Dr. McMeekin is a psychiatrist in private practice at Piedmont Psychiatric Associates in Rock Hill, SC.
Acknowledgments: Dr. McMeekin is a regional speaker for Novartis Pharmaceuticals. The author reports no financial, academic, or other support of this particular work.
A case of bipolar illness is presented demonstrating the varied presentations of the illness longitudinally, the effects that hormonal events and therapy can produce in bipolar patients, and how adequate mood stabilization can modify those events.
Most gender-related studies and those that examine the impact of hormones on the onset of emotional illness have focused on major and minor depression. It is only recently that the effects of hormones and reproductive-related events have been studied in larger bipolar populations. The results have shown significant hormonal sensitivity in bipolar women.1 The more subtle and comorbid presentations of bipolar illness are often difficult to diagnose. This can delay accurate treatment and lead to significant psychosocial morbidity. Treatment based solely on current symptoms can be misleading, and a detailed longitudinal history accompanied by input from family members is often necessary for accurate diagnosis.2 Described here is a longitudinal case history illustrating the variability of symptoms and hormonal sensitivity in a female bipolar patient.
A 45-year-old white woman was referred for treatment of chronic depression not responsive to, or even worsened by, most antidepressant medications.
During her initial interview she presented as poised and organized. However, this changed as she spoke; she became more disorganized in her thinking and speech, as she would become distracted by a thought or an outside diversion (such as a noise or a movement) and “block,” forgetting her line of thought. When questioned about this, she replied that she had often wondered if she had attention-deficit/hyperactivity disorder. Her main symptoms were compatible with mixed bipolar depression and included racing thoughts, insomnia, blunting of emotions with decreased ability to feel pleasure and intimacy, and marked anxiety with periods of panic, depressed mood, irritability, decreased energy, and a sense of boredom. There was a marked obsessive quality to her depression, as she was constantly ruminating about her “mistakes” and whether she should change jobs or marry her current boyfriend. She denied suicidal thoughts or psychotic thinking. Her memory was good. She sat rigidly and appeared tense, with little spontaneous movement other than her leg, which shook constantly. When she did move, her gestures were quick and hesitant.
In retrospect, she had first noted mild depression at the age of 9 years. She experienced her first hypomanic period at age 18 years, where she enjoyed an elevated mood, decreased need for sleep, increased energy, increased sexual drive, and an increased sense of well-being. This lasted for several months before she returned to her usual mildly depressed state. This pattern continued throughout her life, worsening with time. By age 35 years, her illness had progressed so that she felt “addicted to men.” She would “fall in love” and engage in “whirlwind romances,” which often involved activities such as sky diving, jaunts to foreign countries, and other exotic and sometimes dangerous activities. Her mood would then shift to an anxious, agitated depression and she would begin to worry about whether “she was making the wrong choice.” She broke numerous engagements while depressed and would ruminate about her career and lifestyle choices until her mood shifted into mania, after which she would begin the process anew. Some years she experienced four complete cycles. She would make impulsive decisions during her excited manic periods, changing jobs and residences often. This pattern shifted after she was diagnosed with Crohn’s disease at age 39 years and began treatment with prednisone.
With prednisone her mood shifted into a sustained period of mild mania that continued as long as she was given the medication. When the medication was stopped, she would shift into a chronic mixed depression. This pattern repeated each time prednisone was used to control an exacerbation of her Crohn’s disease. Control of her emotional state was complicated by her becoming perimenopausal and requiring hormonal replacement with 0.2 mg estrogen patches and 5 mg of progesterone for 10 days every 3 months to induce menses. She reported that the estrogen had no effect on her mood, but that she became “depressed” during and for a time following the progesterone therapy. She had not responded to or become irritable and hyperactive on clomipramine, sertraline, paroxetine, and bupropion. She reportedly had not responded to a trial of lithium or valproate, but tolerated and had a partial response to venlafaxine 225 mg/day that decreased with time. Her medications, when first evaluated, included venlafaxine 37.5 mg sustained release tablets, alprazolam 0.125–0.25 mg three to four times per day as needed for anxiety, and zolpidem 5–10 mg for sleep. Her other medications included the previously mentioned estrogen and progesterone, and mercaptopurine 25–50 mg/day for her Crohn’s disease.
Family, Medical, and Social History
There was a family history of depression and bipolar disorder. Her birth and early development were without difficulties. She had her menarche at age 9 years and gradually developed severe premenstrual symptoms, including racing thoughts, irritability, sensory hypersensitivity, and difficulty sleeping prior to each menstrual period. She had no allergies, accidents, or severe reactions to medications.
