of these agents? Do neuroendocrine effects of these drugs in any way support a formulation that each has relatively specific effects on either noradrenergic or serotonergic functional activity?

Methods Patients. Eleven inpatients (seven females, four males), aged 17 to 67 years, were treated as part of a double-blind, crossover design with ZIM or DMI. Details of the study design have been published previously (Potter et al., 1981). One outpatient, aged 55, participated in part of the study as well. Not all patients completed all aspects of the protocol. Because of the study design some patients were tested at various stages of their illness. They were in good physical health without evidence of cardiovascular, renal, or endocrine disease. All were diagnosed by Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) before entering the study as having major affective disorder. Eight had no history of mania (unipolar) while four met RDC for bipolar I

affective illness. Inpatients lived on a psychiatric research unit at the National Institutes of Health Clinical Center and were on a controlled diet low in monoamine precursors. Behavioral ratings were monitored daily with the revised National Institute of Mental Health (NIM H) scale for depression. mania. anger. and psychosis (Bunney and Hamburg, 1963). Complete blood tests. including SMA I2 and CBC, were performed weekly as part of the evaluation of drug effects. Drug and Sampling Protocol. Patients were drug free before entering the study. They were placed on placebo for 2 to 4 weeks before beginning treatment with either ZIM or DMI. Five patients received ZIM first. Each drug trial lasted 4 to 6 weeks, and in between there was a 2-week placebo period. Drug Administration. Each patient received a single oral loading dose of 100 mg of ZIM or DMI at IO a.m. during either the initial placebo period or the between drug placebo period before initiating chronic drug treatment. Premenopausal women were studied during the early follicular phase of their menstrual cycle. All patients were at bedrest that morning and were NPO from midnight the night before. A l9-gauge needle was inserted into an antecubital vein and kept open with heparinized saline. Blood was drawn every I5 minutes for I hour before. and 15. 30, 45. 60. 90. 120. 150. and 180 minutes after drug administration. Three additional samples were collected at 24. 48. and 72 hours postdrug for determination of drug concentration in plasma. Details of sample preparation. storage. and pharmacokinetic results are reported elsewhere (Potter et al., 1979). Acute

Drug Administration. For the long-term drug trials, patients were begun randomly on either ZIM or DMI. No other active medication was given during the protocol. Both drugs were administered in b.i.d. doses at 9 a.m. and IO p.m.: ZIM dosage was gradually increased up to a maximum of 300 mg; day. and DMI doses ranged from 100 to 300 mg; day so as to produce a plasma concentration of DMI in the 75 to I50 ng ml range, according to a previously reported prediction technique based on data from the single dose (Potteret al.. 1980). During the third or fourth week on each drug and under steady-state conditions. the morning dose was withheld and substituted by a fixed 100 mg dose. which was again administered at IO a.m. to patients at Chronic

233 bedrest under NPO conditions. As with the acute study, blood samples were drawn every 15 minutes for I hour before the study and during the same intervals as described above (i.e., at 15, 30, 45, 60, 90, 120. 150, and 180 minutes). Steady-state plasma levels were also determined before the drug was taken. Analysis. Plasma samples were analyzed for concentrations of ZIM, its active metabolite norzimelidine, and DMI as previously reported (Potter et al., 1979). Each plasma sample was also analyzed by radioimmunoasssay for prolactin (PRL) (Hwang et al., 1971). growth hormone (GH) (Schalch and Parker. 1964). luteinizing hormone (LH) (Ode11 et al., 1967). and cortisol (Brown et al., 1970). Intra-assay variabilities were as follows: PRL 8%, GH 7%. LH 8c/c, and cortisol 9%. Interassay variabilities were as follows: PRL 12%). GH 12% LH 154%.and cortisol 12%. Chemical

Data Analyses. Hormone concentration was graphed over the l-hour period following insertion of the indwelling catheter and before drug administration over the subsequent 3-hour period. On the basis of the fall in concentrations during the predrug period, the “zero” (0) time point was taken as the baseline value. A paired I test was used to test the significance of the alteration in hormone level between time of catheter insertion and the 0 time point. Values at 180 minutes after drug were taken as the peak comparison point. Baseline and peak were compared by paired f tests or by group f tests (when not all pairs were complete for all conditions). Correlations between baseline and/or change from baseline to peak and drug neurotransmitter metabolite concentrations were tested using Pearson’s product-moment coefficient.

