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 RESEARCH ARTICLE

Antidepressant-induced excessive sweating: Clinical features and treatment with terazosin

Rajnish Mago, MD

Department of Psychiatry and Human Behavior, Jefferson Medical College, Philadelphia, PA, USA

Michael E. Thase, MD

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Barry W. Rovner, MD

Department of Psychiatry and Neurology, Jefferson Medical College, Philadelphia, PA, USA

BACKGROUND: Antidepressant-induced excessive sweating (ADIES) occurs in 5% to 14% of patients taking antidepressants, usually persists throughout treatment, and causes subjective distress and functional impairment. We conducted the first clinical trial of any treatment for ADIES.

METHODS: Clinical features of ADIES were assessed using a semi-structured form. Twenty-three patients with moderate or greater ADIES were assessed for a 2-week baseline period, followed by 6 weeks of open-label treatment with flexible dose terazosin, 1 to 6 mg/d. Improvement in ADIES was measured by the Clinical Global Impressions (CGI) scale and other measures.

RESULTS: ADIES commonly was prominent in the scalp (62%), face (95%), neck (48%), and chest (57%); usually occurred either episodically or with episodic bursts (82%); and was persistent (median 63 months). Twenty-two of the 23 patients responded to terazosin (CGI-I scores 1 or 2), with CGI-Severity improving from median of 5 to median of 2 (P < .0001). Patient-rated daytime and nighttime severity of ADIES and proportion of time in ADIES also improved significantly. The most common adverse effects of terazosin therapy were dizziness/lightheadedness (n = 9) and dry mouth (n = 4). No patient dropped out because of adverse effects. Sitting and standing systolic blood pressure decreased by median values of 3 (P = .044) and 5 (P = .063) mm Hg, respectively.

CONCLUSIONS: Terazosin may be an effective treatment for ADIES. Although dizziness/lightheadedness may occur in some patients, the treatment generally was well tolerated.

KEYWORDS: antidepressants, excessive sweating, terazosin, hyperhidrosis

ANNALS OF CLINICAL PSYCHIATRY 2013;25(3):186-192

  INTRODUCTION

Antidepressant-induced excessive sweating (ADIES) occurs with a variety of medications, including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion. The Physician’s Desk Reference states that 5% to 14% of patients on an SSRI or SNRI report sweating, rates that are at least twice that observed with placebo (www.pdr.net). In a meta-analysis of clinical trials of SSRIs, 10% of patients reported sweating as an adverse event.1 Using systematic assessment for adverse events associated with a variety of antidepressants, excessive sweating was found in 8.3% (moclobemide) to 40% (bupropion) of patients.2

ADIES causes significant distress and functional impairment and may require patients to make lifestyle changes to adapt. Treating ADIES may improve patients’ quality of life.3 Although patients tend to develop tolerance to some common adverse effects, ADIES may continue to be a problem ≥6 months after taking the antidepressant.4 ADIES also may effect antidepressant nonadherence, although this has not been evaluated formally. One strategy to improve adherence to antidepressants is to actively manage adverse effects,5 and treating ADIES may reduce suffering and reduce nonadherence to antidepressant treatment.

Patients often do not realize that excessive sweating is caused by an antidepressant, and ADIES, similar to many other adverse effects, often is not reported to the prescribing physician. Even when patients do report ADIES, physicians often do not realize that it is an adverse effect of the medication.

Given these facts, it is surprising and concerning that only a few case reports of treating ADIES have been published and no clinical trial of any treatment for ADIES has been published. Reducing the dose or changing or discontinuing the antidepressant should be considered first.6 However, dose reduction7,8 or antidepressant change may not resolve ADIES. Also, these strategies may not be viable options because of the risk of worsening depression.9 It is common to encounter patients who have shown a good response to a particular antidepressant but not to others, and such patients understandably are reluctant to change the antidepressant. In such situations, it may be advantageous to be able to treat the ADIES.

ADIES is thought to be caused by central serotonergic dysfunction. Sweat glands are innervated by the sympathetic nervous system even though the nerve endings on the sweat glands are cholinergic. Therefore, serotonin, norepinephrine, and acetylcholine all are involved in the physiology of sweating. Consistent with this, published case reports suggest that antiserotonergic (eg, cyproheptadine,8 aripiprazole,9 mirtazapine10), antiadrenergic (eg, clonidine,11,12 terazosin7,12), and anticholinergic (eg, benztropine,13,14 oxybutynin15) medications may be effective.

