Case report of prolactin and bipolar illness: A longitudinal study

Pmg Neum-Psychophormocol Printed in Great Britain.

b

Biol.

Psychiat.

CASE REPORT

GIOVANNI

A.

FAVAl, LEILA

1985,

Vol.

9, pp.

0278-5846/85 $0.00 + .50 Pergamon Press Ltd.

451-457

OF PROLACTIN AND BIPOLAR A LONGITUDINAL STUDY

ILLNESS:

2 ANN GEORGE MOLNARl, MARY SPINKS and MURRAY A. MORPHY '1 EDWARDS3

State lDepartment of Psychiatry, Erie County 2Lithium Clinic, 3Department of Clinical Chemistry,

(Final

LORETAN',

University of New York at Buffalo, USA Medical Center, Buffalo, NY, USA Erie County Medical Center, Buffalo, NY

form,

June

1985)

Abstract Fava, Giovanni A., George Molnar, Mary Spinks, Ann Loretan, Leila Edwards and Murray A. Morphy: Case report of prolactin and bipolar illness: A longitudinal study. Prog. Neuropsychopharmacol. & Biol. Psychiat 1985, 2 (4): 451-45,. 1. 2, 3. 4. 5. 6.

A longitudinal and naturalistic study of nine bipolar patients attending a lithium clinic during a six-month period was undertaken. Prolactin plasma levels and psychiatric symptoms were evaluated biweeekly. Wide interindividual and intraindividual fluctuations were observed both in prolactin levels and psychiatric symptoms. The relationship between prolactin and affective episodes was found to be complex. In a few instances, sharp prolactin changes preceded behavioral modifications. Bipolar disorders, even if treated, appeared to be unstable conditions, from both the phenomenological and neuroendocrinological viewpoints.

Keywords: bipolar disorder, depression, dopamine, lithium, mania, prolactin Abbreviations: Brief Psychiatric Rating Scale (BPRS); prolactin (PRL) Introduction Neuroendocrine strategies in clinical psychiatric research have become well developed over the past decade. Since dopaminergic transmission is a major regulator of pituitary prolactin secretion (Gudelsky 1981), the measurement of circulatin prolactin is of interest in bipolar disorders, where mania and depression may also reflect imbalances of the dopaminergic system (Garver and Davis 1979). Prolactin (PRL) plasma levels have been carefully investigated in depressed bipolar patients: bipolar depressed women appear to display lower basal PRL levels than controls (Linkowski et al 1980), probably because of a lack or reduction of sleep-associated elevation (Mendlewicz et al 1980). The finding of low basal PRL levels in depressives is consistent with the increase in PRL after antidepressant treatment (Lisansky et al 1984). Prolactin in mania has been studied mainly in relation to neuroleptic treatment (Cookson et al 1983): during a two-week treaq ment of 11 manic patients with pimozide there was close correspondence beetween the time course of improvement in clinical ratings and the rise in plasma PRL (Cookson et al 1982). 451

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Cohen (1983) has recently stressed both the wide interindividual variability of normal basal PRL levels, and the fact that intraindividual variability has been little studied. Individual basal serum PRL levels were found to be stable over a mean period of 10 months in healthy subjects, with interindividual variance vastly greater than intraindividual variance (Cohen 1983). Thus, state alterations in mental illness may be studied using a longitudinal design. Rapidly cycling bipolar patients, i.e. with a history of four or more affective episodes per year prior to treatment (Dunner and Fieve 1974), provide good models for studying the relationship between PRL and affective states. The aim of the report is to provide such longitudinal observation, including bipolar 1 patients, i.e. with less than four affective episodes per year (Dunner and Fieve 1974), as a source of comparison. Methods Patient Population. We studied nine outpatients who fulfilled the diagnostic criteria for bipolar disorder (American Psychiatric Association 1980) and attended the Lithium Clinic of the Erie County Medical Center (Buffalo, New York, USA) for six months. Demographic and clinical characteristics of the patients are described below. Informed consent was obtained from all patients. Study Design. During the six-month study period, all patients had biweekly plasma PRL and lithium determinations. To minimize the effect of circadian rhythm on PRL levels, all samples were drawn between 09:OO and 09:30 hr in the Lithium Clinic on Mondays or Tuesdays. No attempt was made to time the tests according to changes in affective cycling. Thus, by coincidental synchrony with the affective cycles, some PRL assays were conducted during depression, some during euthymia, others during hypomania or mania, and yet others during "mixed" states. The investigators were always blind as to PRL values. All patients were on lithium (0.6-1.2 mEq/l); some of them were taking other psychotropic medications as well. Any change in medication, either by the physician or the patient, was recorded and will be described later. Instruments. On the same day blood for PRL and lithium assays Clinical was drawn, a psychiatrist and a nurse clinician rated patients on the Brief Psychiatric Rating Scale (Overall and Gorham 1962), on a global depression scale ranging from 0 (non depressed) to 3 (severe depression) (Greden et al 1982), and on a global mania scale ranging from 0 (not hypomanic or manic) to 3 (severe mania) (Greden et al 1982). Laboratory Instruments. Blood for PRL assay was stored in ice, centrifuged at 4OC, plasma separated and frozen at -20°C until assayed. Plasma PRL was determined utilizing the PLAC radioimmunoassay kit (Nuclear Medical Laboratories, Dallas, Texas). Results Individual prolactin plasma levels and Brief Psychiatric Rating Scale (BPRS) scores are shown in Fig. 1 (bipolar patients with less than four affective episodes per year prior to treatment) and in Fig. 2 (rapid cyclers) Patient 1 was a 27-year-old female, with a relatively recent history of bipolar disorder, type 1, characterized by regular cycles, with severe manic phases. For the entire study period she was on lithium only, within the therapeutic range. At the beginning of the study, she was rated 0 on the global depression and mania scales, and maintained these scores until almost the end, when she became hypomanic (Fig. 1). After her eleventh PRL