Results As shown in Fig. I, from the point of catheter insertion (-60 minutes) to the point of oral drug administration (0 minutes), there was a 25% fall in PRL concentration @ < 0.02). This pattern was also present for cortisol, and some patients showed a Fig. 1. Elevated prolactin after insertion

of i.v.

25

20

15

10

t

t

I.V. Inserted

Drug

a TIME (min.) Plasma prolactln concentrations I+ SEMI in patients on placebo during the first hour after insertion 19-gauge butterfly in an antecubital vein. + = p < 0.05 and ** = p G 0.2 from -60 minutes by paired t test.

of a

234 transient increase in GH which returned to low levels by the 0 time point. There was, however, no difference between the -15 and 0 time points, indicating that PRL release was stable by this time. The 0 time point was therefore taken as the baseline rather than the mean of all five predrug points. There were no differences in the mean baseline levels of any hormone when values and 2 weeks between the two placebo periods (i.e., before any drug treatment following discontinuation of the first drug) were compared. Table I summarizes the effects of DMI and ZIM on PRL concentrations; one subject in whom baseline PRL was extremely elevated during chronic ZIM was excluded. DMI (Table 1) produced an increase in PRL both after single (acute drug/3-hour peak) and repeated (chronic drug-baseline) doses. The morning dose of DMI during the chronic drug condition produced no further increase of PRL (28.2 ng/ml vs. 32.6 ng/ ml). Acute ZIM did not increase PRL. whereas the 180-minute point following the morning dose of ZIM given in the presence of chronic ZIM did show a significant @ < 0.05) elevation of PRL compared to the original predrug baseline (Table I). Table 1. Plasma prolactin after acute and chronic desipramine Plasma txolactin

Inalml.

Acute drug Drugs1

Baseline

Chronic drug

3-hour peak

Baseline

Desipramine

14.36

k 5.57

23.73

-t 10.742

28.182

Zimelidine

20.2

ir 7.15

22.16

+

22.68

1. 2. 3. 4.

and zimelidine

mean f SD\

9.7

t

3-hour peak

11.763

32.58

rf- 17.10

5.07

30.6

k

7.824

There were no slgniflcant differences between drugs on any condition. p < 0.01 lfollowing loglo transformation, compared to predrug basellne p < 0.02 ifollowing loglo VansformatIon, compared to predrug basellne. p < 0.05 vs. predrug baseline.

When the patient with hyperprolactinemia is included (patient ##9, Fig. 2). a parametric statistical comparison by t tests is inappropriate even following log,,, transformation because of the extreme distribution (Fig. 2). Nonetheless, a ZIMrelated increase in PRL concentration is particularly apparent following the morning dose of ZIM under conditions of chronic treatment with ZIM in this patient. Log,,, transformations of PRL following DMI produce narrower distributions which show that there is an acute and chronic elevation of PRL but no additional change following the morning dose under chronic conditions (Fig. 3). There was no correlation between 180-minute or chronic steady-state plasma concentrations of drug (DMI, ZIM and/ or norzimelidine) and increases in PRL. The trough steady-state concentrations of DMI and norzimelidine were several-fold higher than 3 hours after a single acute dose (Table 2). There was only a modest increase over the steady-state 3 hours after the last dose for both compounds. ZIM itself, however, followed a different pattern. The trough steady-state concentration of ZIM was several-fold lower than at either the acute or chronic 3-hour points (Table 2). Baseline plasma PRL and changes in its concentration were compared to cerebrospinal fluid (CSF) concentrations of the neurotransmitter metabolites 3methoxy-4-hydroxyphenylglycol (MHPG). homovanillic acid (HVA). and 5-

235

Fig. 2. Effects of acute and chronic ZIM on prolactin 9

/

2.0-

a $ = 7 B z F

1.5-

I

&-/SF

s: h d

\'2 11 10 F

l.O-

11

A

1

-0

L

1

baseline

I

I

I

peak

baseline

peak

CHRONIC ZIM PRE-DRUG Baseline and peak plasma prolactin concentrations in patients beforeand after treatment Numbers Identify individual patients. Peak prolactin was that obtained 180 minutesafter ZIM isee Methods,.

with zimelidine fZIMj. a lOO-mg oral dose of

Effects of acute and chronic DMI on prolactin

1

I

I

baseline

peak

PRE-DRUG

I

baseline CHRONIC

I

peak DMI

Baseline and peak plasma prolactin concentrations in patients before and after treatment wth desipramine DMI Peak prolactin was that obtained 180 minutes after a lOO-mg oral dose of DMI isee Methodsi.