She was a high school and college graduate. She never married and had never been pregnant. She was extremely successful in her chosen profession. She had no police record, had never been in serious financial problems, and had never used illegal drugs or abused alcohol.
The patient’s treatment was typified by disappointing responses to medications. She was continued on venlafaxine, alprazolam, and zolpidem. To this regimen was first added quetiapine 25 mg/day (discontinued due to sedation) and then lamotrigine 25 mg/day (discontinued due to agitation). She responded to 7.5 mg of olanzapine with less anxiety and a stabilization of her mood cycles. Topiramate 50 mg was added for further mood stabilization and to prevent weight gain. Her mood improved and stabilized, her concentration improved, and she became less obsessive. She then decompensated, with her thoughts becoming disjointed and speeded, her sleep becoming broken, and her irritability and depression worsening. Her symptoms then began to decrease and she restabilized on olanzapine and topiramate.
After several months of increased stability and decreasing need for the olanzapine, she decompensated again. This time it was noted that it occurred after she had taken progesterone 5 mg for 10 days. Further discussions confirmed this pattern of deterioration coinciding with her course of progesterone. Her gynecologist prescribed norethindrone 0.35 mg in place of the progesterone, with the same increase in symptoms resulting. Her gynecologist then stopped her hormones and prescribed an injection of 3.75 mg leuprolide. The patient gradually began to feel more agitated and pressured, her anxiety and depression worsened, and her sleep deteriorated. This state lasted approximately 6 weeks. The leuprolide was determined to be the cause and no further injections were given. Hysterectomy was discussed and rejected by the patient.
The patient was able to tolerate a maximum of olanzapine 10 mg/day due to sedation, and topiramate 50 mg/day due to agitation. Neither was sufficient to fully control her symptoms while using the progesterone and norethindrone, or after taking the leuprolide. When taking estrogen alone she stabilized with olanzapine 1.25 mg, topiramate 25 mg, and venlafaxine 25 mg/day. She continued taking mercaptopurine 25 mg/day and promethazine 12.5 mg as needed for nausea caused by the mercaptopurine.
In an attempt to find a medication that the patient could tolerate at higher doses, she was given a trial of oxcarbazepine, and topiramate was stopped. The result was a complete remission of symptoms at 1,200 mg/day. The patient was able to concentrate and her distractibility ceased. Her movements were smoother and her facial expressions became more fluid, better following and reflecting her inner emotions and thoughts. Her obsessions stopped and she was able to make decisions without difficulty.
Unfortunately, side effects of nausea and stomach pain caused by the oxcarbazepine forced a decrease in the dose to 150 mg BID. Her side effects stopped, but her baseline depression, obsessions, and racing thoughts returned. When she returned 1 month later, she had gone through a course of progesterone and had an exacerbation of her symptoms. She decided to increase her oxcarbazepine by adding “micro” doses as tolerated. By her return she was taking 1,200 mg/day and was back in remission.
When she returned in 3 months she was taking olanzapine 1.25 mg, venlafaxine 25 mg, and oxcarbazepine 600 mg BID. Several events had occurred: First, she had gone through a progesterone-induced period with minimal effect. She also reported that she became irritable “the last 4 days,” but that this irritability remitted shortly after the progesterone was stopped. There was no evidence of bipolar illness on her return. She appeared confident; spoke clearly and to the point; and her movements, affect, and speech reflected the emotional stability she now felt.
One year later, her symptoms remain in remission except for some mild anxiety following her use of progesterone. Her Crohn’s disease is also in remission and she has stopped the mercaptopurine.
This case demonstrates the overlapping and sometimes confusing effects of steroids and neuropeptides on mood and behavior in many patients with bipolar disorder. The suspected reason for variability is the probability that no single gene is responsible for the disease, but rather multiple genes interact to determine severity, symptoms produced, and treatment response.3
One area of increasing interest in mood disorders is the hypothalamic-pituitary-adrenal (HPA) axis. Patients with major depression have been shown to have enlargement of the pituitary and adrenal glands. This is believed to reflect an increased production of corticotropin-releasing hormone (CRH), which has been shown, in animals, to produce behavior resembling depression, increased vigilance, anxiety, and dysregulation of sleep. Normally, glucocorticoid receptors regulate the activity of the HPA axis and the production of CRH, adrenocorticotrophic hormone, and, ultimately, cortisol. Inability of a standard test dose of the steroid dexamethasone to suppress HPA axis overactivity is the basis of the dexamethasone suppression test (DST).
