Successful Concomitant Treatment of Raynaudâ€™s Phenomena, Premenstrual Dysphoric Symptoms, and Bipolar Disorder With Oxcarbazepine and Venlafaxine
Primary Psychiatry. 2003;10(3):53-56
Dr. McMeekin is in private practice at Piedmont Psychiatric Associates in Rock Hill, South Carolina.
Disclosure: Dr. McMeekin is a regional speaker for Novartis Pharmaceuticals.
Please direct all correspondence to: Hayne McMeekin, MD, Piedmont Psychiatric Associates, PO Box 36024, Rock Hill, SC 29732-0500; Tel: 803-327-6103 ext. 233; Fax: 803-328-5443; E-mail: firstname.lastname@example.org.
Stress in association with depression and anxiety has been increasingly defined in relation to the hypothalamic-pituitary axis, which regulates physical and emotional processes. Thus, is it possible that there are physical as well as emotional consequences to depression and anxiety associated with stress? This case study describes a patient’s psychological and physical findings during the process of successful resolution of the illness. Adiscussion of modulation of the hypothalamic pituitary adrenal axis and the sympathetic nervous system in relation to mood, anxiety, and pharmacotherapy follows.
Perceived internal or external stress affects organ function via the hypothalamic-pituitary-adrenal axis (HPA) and the sympathetic nervous system. The central nervous system components of these two systems interact with each other on a regular basis.1 Stress causes the release of corticotrophin-releasing-factor (CRF) and subsequently adrenocorticotropic hormone (ACTH), which stimulates the adrenals to release cortisol. Cortisol at first acts to protect neurons from the chemical results of stress. With continued stress the body’s ability to control the HPA axis becomes impaired and with that, levels of cortisol, CRF, and glutamate become elevated. This increases the chance of neuronal toxicity and may be the reason for the hippocampal atrophy seen in chronic depression. Sympathetic activation from the locus ceruleus increases peripheral catecholamines. The circulating glucocorticosteroids and catecholamines (primarily norepinephrine) then act at diverse sites to produce wide-ranging effects across a number of systems.1-3 Many of these changes such as increases in alertness, respirations, and heart rate, and decreases in feeding, digestion, and sexual behavior, result in the fight-or-flight response to threat.1
Glutamate is the major excitatory neurotransmitter in the central nervous system. Mathew and colleagues3 have postulated that glutamate plays an important role in modulating the HPA axis and, therefore, mood and anxiety. Skolnick4 has proposed that tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may stabilize the HPA axis in two ways. The first would be through the process of reuptake inhibition of norepinephrine and serotonin, thereby promoting the production of protective and growth-enhancing neurochemicals such as brain-derived neurotropic factor (BDNF). BDNF causes stabilization of the neuron’s cell membranes, increased branching and connections between neurons, and reverses the potential overstimulatory and cytotoxic effects of the glutaminergic system by stabilization of glutamate sensitive receptors. This promotes healing of neurons which then improves mood and anxiety. Drugs that modulate the effects of glutamate (such as lamotrigine and oxcarbazepine) may also increase BDNF by protecting neurons from overstimulation.4,5 The anticonvulsant oxcarbazepine modulates sodium channels, calcium channels, reduces glutaminergic transmission, and enhances dopaminergic neurotransmission.6 Oxcarbazepine has been reported effective in bipolar disorders.7
Intense vasospastic phenomena have been noted in anorexia nervosa. Bhanji and Mattingly8 examined an unselected series of 155 anorectics and found acrocyanosis in 32 patients. The patients with intense vasospastic phenomena were judged more ill than their counterparts. The characteristic cyanosis and coldness of the hands and feet in acrocyanosis is caused by constriction of the skin arterioles and venous dilatation.8 Anorexia nervosa, like migraine, has been genetically linked to bipolar disorder.9 Vasospastic phenomena have also been noted in bipolar disorder.
Endicott10 studied 400 patients who fell within the bipolar spectrum. He noted a significant positive correlation with migraine headaches, Raynaud’s “disease,” enuresis, “episodic phenomena,” (which may have been migraine auras), fingernail biting, and learning disorders. Forearm blood flow has been noted to be reduced compared to controls in depersonalization disorder.9
In a study of 186 bipolar I women, Blehar and colleagues11 found that 6% reported regular mood changes in the menstrual or premenstrual phase of their cycles. In addition, 75% described their premenstrual symptoms primarily as increased irritability, anger outbursts, and mood lability; 25% reported that their chief symptom was depression. Only five women reported symptoms as minor, while 20 described them as severe. Other disturbances related to hormonal changes were reported as well. Of those bipolar I women who reported a pregnancy, 45.3% reported experiencing severe emotional problems during pregnancy or within 1 month after childbirth and 19.3% reported increased symptoms during perimenopause or menopause. Blehar and colleagues11 also noted a higher rate of migraine headache in their sample of bipolar women than reported in the general population.