The adrenergic system is important in normal and pathophysiological sweating. Yohimbine, an α-2 antagonist that increases central adrenergic output, causes an increase in sweating.16 Adrenergic output is the final common pathway that stimulates sweating, and previously antiadrenergic drugs have been used to treat excessive sweating caused by other etiologies. Clonidine, a centrally acting α-2 agonist, has been used to treat excessive sweating during menopause.17 In an open-label study of 24 patients with spinal cord injury and recurrent symptoms of autonomic dysreflexia, including sweating and flushing of the face, the non-selective α-1 receptor blocker terazosin (1 to 10 mg/d) was effective in all patients.18 Terazosin also was reported to be effective in a patient with ADIES caused by imipramine.7 Subsequently, 2 case reports described patients who had an excellent response to terazosin, 2 mg/d, without any adverse effects; excessive sweating returned when terazosin was discontinued.12

To preliminarily assess the potential utility of terazosin and to obtain more systematic information about its tolerability we conducted 2 open-label clinical trials.

  METHODS

An unfunded, uncontrolled study (NCT00237510) was followed by a study of similar design funded by NARSAD (NCT00449683); results of both studies have been combined here. Patients were recruited from the outpatient services of Thomas Jefferson University (Philadelphia, PA, USA), by referrals from physicians, and by newspaper advertisements. The studies were approved the institutional review board of Thomas Jefferson University and all patients provided written informed consent. Patients were included if they had a clinical diagnosis of major depressive disorder, were age 18 to 75, and had excessive sweating associated with use of an antidepressant. The ADIES was required to be of at least moderate severity, occur at least twice a week, and have lasted for at least 4 weeks. In these patients, reduction in dose or changing or discontinuing the antidepressant was not feasible or had not ameliorated the ADIES. A history of hyperthyroidism, orthostatic hypotension, or priapism, abnormal thyroid-stimulating hormone at screening, and taking a phosphodiesterase inhibitor for erectile dysfunction were exclusion criteria.

Clinical features of the excessive sweating were collected with a semi-structured form. The study consisted of a 2-week baseline period during which excessive sweating was assessed without any change in medications, followed by treatment period of up to 6 weeks. The Clinical Global Impression (CGI) scale (for excessive sweating) and Patient Global Impression (PGI) scale (for excessive sweating; study 2 only) evaluated overall improvement in excessive sweating. Patients recorded the severity and frequency of excessive sweating during the night and day on a short, daily, self-rated questionnaire for excessive sweating prepared for this study. In the morning, no later than 2 hours after waking up, patients recorded the extent of sweating experienced during the night (if they were aware of it) and/or immediately upon awakening. In the evening, no earlier than 1 hour before their scheduled bedtime, they recorded sweating experienced during the day. Patients also completed the Hyperhidrosis Disease Severity Scale (HDSS; study 2 only),18 which is a 4-point self-rating of their sweating based on its severity (never noticeable, tolerable, barely tolerable, intolerable) and interference with daily activities (never, sometimes, frequently, or always interferes). A score of 1 or 2 on the HDSS indicates mild or moderate hyperhidrosis and a score of 3 or 4 indicates severe hyperhidrosis.19 The HDSS has been found to be reliable and valid based on moderate to strong correlation with other measures of sweating, both self-rated questionnaires and gravimetric measurement of sweating.20 A 1-point improvement in HDSS score has been reported to correspond to approximately 50% reduction in sweat production and 2-point improvement with about an 80% reduction.20

The effect of the excessive sweating was measured using the Illness-Intrusiveness Rating Scale sweating questions (IIRS; study 2 only).21 The IIRS sweating questions are 8 questions related to sweating that were developed to supplement the IIRS. Patients rate the questions on a 7-point scale including an overall rating, number of times a day 4 coping methods were used (cosmetic preparations, showering/bathing, changing clothes, limiting the type of clothing worn), and the extent to which 3 possible aggravating factors increased sweating or blushing (alcohol, spicy food, caffeinated drinks). In addition, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF; study 2 only),22 a 16-item, patient-rated tool, assessed satisfaction over the preceding week with a variety of life domains rated on a 5-point scale.

Two weeks after the screening visit—ie, at the baseline visit—patients were started on terazosin, 1 mg/d taken at bedtime. Patients were assessed at weekly intervals and terazosin was increased by 1 mg/d every week if needed and tolerated, to a maximum of 6 mg/d. Patients who showed significant adverse events could have their dose reduced by 1 mg every 2 to 3 days until they were able to tolerate the dose, and would continue at this maximum tolerated dose for the duration of the study.