Evidence of continued HPA axis hyperactivity, even with symptomatic improvement with treatment, is a predictor of relapse. DST nonsuppression has been a consistent finding in major depression and a frequent (but not consistent) finding in mixed bipolar states (a combination of irritable-anxious mania and depression), but has not been found in euphoric mania.4,5
Regulation of female reproductive hormones is controlled by the hypothalamic-pituitary-ovarian (HPO) axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile fashion that stimulates follicle stimulating hormone (FSH) and luteinizing hormone (LH). Of these, the matching LH pulse frequency is most critical. LH pulse frequencies that are too rapid (as in polycystic ovary disease) or too slow (as in hypothalamic amenorrhea) lead to anovulation.6 Leuprolide is a potent GnRH agonist which initially overstimulates and then “down regulates” the receptor, causing an initial rise then a reversible suppression of the synthesis and release of LH and FSH.
The GnRH agonists have been used effectively in premenstrual dysphoric disorder, precocious puberty, carcinoma of the prostate, endometriosis, uterine fibroids, and polycystic ovarian disease. The frequency of psychiatric symptoms incurred by the use of GnRH agonists appears to be underappreciated. These symptoms include anxiety states, delirium, mania, depression, and psychosis associated with paranoia and auditory hallucinations. Sertraline has been reported to correct these symptoms even when the leuprolide injections are continued.7
Stress activates the HPA axis and may inhibit the HPO axis and reproductive functioning in women with depression. There have been findings of mean plasma estradiol levels being 30% less in women with major depression compared to matched controls. Estradiol has effects on brain levels of serotonin and norepinephrine. Estradiol also has anxiolytic effects6 and, when used with a transdermal delivery system, 17-β-estradiol has been shown to have antidepressant effects in perimenopausal women.8 Bipolar patients report a 20% increase in psychiatric problems during the perimenopausal/ menopausal phase of life. Seventy percent report depressive syndromes, 20% report anxiety and agitation, and 20% have manic episodes (some for the first time).1
Progesterone’s role in producing psychiatric symptoms in the general population has been studied by examining users of depot-medroxyprogesterone acetate in a health maintenance organization. Depressive symptoms were found in 40% of users and 60% of those discontinuing its use.9 The effects of estrogen or estrogen plus progesterone have been studied in postmenopausal women without psychiatric histories. No change in mood was found with estrogen alone; a slight but statistically significant increase in daily anxiety was noted when progesterone was added.10 There is more evidence for exacerbation if a prior psychiatric illness is present. If women with a prior history of postpartum depression are first given leuprolide to induce a hypogonadal state for 1 month, are then given supraphysiologic levels of estradiol and progesterone for 8 weeks to mimic pregnancy, and are then abruptly withdrawn from those hormones to mimic delivery, 62.5% will develop significant mood symptoms, with some showing mania.11
There is evidence of a hormonal effect in bipolar I women. In a survey, 45.3% reported severe psychiatric symptoms either during pregnancy or within 1 month after childbirth, with 86% of these women reporting depression as their major symptom. A small percentage reported “increased mood cycling or shifts from manic to depressed mood after delivery.” Also, 66% reported mood changes either prior to or during their menstrual cycles, with the majority (75%) reporting anger and mood lability as their primary symptoms. As noted previously, approximately 20% of bipolar women describe an increase in psychiatric symptoms during the perimenopausal and postmenopausal phase of their reproductive life.1
Leuprolide-induced sustained mania and mania followed by depression have been reported previously.12,13 The patient noted here had a prior history of documented bipolar disorder with a moderate but stable response to treatment that was destabilized by leuprolide, norethindrone, and progesterone. With the use of these drugs, a mixed anxious and depressed state resulted that was similar to that seen during her depressive episodes, but with greater intensity. To my knowledge, this is the first evidence of leuprolide-exacerbated mixed bipolar disorder to be reported in the literature.
In reporting her symptoms during an initial evaluation, she emphasized their depressive and anxious qualities. It was only on direct questioning that she recounted her racing thoughts, her nonstop intrusive and obsessive negative thinking, and her marked distractibility and sensory hypersensitivity to repetitive noises and noxious stimuli, suggesting a dysphoric manic diagnosis. It was only after some improvement that she was able to recount earlier euphoric manic episodes. No evidence of euphoric mania was seen during her period of treatment.
The patient’s symptoms show the myriad ways that steroids affect patients with bipolar spectrum disorder, and the beneficial effects that adequate mood stabilization can produce. Problematically, most of these patients present in a depressed or anxious and irritable state, and are often treated with antidepressants. While antidepressants as monotherapy in bipolar patients may be helpful,14 they may (as occurred in this patient) have no effect or have an initial response with decay. Antidepressants remain an important and effective therapeutic tool, but there is increasing awareness of their limitations in controlling symptoms and preventing suicide in bipolar patients,15 and of the need for adequate mood stabilization with drugs such as lithium or anticonvulsants as the cornerstone of therapy.16 PP
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