Intense vasospastic and/or vasodilatory phenomena has been reported in anxiety and affective disorders, koro, eating disorders, depersonalization disorder and disorders genetically linked to bipolar disorder, such as migraine, and Raynaud’s phenomenon.8,10,12,13 The following patient presented with severe premenstrual psychiatric symptoms, Raynaud’s phenomenon, and migraine headaches. All resolved or improved following successful concomitant treatment of the patient’s affective syndrome.
A 42-year old married, white female was referred for anxiety attacks, chronic generalized anxiety, and severe premenstrual symptoms only partially responsive to sertraline.
She had originally noted the onset of distractibility following the birth of her children. Her anxiety began at 32 years of age following a severe case of Bell’s palsy. The anxiety persisted and gradually worsened so that she became increasingly more “on guard” when leaving home, driving, or seeing others outside her home. In retrospect, she also noted during that time the onset of Raynaud’s phenomena in her hands and feet when she was anxious, and a feeling of sporadic sadness sometimes without reason. Three years later she experienced her first panic attack during a business meeting. She noted shortness of breath, feelings of terror, loss of feeling in her arms and legs, and a feeling of being overwhelmed (Table).
This intensified her level of anxiety and she shortly became frightened to drive or to leave her home except to walk next door to the family business and, as a result, became socially isolated. The vasoconstriction in her extremities intensified during her attacks and she began to feel pain in her extremities as though “someone was pouring hot oil over her hands and feet” (while her hands and feet would become “icy cold”). She also noted her nose, ears, and nipples would be affected and that her nipples would become erect and cold, and then excruciatingly painful, as did her hands and feet. These symptoms would reliably occur when she would become frightened, such as when forced to make a sales call or go outside the home to shop. She would also often have an urgent bowel movement accompanied by diarrhea.
None of these autonomic phenomena would be preceded by aura-like phenomena, but were triggered by fear. The pattern of her baseline psychiatric symptoms included problems concentrating due to distractibility, being easily startled, her mind being flooded with thoughts (or, as she described it, “rushing”), a mixture of anxiety and painful awareness (a sensation of being overwhelmed by events, noises, and movement around her), and restlessness. The restlessness could gradually increase to overactivity, agitation, and mild elation with a decreased need for sleep. This was followed by periods of depression, during which she had difficulty falling and staying asleep. These cycles were unpredictable and brief in duration, sometimes lasting only 5 days.
The cycles often began following the patient’s menses. Her premenstrual symptoms were an intensification of her basic mixed anxiety and depressive symptoms and began 7 days prior to her menses as tracked using a calendar. The patient’s gynecologist had prescribed sertraline that helped her depression at a dosage of 50 mg/day, and helped her premenstrual symptoms at a dosage of 100 mg/day 2 days prior to her menses. However, the increased dose of sertraline intensified her anxiety and mood swings at other times. She became severely depressed when the sertraline was discontinued. The patient was referred for psychiatric evaluation.
Medical, Social, and Family History
The patient’s medical history was significant for occasional hemicranial migraine headaches that were accompanied by nausea and photophobia. Her aura consisted of nonspecific “vision changes” in her left eye and lessened sensation in her tongue. Computerized axial tomography (CAT) and magnetic resonance imaging (MRI) scans of her brain were read as normal and her neurologist reported her examination as unremarkable. She had not been given an electroencephalogram (EEG). No migraine-specific treatment was required. Her Bell’s palsy was mostly resolved and not noticeable. She was unable to take oral contraceptives as they increased her blood pressure. She was allergic to levofloxacin, trimethoprin and/or sulfamethoxazole, and erythromycin. She had gained 20 pounds since treatment with sertraline began and was unable to reach orgasm. Her two preadolescent children were in good health. She had no accidents, head injuries, operations, or hospitalizations other than for childbirth. She denied a history of fainting or any phenomena reminiscent of seizure activity.
There was a family history of diabetes mellitus, hypertension, cardiovascular disease, and a history of depression in her mother, both sisters, and her maternal aunt. Two family members had been treated successfully with sertraline.
The patient was in a successful second marriage. Both of her children were symptom-free and successful in their academic and social life. The family business was successful. The patient was a college graduate, denied alcohol or drug abuse, and reported no problems with authority figures during her life, but had a difficult relationship with her mother, whom she described as critical and dominating. There was no history of sexual or physical abuse.
Mental Status Exam
At initial evaluation the patient presented as an anxious, hyperactive, overstimulated woman who spoke rapidly and whose speech was poorly modulated. She was neatly dressed and of average weight. She tended to become distracted easily and lose her train of thought. Her eyelids were over-retracted and her pupils were 5 mm in diameter and reacted sluggishly to distance and changes in light. Her eyes moved in jerky arcs and she tended to glance quickly about the room as she became distracted.14 Her movements were hesitant and poorly modulated. Her hands, ears, and nose were cool and her hands showed slowed capillary filling after pressure was placed against the skin; they also had a curious pale dusky hue.
She was intelligent, well informed, pleasant, and frustrated by her symptoms. She described herself as easily angered, often losing control of her temper to her later embarrassment and shame. She described herself as being depressed at times but not suicidal, and felt that her main problem was her anxiety. She described her premenstrual symptoms as an intensification of her basic symptom pattern complete with increased irritability and racing of her thoughts. She was unable to stop her anxiety and panic attacks once they started and arranged her life to minimize those activities and situations that she thought triggered the attacks. She described herself as feeling almost constantly “on guard.”