236 Table 2. Plasma concentrations of desipramine (DMI), zimelidine (ZIM), norzimelidine (Nor-ZIM): 3 hours following a single dose, at trough steadystate, and 3 hours following a.m. dose at steady-state Concentrations @g/ml) (mean f SD) Acute 3 hours

Trough steady-state1

Steady-state, 3 hours2

a

b

C

DMI

29 t 11 .a

ZIM Nor-ZIM

Increase % (c-b)

147 t 50.5

103t44

91?53

37.5 ?I 26.5

43.5 f 9

200 2 68.5

1492

42.5

115.5

297.5

229 ? 43.5

14.5

1. Trough indicates steady-state value immediately before a.m. dose after 3-4 weeks on b.1.d. schedule. 2. Steady state, 3 hours. refers to sample 3 hours after trough steady-state and a.m administration of drug.

hydroxyindoleacetic acid (SHIAA) for each individual in whom all parameters were available. Significant negative correlations between PRL and HVA (r = -0.67, p < O.OS)and PRLand SHlAA (r=-0.67,p<0.05) were present under predrugconditions. In these same subjects, SHlAA and HVA were positively correlated (r 0.94). GH, LH, and cortisol were analyzed in the same manner. Mean values under each condition, as tabulated for PRL in Table I, are shown in Table 3. There were no consistent changes in mean values for any of the three hormones under the conditions of the study. For GH. however, there was a large variation in the peak 180-minute level q

Table 3. Growth hormone (GH), luteinizing hormone (LH), and cortisol (mean + SD) in plasma at baseline, and after acute and chronic treatment with desipramine (DMI) or zimelidine (ZIM) Chronic drug

Acute drug

GH ing/mli LH (mlU/mli

Cortisol

ipg/ll

Baseline

3-hour peak

Baseline

3-hour peak

DMI

2.7 + 1.1

6.3 ? 5.9

3.8 i 8.5

4.1 + 4.7

ZIM

3.1 t

2.3 i 0.8

5.3 ? 7.6

1.8

DMI

99.1 + 127.3

ZIM

140.7 ? 199.5

DMI

112.5

i 36.8

ZIM

112.6 k 26.8

107.6 174.7

i- 150 + 246.8

109.4 174.0

1148.7 2 185

2.0 t 0.0 143.3?

219.3

199.4 i

202.8

? 18.4

NA

NA

138.8 i 46.9

NA

NA

117.4

following a single dose of DMl. It was observed that three subjects showed a substantial GH response to DMl. These subjects. although they had underlying recurrent major affective disorder, were not depressed at the time of the single dose of DMl. As shown in Fig. 4, there was a significant difference @ < 0.01) in the response of the depressed vs. the nondepressed subjects. Plasma concentrations of DMI at the time of peak response were the same in the depressed and nondepressed subjects.

237 Fig. 4. GH response to acute DMI

Plasma growth hormone over time after a single lOO-mg oral dose of desipramine as a % of baseline concentrattons {see Methods and Table 31. Dotted line ieuthymici shows patients on placebo who were not significantlydepressedat the tlmeof thestudy. Solid linereferstodepressedpatientsonplacebo,andonlyone of them was postmenopausal.

Discussion The present data show that acute DMl in depressed patients consistently increases plasma PRL concentrations. After chronic treatment with this antidepressant drug, the baseline (before the a.m. dose) PRL concentration is increased significantly, but a subsequent dose of DMI is unable to produce a further “acute” increase. In contrast, acute ZIM does not produce consistent effects. But after chronic treatment, a further single dose of ZIM is associated with a significant increase in plasma PRL concentration (Table I, Fig. 2). None of the effects observed after acute or chronic treatment with either DMl or ZlM predict effects observed with the other. For the patients in whom paired data were obtained during the crossover study, no consistent pattern was observed following both DMI and ZIM. Moreover, a single patient who became truly hyperprolactinemic (202 ng,/ml) during the chronic ZlM phase showed relatively modest increases of PRL during DMI treatment (Figs. 2 and 3). It therefore seems likely that DMI and ZIM affect the release of PRL in different manners. At the pituitary level, PRL release is generally thought to be regulated by one or more inhibitory hypothalamic factors of which dopamine is the most studied. As for stimulatory pathway(s) regulating PRL secretion, a hypothalamic stimulatory factor has been hypothesized. Many substances have been identified as capable of playing a stimulatory role in this pathway: thyroid-stimulating hormone, angiotensin II, vasoactive intestinal peptide (VIP), histamine, endogenous opioids, and serotonin (5HT) (Weiner and Ganong, 1978; MacCann, 1982).