Adverse effects were assessed at each visit after the screening visit using open-ended questioning about the presence of side effects or new symptoms that could be side effects of the study drug, specific questioning regarding presence of dizziness (especially when standing up), measurement of vital signs including orthostatic pulse and blood pressure, ECG at the screening and last visits, and the Systematic Assessment for Treatment-Emergent Events-General Inquiry (SAFTEE-GI, study 2 only).23 SAFTEE-GI consists of standardized, but general, open-ended questions about adverse health events followed by a series of items about onset, duration, course, and severity of the symptom, its potential relationship to the drug, and any action taken.

Data were analyzed using Stata 11.0. No corrections were made for multiple comparisons.

  RESULTS

Twenty-four patients were recruited for the studies. Twenty-three patients (10 for study 1 and 13 for the second, funded study) had at least 1 post-baseline visit; efficacy and safety analyses were limited to these patients. Nineteen of 23 patients completed the studies. The 4 patients who discontinued prematurely were much or very much improved at the last visit and had only minimal or mild adverse events at that visit.

TABLE 1 shows patients’ baseline characteristics. The median age was 48 (range 22 to 72), 78% were female, and 87% were white. Patients were taking a variety of antidepressants: venlafaxine (n = 5), duloxetine (n = 3), escitalopram (n = 3), sertraline (n = 3), bupropion (n = 2), citalopram (n = 2), fluoxetine (n = 2), and clomipramine (n = 1), sertraline plus bupropion (n = 1), or venlafaxine plus bupropion (n = 1).


TABLE 1

Baseline characteristics (N = 23)

  n %
Sex
Female 18 78
Race
White 20 87
African American 3 13
  Median Range
Age 48 22 to 72
Clinical Global Impression-Severity (for ADIES) 5 4 to 6
Daytime sweating
Mean severitya 2.0 0 to 3.0
Proportion of day 0.26 0 to 0.70
Nighttime sweating
Mean severitya 0.57 0 to 2.35
Beck Anxiety Inventory score 12 3 to 41
Depression severity
Beck Depression Inventory (N = 10) 21.5 8 to 53
Quick Inventory of Depressive Symptomatology (N = 13) 7 2 to 10
aMean of ratings for the week; 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe.

ADIES: antidepressant-induced excessive sweating.

Excessive sweating was prominent in the upper body; face (95%), scalp (62%), neck (48%), and chest (57%). Prominent excessive sweating in the armpits (0%) or palms (9%) was uncommon. TABLE 2 shows other clinical features of excessive sweating. ADIES usually was episodic or continuous with episodic bursts (56% and 26%, respectively). As many as 43% of patients indicated that they tended to sweat more than other people before taking an antidepressant, although since starting the antidepressant the sweating had become much worse. More than one-third of patients had a family history of excessive sweating with or without an antidepressant. Two-thirds of patients had had excessive sweating with a previous antidepressant.


TABLE 2

Clinical features

  n %
Temporal pattern (N = 23)
Continuous 4 17
Episodic 13 56
Continuous with episodic bursts 6 26
Frequency (N = 24)
Daily 19 79
3 to 4 days a week 5 21
Worst time(s) of the day (N = 24)
Morning 13 54
Afternoon 13 54
Evening 8 33
Night 10 42
Time to onset (N = 14)
≤1 week 4 29
>1 week and <1 month 6 43
>1 month 4 29
Sweating before antidepressant (N = 14)
Tended to sweat more than others 6 43
Same as others 6 43
Less than others 2 14
Family history of excessive sweating (N = 17)
None 11 65
On an antidepressant 1 6
Not on an antidepressant 5 29
Excessive sweating with a previous antidepressant (N = 14) 9 64
Worse in spring or summer (N = 17) 14 82
  Median Range
Total duration, months (N = 18) 63 3 to 300

Patients reported various outward signs of excessive sweating including clothing feeling wet (n = 18), clothing being visibly wet (n = 15), drops of sweat being visible to others (n = 18), drops of sweat falling off the body (n = 16), and wiping off sweat repeatedly (n = 18). Patients also reported that excessive sweating was distressing in a variety of ways including making them “extremely” or “very” uncomfortable (n = 22), being embarrassing (n = 19), causing them to stay home (n = 11), requiring them to change their clothes repeatedly (n = 13), interfering with their sleep (n = 8), and making them feel irritable (n = 10).