Due her mood swings, irritability, racing thoughts, and increased anxiety following the increases in her sertraline, a diagnosis of comorbid or primary bipolar disorder was considered and oxcarbazepine 300 mg BID was prescribed with instructions to increase the dose by 300 mg/week to a maximum of 1,200 mg/day. Sertraline was continued and alprazolam 0.5–1.0 mg/day was added as needed to help with panic attacks. At her return in 1 month, she was taking oxcarbazepine 600 mg BID and had noticed improved concentration; her mind had “stopped rushing,” and her extremities (and nipples) were warm and no longer painful. Her premenstrual symptoms had been much improved, but she was still having difficulty sleeping and still felt moderate anxiety in stressful situations.
Her oxcarbazepine dosage was changed to 600 mg in the morning and 900 mg in the evening with remission resulting. The only side effect noted was mild morning sedation. Attempts to decrease the total dosage, or to further decrease the morning dose and increase the evening dose (to maintain the same total daily dose) resulted in an increase in her premenstrual symptoms and a return of her peripheral vasospasm. Returning to her previous dosing schedule brought the patient to her asymptomatic state. Her sedation has gradually abated. Attempts to stop the sertraline to help with weight loss resulted in a return of sustained depressive symptoms. Venlafaxine 37.5 mg BID was substituted with resulting normalization of mood, weight, and sexual functioning. She reported no further need for the alprazolam.
This combination of medications has resulted in a near complete remission of the patient’s affective and depressive psychiatric symptoms, her Raynaud’s phenomenon, and a marked decrease in her migraine headaches. She had earlier noted some “bloating” prior to menses, but has increasingly had no premenstrual symptoms. She is now able to drive about freely and go to public gatherings such as church and shopping malls and has joined her church choir. She has had a decrease in the severity of her allergic reactions to bee, wasp, and fire ant bites. Although she used to required steroid and epinephrine injections, she now responds to diphenhydramine injections alone. Her improvement has been maintained for over 9 months.
The case patient presented with mixed, rapidly-cycling mania, Raynaud’s phenomenon, peripheral pain accompanying vasoconstriction, migraine, and severe premenstrual discomfort. All these syndromes resolved or improved with treatment, suggesting some commonality of process.
There is evidence of an interaction between the hypothalamic-pituitary-ovarian axis and the HPA axis. Stress can induce amenorrhea and women normally show a hyperresponsiveness of the HPA axis when compared to men.15 Interestingly, when estradiol patches are given to normal men, they then show an increase in plasma cortisol, ACTH, and norepinephrine from baseline when subjected to unexpected stress.16 This patient’s premenstrual symptoms were best described as a cyclical exacerbation of her basic manic process and her panic attacks as a painful, intense exacerbation of the flight-or-flight process causing sensory overload.
In a 10-year study of 135 patients diagnosed with obsessive-compulsive disorder, Perugi and colleagues17 noted that in 27.4% of their patients, symptoms followed an episodic course with periods of remission and exacerbation and that those patients were more likely to respond to mood stabilizers such as lithium. While the patient discussed in this case study did not have periods of remission, her symptoms did vary in intensity and on closer investigation brief cyclical episodes were noted. Perugi and colleagues17 suggested that in some patients obsessive and compulsive symptoms were the “phenotypic expression of an underlying affective genotype.” The case patient’s premenstrual, anxiety, and panic symptoms may well fit that pattern of an affective syndrome mimicking other disorders or making latent syndromes overt.17
In an open case series, Blumer and colleagues18 reported that premenstrual dysphoria responded to a combination of anticonvulsants and antidepressants in both patients diagnosed with and without epilepsy. They noted that chronic epilepsy involving the mesial temporal lobe often results in hippocampal sclerosis and that interictal dysphoria in those patients often results in a syndrome which varies in intensity and presents in a characteristic pleomorphic and intermittent pattern of depressed mood, anergia, irritability, euphoric mood, insomnia, pain, anxiety, and fears. They reported that this syndrome often responded to the addition of modest doses of antidepressants to the optimal antiepileptic regimen. While an EEG was not performed for the case patient, both MRI and CAT scans of her brain were negative and there were no symptoms or history suggestive of a seizure disorder.
There is increasing evidence that dysregulation and hyperresponsiveness of the HPA axis plays a role in psychiatric disorders and symptoms.3,19 As the brain structures involved in the HPA are involved in the regulation of physical and emotional equilibrium one might expect to see somatic symptoms as well as emotional distress in such patients’ presentation.1
From the work of Bhanji and Mattingly8 one might suspect that a subgroup of more ill psychiatric patients would show such symptoms. The case patient presented demonstrated or reported mixed, rapid-cycling mania, Raynaud’s phenomena, peripheral pain accompanying vasoconstriction, migraine, severe premenstrual discomfort, and symptoms suggestive of the fight-or-flight process. All these syndromes resolved or improved with treatment. PP
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