238 In animal studies, peripheral injections of the 5HT precursor 5-hydroxytryptophan (SHTP), the 5HT receptor agonist quipazine, and/ or the 5HT releaser fenfluramine. as well as the intracerebroventricular administration of 5HT, are able to induce an increase in PRL secretion (Weiner and Ganong, 1978). The specific 5HT uptake inhibitors are unable to produce such an effect but clearly potentiate the 5HTP or the stress-induced PRL release. Moreover, 5HT antagonists are able to antagonize these effects as well as stress or suckling-induced PRL release (Krulich, 1975; Meltzer et al.. 1981). From these data, even though 5HT seems to be implicated in the secretion of PRL, the mechanism is unclear. Because of the lack of direct effects of 5HT on pituitary cells in vitro (Lamberts and MacLeod, 1978) two main hypotheses are possible: Either 5HT decreases the release of dopamine (i.e., reduces a PRL-inhibiting factor) or it stimulates an unknown PRL-releasing factor (Pilotte and Porter, 198 1). In man the effects of SHTP, tryptophan, or acute and chronic antidepressant drugs are more uncertain. However, methodological differences (e.g., drug dosage, route of administration, and procedure for defining baseline) may account for many of these discrepancies. For instance, investigators who have not found any effects of antidepressant drugs on PRL (Meltzer et al., 1977; Cooper et al., 1981) have used a single blood drawing in the morning. As previously established by endocrinological investigators (Adler et al.. 1975) and as shown in this study, the PRL level in the first blood sample drawn after catheter insertion is elevated, presumably because of the stress of this procedure. This elevation could easily obscure a modest drug effect. The clearest results are those obtained after intravenous (iv.) injection of antidepressant drugs (Laakman et al., 1983). Acute i.v. administration of chlorimipramine (Cl-IMI) produces dose-dependent increases of PRL. It is classified as a mixed serotoninnorepinephrine uptake inhibitor because of its extensive metabolic conversion to desmethyl-Cl-IMI in vivo (Traskman et al., 1979). Daily treatment with IO-minute infusions of Cl-IMI over a l-week period elevates basal (i.e., 24 hours after the last infusion) PRL as well (Laakman et al.. 1983). Acute i.v. DMI also increases PRL. although not so potently as with Cl-IMI. The acute PRL increases induced by Cl-IMI and DMI are blocked by pretreatment with methysergide. These data have been interpreted to mean that PRL elevations induced by both Cl-IMI and DMI derive from a serotonergic mechanism (Laakman et al.. 1983). We would suggest on the basis of the present study comparing ZIM and DMI that more than a serotonergic mechanism is involved. It appears highly unlikely that acute oral DMI is much more potent as a 5HT uptake inhibitor than acute oral ZIM. although such an argument might be made for acute i.v. Cl-1MI. It is difficult to explain the effects after DMI as secondary to 5HT uptake inhibition. There may be some complex interaction at the hypothalamic level among the noradrenergic. serotonergic. dopaminergic. and opiate (Moore and Johnston, 1982) systems such that a selective norepinephrine (NE) uptake inhibitor and. more potently, a mixed NE-5HT uptake inhibitor would increase PRL whereas a selective 5HT inhibitor would not. On the basis of combined CSF and urinary measures, we found that chronic DMI and ZIM in the present group of patients reduced the metabolism and turnover of both