The most common final daily dose of terazosin was 4 mg/d (n = 7). Four patients each received 2 mg/d, 3 mg/d, or 6 mg/d. Three patients received 1 mg/d and 1 patient was taking 5 mg/d.

TABLE 3 shows the change in excessive sweating on clinician- and patient-rated measures. The CGI-Severity scale rating (for excessive sweating) was a median of 5 (marked) with a range of 4 (moderate) to 6 (severe) at the baseline visit. At the last visit it decreased to a median of 2 (borderline) with a range of 1 (normal) to 4 (moderate; Wilcoxon signed rank test P < .0001). The CGI-Improvement (CGI-I; n = 23) scale was rated 1 (very much improved) for 13 patients (57%), 2 (much improved) for 9 patients (39%), and 3 (minimally improved) for 1 (4%) patient. The PGI-Improvement (PGI-I; n = 13) scale was rated 1 (very much improved) for 7 patients (54%), 2 (much improved) for 5 patients (39%), and 3 (minimally improved) for 1 (8%) patient. Using a CGI-I or PGI-I rating of 1 or 2 (very much or much improved) as the criteria, 22 of 23 and 12 of 13 patients respectively were considered to respond to treatment.

TABLE 3 shows that self-rated excessive sweating during the day and night significantly decreased during the study. The Hyperhidrosis Disease Severity Scale (study 2 only) decreased from a median of 3 to a median of 1. Of quality of life measures used in study 2, the sweating questions of the Illness Intrusiveness Rating Scale showed a statistically significant improvement during the study but the general Q-LES-Q-SF did not.


TABLE 3

Change in severity of excessive sweating

  Baseline visit, median (range) Last visit, median (range) Pa
Clinical Global Impression (CGI)b
CGI-Severity 5 (4 to 6) 2 (1 to 4) <.0001
CGI-Improvement n/a 1 (1 to 3) n/a
Patient Global Impression-Improvement n/a 1 (1 to 4) n/a
Self-rated excessive sweating
Daytime
   Mean severityc 2 (0 to 3) 0.80 (0 to 2.82) .004
   Proportion of day 0.26 (0 to 0.70) 0.07 (0 to 0.72) <.001
   Severity × proportion of day 0.48 (0 to 1.50) 0 (0.03 to 2.03) .005
Nighttime
   Mean severityc 0.57 (0 to 2.35) 0 (0 to 1.3) .001
Hyperhidrosis Disease Severity Scale (n=13) 3 (2 to 3) 2 (1 to 2) .002
Illness-Intrusiveness Rating Scale (n=13) 21 (15 to 37) 18 (5 to 27) .003
Q-LES-Q-SF (n = 13) 52 (33 to 55) 52 (24 to 62) .483
aWilcoxon signed rank test for matched pairs comparing baseline visit to last visit.
bFor excessive sweating.
cMean of ratings for each week; 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe.

Q-LES-Q-SF: Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form.

Sixteen of the 23 patients reported ≥1 treatment-emergent adverse event. Treatment-emergent adverse events reported by >1 patient and possibly were related to terazosin were: dizziness (n = 10), dry mouth (n = 5), nausea (n = 3), headache/heaviness of head (n = 2), and fatigue/lethargy (n = 2). In addition, 1 patient each reported heaviness of the head, bloating, tingling and numbness, and heartburn. Patients first reported dizziness/lightheadedness when they were taking 1 mg/d (n = 4), 2 mg/d (n = 5), or 3 mg/d (n = 1) of terazosin suggesting that this adverse effect often occurs at low doses.

By the last visit, number of patients in whom the adverse effect had resolved were as follows: dizziness/lightheadedness (6 of 10 patients), dry mouth (3 of 5 patients), nausea (2 of 2 patients who reported it before the last visit), fatigue/lethargy (2 of 2 patients). Of symptoms reported by only 1 patient each, all had resolved by the last visit except heaviness of the head, which was only reported at the last visit.

All 3 patients who had an orthostatic change in systolic blood pressure (SBP) of ≥10 mm Hg reported dizziness/lightheadedness. However, 7 other patients reported dizziness/lightheadedness but did not have an orthostatic change of ≥10 mm Hg.

As shown in TABLE 4, sitting and standing SBP decreased a median of 3 and 5 mm Hg from baseline to last visit (P = .044 and .063 respectively). However, there was no statistically significant change in sitting or standing pulse and in orthostatic change in SBP. At the last visit, the maximum orthostatic decrease in SBP was 10 mm Hg. Orthostatic change in SBP at the last visit was significantly associated with standing SBP at that visit (P = .002) and to orthostatic change in SBP at the baseline visit (P = .028). Despite a significant decrease in sweating, oral temperature did not change from baseline to last visit. None of the patients had an abnormality or a change on the ECG from the screening visit to the last visit.