453

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Fig. 1. Bipolar I patients: plasma prolactin levels (ng/ml) and Brief Psychiatric Rating Scale scores rated biweekly during a six month period. Values of ) and of Brief Psychiatric Rating Scale (-------) are along prolactin ( are along the abscissa the ordinate (vertical axis); the biweekly intervals (horizontal axis).

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determination, she discontinued lithium and her affective state reached a full blown manic phase, which required hospitalization and neuroleptic treatment. Her mean PRL level was 18.1 ng/ml (_t5.8). Patient 2 was a 35-year-old male, with a lo-year history of bipolar disorder, type 1, with regular and prolonged cycles. He was on lithium and amitriptyline (200 mg per day) and was mildly depressed throughout the study. Shortly after the study was completed, he discontinued both amitriptline and lithium; his condition turned into mania and required hospitalization and neuroleptic treatment. His mean PRL level was 8.4 ng/ml (2 1.4). Patient 3 was a 54-year-old male with a long standing history of bipolar disorder, type 1. During all the time of the study he was assuming, besides lithium, hydrochlorotiazide for a mild hypertensive state. He was euthymic until the eight PRL assay when some hypomanic symptoms, which in a month abated, were noticed. His mean PRL level was 7.6 ng/ml(t 3.1). Patient 4 was a 59-year old female, also with a long standing history of bipolar disorder, type 1. She was on lithium and amitriptline (150 mg per day). Her affective state varied from mild depression to euthymic. Her mean PRL level was 18.6 ng/ml (2 4.6). Patient 5 was a 55-year-old female suffering from bipolar disorder, type 1, characterized by prolonged and intense affective episodes. She was treated with lithium, diazepam, and amitriptyline for the entire duration of the study. At the beginning, she was in a moderate depressive state, which improved to euthymia toward the end of the study period. Her mean PRL level was 6.3 ng/ml (20.9). Patient 6 ( Fig. 2) was a 25-year old female, rapid cycler, with a fouryear long history of bipolar illness. Initially she was treated with lithium and chlordiazepoxide; the latter was substituted by thioridazine (100 mg per day) at the time of her fifth assessment; she was on lithium only after the eight assessment. At the beginning, she was slightly hypomanic. At the time of her fifth assessment, she had a mixed state with intense depression, anxiety and hostility. She was euthymic towards the end (when thioridazine was discontinued). Her mean PRL level was 7.6 ng/ml (2 2.2). Patient 7 was a 41-year-old female patient, rapid cycler, with long standing history of bipolar illness, characterized by affective fluctuations (often mixed states) which were almost monthly in rhythm. The patient was treated with lithium and thiothixene (20 mg per day) throughout the study. She was predominantly depressed on her first and fifth to ninth assessments (with a mixed state in between), and hypomanic at other times. While her lithium level was always within the therapeutic range, her thiothixene dosage was difficult to control since the patient had her own flexible schedule (allegedly, however, it was never interrupted). Her mean PRL level was 55.9 ng/ml (+ 17.4). Patient 8 was a 32-year-old female with a history of rapid cycles prior to lithium treatment. She was treated with lithium and diazepam (15 mg daily) troughout the study. Initially, she had a depressive state with a more pronounced depressive episode toward the end, and a relatively euthymic state in between. Her mean PRL level was 18.2 ng/ml (24.6). Patient 9 was a 63-year-old female with history of rapid cycles prior to treatment, but with a good response to a steady combination of lithium and chlorpromazine (100 mg daily). She had a slight hypomanic episode at the beginning; otherwise, she was judged to be euthymic. Her mean PRL level was