239 NE and 5HT (Linnoila et al., 1982; Potter et al., 1983). It is therefore impossible to conclude that either NE or 5HT is specifically affected by either drug or that changes in one neurotransmitter are directly associated with changes in PRL. The data show only that acute and sustained NE uptake inhibition following DMI (Ross et al., 1983) with subsequent decreased serotonin turnover in the central nervous system (Potter et al., 1983), is associated with a modest and sustained increase of PRL secretion. In contrast. acute and chronic 5HT uptake inhibition after ZIM, accompanied by presumed secondary decreased NE turnover (Linnoila et al., 1982; Potter et al., I983), produces a system which responds with PRL release to the same dose of ZIM that fails to produce an effect when administered acutely. The negative correlation between the metabolites of dopamine or serotonin in the CSF during the pretreatment condition and resting plasma PRL is obviously compatible with the known inhibitory role of dopamine but is incompatible with a stimulatory role of serotonin. Given the high intercorrelation of HVA and SHIAA, however, it is possible that another factor is controlling their variance and that their CSF levels are not particularly representative of amounts at sites of action. Given this point of view, the lack of effect of acute ZI M that we observe in depressed patients (in agreement with the 1979 data of Syvalahti et al. in normal volunteers) could be interpreted to show that the inhibition of 5HT reuptake achieved after oral administration of drug is not sufficient to modify the functional activity of the systems controlling PRL release. Chronic oral ZIM, which should produce greater as well as sustained 5HT reuptake inhibition, may be more likely to modify the functional capacity of those systems, thereby explaining the ability of a subsequent dose of ZIM to stimulate the release of PRL (Fig. 2). It should be noted that both patients who clinically improved during the ZI M treatment (patients 4 179 and 4 I8 I from Potter et al., 198 I) are those who showed an increase in PRL level induced by ZIM after chronic treatment but not in the baseline conditions (patients 12 and IO, Fig. 2). There is a possible pharmacokinetic explanation for the apparent ability of ZIM to potentiate its own action. When ZIM was administered chronically every 12 hours, the steady-state concentration of ZIM itself before the next dose was significantly lower than 3 hours after a single dose, whereas the concentration of the active metabolite, norzimelidine, was 45OYc higher than at 3 hours (Table 2). Therefore, any chronic changes are presumably related to the steady-state norzimelidine concentration, which may produce an altered state of the system controlling PRL release such that the next dose of ZIM, which raises ZI M concentrations by 300% (Table 2), increases PRL. Obviously, after DMI, no such pharmacokinetic“shift”occurs. In other words, the chronic steady-state DMI is already 350% higher than that observed 3 hours after the first dose and an additional dose only increases the DMI concentration by 42%. Therefore. the pharmacodynamic effects should be relatively stable. There is another aspect of the PRL response after DMI which requires comment. In a very’ recent study of Laakman et al. (1984) acute iv. administration of DMI to normal \,olunteers produced greater increases of GH than of PRL. In the present study. the same subjects who showed a blunted GH response had a substantial PRL response. Since the effects of DMI on GH are presumed to act through a noradrenergic mechanism, it is difficult to interpret DMl’s effect on PRL as resulting

240

from similar noradrenergic stimulation. Perhaps there is a different balance in the factors regulating the PRL release in patients than in normal volunteers as suggested by the blunted GH response in the former group. With regard to effects on other hormone systems, we essentially replicate the few reports in the literature. In agreement with Syvalahti et al. (1979). we fail to detect any clear effect on cortisol or LH either in the acute or chronic condition. At the same time, as reported for an acute study of ZIM in normal volunteers (Syvblahti et al., 1979), we also failed to observe the expected morning fall in plasma cortisol. DMI also appeared to block the morning fall, although saline control studies in these same patients were not available. Finally, the mood-dependent blunted GH response to DMI is compatible with the reports of Matussek and Laakman (198 1). Interestingly, the GH data support the notion that following acute administration DMI primarily affects the noradrenergic system and that ZIM does not have such effects. Thus, with regard to the question of the mechanism of PRL increase after DMI, it would appear most parsimonious to invoke a role for NE. There remains the likelihood that 5HT is involved in the chronicZlM effect. Acute i.v. administration of other specific 5HT uptake inhibitors might answer the question. We therefore conclude with regard to the three questions which we raised at the outset: l l

l

DMI but not ZIM produces acute elevation of PRL as well as of GH. The same dose of ZIM which fails to increase PRL acutely is able to do so when administered to patients who have received chronic ZIM, suggesting that the overall regulation of the system is altered. Neuroendocrine effects of DM I and ZIM are difficult to interpret in terms of known in vitro specificity and instead highlight the complex interrelationships of the monoamine and neuroendocrine systems.

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