TABLE 4

Pre- and post-treatment vital signs

Vital sign, median (range) Baseline visit Last visit Change Pa
Pulse (sitting), bpm 80 (55 to 105) 80 (54 to 106) 3 (-32 to 35) .287
Pulse (standing), bpm 80 (56 to 111) 80 (56 to 108) -2 (-31 to 37) .681
SBP (sitting), mm Hg 120 (100 to 135) 115 (98 to 138) -3 (-18 to 10) .044
SBP (standing), mm Hg 120 (100 to 130) 110 (90 to 139) -5 (-18 to 14) .063
Orthostatic change in SBP, mm Hg 0 (-17 to 8) 0 (-24 to 11) 0 (-10 to 21) .418
Temperature, °F 98.2 (96.0 to 98.9) 98.2 (97.5 to 99.3) -0.1 (-0.7 to 3.3) .602
aWilcoxon signed rank test for matched pairs comparing change from baseline visit to last visit.

bpm: beats per minute; SBP: systolic blood pressure.

  DISCUSSION

Given that ADIES is relatively common, often persists for long periods, and can be disabling, it is important to conduct clinical trials for its treatment. The 2 studies reported here were the first clinical trials of any treatment for ADIES and the first to provide a systematic description of the clinical characteristics of this adverse effect. All but 1 patient responded during this study, which is not surprising because terazosin blocks the common pathway for sweating. Terazosin treatment also resulted in significant improvement in quality of life related to excessive sweating. The lack of significant improvement in general quality of life may reflect the Q-LES-Q-SF’s lower sensitivity to issues related to excessive sweating and the smaller sample size for that instrument.

The main potential adverse effect of terazosin is dizziness/lightheadedness. However, changes in vital signs were small and no patient had an orthostatic decrease in SBP >10 mm Hg. Nevertheless, caution is appropriate in patients who are on antihypertensive treatment or other medications that may cause orthostatic hypotension and in geriatric patients. Other adverse effects were mild to moderate and resolved during the study in many patients. Therefore, benefit-to-risk ratio was quite high.

An important limitation of this study is its uncontrolled, open-label design, therefore its findings should be considered preliminary. However, it was striking that patients with excessive sweating for many months or years showed substantial improvement in a short period. Another limitation was the use of some of the outcome measures only in study 2, reducing the sample size for those measures. In addition, because this was a pilot study and although several different outcome measures were used, no correction was made for multiple comparisons.

  CONCLUSIONS

The high response rate, along with terazosin’s mechanism of action and efficacy—and that of other antiadrenergic medications—in other conditions with hyperhidrosis, suggests that terazosin, 1 to 6 mg/d, may be highly and predictably effective for ADIES when changing or discontinuing an antidepressant or reducing the dose is not appropriate. However, these findings need to be confirmed in randomized, placebo-controlled trials.

DISCLOSURES: Dr. Mago receives grant or research support from Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, Genomind, and Shire. Dr. Thase has been an advisor or consultant to Alkermes, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Dey Pharma, Forest Laboratories, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante, Inc. Merck (including Schering Plough and Organon), Neuronetics, Ortho-McNeil Pharmaceuticals (including Johnson & Johnson), Otsuka, Pamlab, Pfizer (including Wyeth Ayerst Pharmaceuticals), Roche, Shire US, Sunovion Pharmaceuticals, Takeda, and Transcept Pharmaceuticals; has received grant support from the Agency for Healthcare Research and Quality, Eli Lilly and Company, Forest Pharmaceuticals, GlaxoSmithKline, the National Institute of Mental Health, Otsuka Pharmaceuticals, and Sepracor; has received honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Merck, and Pfizer (including Wyeth Ayerst Pharmaceuticals); has equity holdings in MedAvante, Inc.; and has received royalties from the American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton and Company. Dr. Rovner reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

ACKNOWLEDGEMENT: Supported in part by a NARSAD Young Investigator Award to Dr. Mago. Clinical Trial Identifiers: NCT00237510, NCT00449683.

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CORRESPONDENCE: Rajnish Mago, MD Director, Mood Disorders Program Department of Psychiatry and Human Behavior Jefferson Medical College 833 S. Chestnut Street, Suite 210E Philadelphia, PA 19107 USA E-MAIL: rajnish.mago@jefferson.edu