Prolactin and bipolar illness

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Patient 6

n

“Patient 7

Patient 0

Fig. 2. Rapid cyclers: plasma prolactin levels (ng/ml) and Brief Psychiatric Rating Scale scores rated biweekly during a six month period. Values of ) and of Brief Psychiatric Rating Scale (-------) are along prolactin ( the ordinate (vertical axis); the biweekly intervals are along the abscissa (horizontal axis). 8.2 ng/ml (+ 1.3). The overall (for all patients and on all occasions) product-moment correlation between PRL levels and total BPRS scores was 0.52 (p 0.001). Discussion A longitudinal and naturalistic study such as this has obvious and considerable limitaions. In female premenopausal patients (patients 1, 6, 7 and 8), spurious results may be obtained due to variable estrogen secretion throughout the cycle (Buckman et al 1980). Treatments were selected solely on clinical grounds, and neuroleptics (patients 6, 7 and 9) amy influence PRL secretion considerably (Miilleret al 1983), especially when they were not given throughout the study (patient 6) or the exact daily dosage could not be ascertained (Patient 7). Benzodiazepines and antidepressants are less likely to alter PRL levels (Miilleret al 1983), yet they may influence some items of the BPRS as well as sleep patterns, which in turn may affect PRL levels in the morning. Nonetheless, some interesting patterns emerged and deserve comment. In some patients suffering from bipolar disorder, type 1 (Fig. l), increases in PRL levels were found to precede a manic or hypomanic attack by a few weeks. This took place for patients 1 and 2 (who however stopped taking lithium at the

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end of the study period), as well as patient 3. In rapid cyclers (patients 6 and 8 in Fig. 2), the same phenomenon took Place for a depressive episode and a mixed state. A few patients showed a certain parallelism between PRL levels and psychiatric ratings (patients 4, 7 and 9). Sometimes PRL changes preceded behavioral fluctuations, whereas other times the opposite was true. The relationship between PRL and type of mood alteration was found to be complex, and mixed states in rapid cyclers certainly complicated the picture: prolactin peaks were associated with both manic and depressive states, although more frequently with the former. This finding is in keeping with knowledge of the complexity of neurotransmitter control of PRL secretion. Although there is evidence for the tonic inhibitory role of the tuberoinfundibular dopaminergic neurons in the regulation of PRL secretion (Gudelsky 1981), it cannot be inferred that the hyperdopaminergic state of mania must result in lower PRL levels and vice versa in depression.In animal studies, the chemical relationship between the hypothalamus and the pituitary gland is bidirectional (an example is the longterm treatment of rats with estrogen which is associated with both elevated systemic PRL levels and elevated dopamine concentration in the portal blood). As a result, elevated PRL levels are not systematically the result of decreased levels of dopamine in the hypophysial portal plasma (Gudelsky 1981). Further, the influence of serotonin on PRL secretion has to be considered: a reduced serotonergic tone may abolish the diurnal rhythm of PRL (Mornex and Jordan 1980). In any case, our longitudinal observation of PRL levels during a six month period in bipolar patients disclosed not only a wide interindividual variability - as had been observed in normals (Cohen 1983) -, but also a considerable intraindividual variability, which does not appear to take place in normals (Cohen 1983). Our data are consistent with the findings of Mendlewicz's group (Linkowski et al 1980; Mendlewicz et al 1980), who found more severe alterations of PRL patterns in bipolar than in unipolar depressed patients. Whether sharp changes in PRL levels may predict or anticipate behavioral fluctuations (with potential preventive interventions such as addition of antidepressants or neuroleptics to lithium treatment in patients who otherwise would not have a long-term favorable outcome with lithium alone) is an issue which warrants further investigation Patients in our study, surprisingly, were extremely compliant and did not miss appointments. All of them perceived the study as an attempt to monitor their illness; the fact that two patients waited - consciously or unconsciously - to be off the study before discontinuing lithium against medical advice could have reflected their positive view of the neuroendocrine monitoring. Conclusion Against the background of clinical, genetic and pharmacological information neuroendocrine disturbances in prolactin secretion may provide the physician with better insights for the treatment of patients suffering from bipolar illness. Our study has shown that both from the psychiatric (fluctuations of BPRS scores over time) and the neuroendocrinological (changes in PRL levels) viewpoints, a sample of bipolar outpatients attending a lithium clinic does not show stable longitudinal patterns.

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