Psychopharmacology Induced Obesity:
An Examination of Treatment Failures
with Successful Retrials.
Background. Some psychiatric medications promote obesity causing increases in morbidity, mortality, non-compliance and relapse. Metformin is being used in some non-diabetic patients to control weight.
Objective. Examine psychiatric patients who were unresponsive to metformin for iatrogenic weight gain to determine if treatment could be improved to yield more responders.
Methods. Nine of twenty-three consecutive obese psychiatric medication patients did not experience benefits from metformin treatment. These nine were examined by interview, laboratory data and chart review, to find possible reasons for their treatment failure.
Results. Our review found five reasons for treatment failure and non-compliance:
1) non-specific dosing, 2) decreased libido and erectile dysfunction, 3) paresthesia, 4) metformin termination or dose decrease to prevent the psychological loss of food unreported to physicians, 5) and afternoon concentration, fatigue and irritability problems.
These were treated respectively with: 1) highly individualized dosing, 2) transdermal bio-identical testosterone, 3) a B-complex vitamin, 4) regular counseling and pill timers to remind about dosing, and 5) late afternoon nutritious snacks. Addressing these issues allowed the initial nine non-responders to lose weight.
Conclusion. Metformin has a role in psychotropic induced obesity, and its utility can be improved with minor treatment adjustments in some patients.
Index Words: Metformin, Obesity, Psychiatry, Psychotropics, Compliance
Many patients need psychotropic medication for years. Any abdominal obesity from these will lead to hypertension, asthma, cholesterol abnormalities, arthritis, cerebral and myocardial infarction, cancer, sleep apnea syndrome, heart disease, polycystic ovarian syndrome, and Type II Diabetes. The latter increases blindness, end-stage renal disease and amputations. 1-5
While manic or psychotic remission is important, iatrogenic abdominal obesity is not an appropriate medical plateu,6 since weight gain is a common cause of non-compliance, causing manic or psychotic relapse. 7 Metformin is emerging as useful in initial research in the management of obesity from psychotropics in adults and children,8,9 along with its use for polycystic ovarian syndrome,11 preventing diabetes12 and decreasing abdominal fat without lean muscle loss.13
Metformin has been used in Europe since the 1930's. 14 According to the FDA,
metformin has been approved in about 80 countries. It was approved in 1994 for Type II, diabetes. Metformin lowers elevated blood sugar levels and increases the body's response to its own insulin.15 It reduces hepatic glucose production, reduces intestinal glucose absorption and increasing insulin sensitivity, i.e., increasing glucose uptake.16
We believe we have found some iatrogenic reasons for metformin failures, which are not true failures. Specifically, we are reporting retrials of nine non-diabetics patients who initially failed metformin treatment being used to curb obesity caused or increased by psychiatric medications.
These nine non-diabetic patients initially failed to lose any weight during from metformin treatment. We focus on these patients because they initially felt the treatment was a failure, but on further exploration and treatment, achieved weight loss success. This subgroup represents nine out of twenty-three patients who did not lose weight. The other fourteen lost weight.
Our method in clinical practice was to routinely offer metformin in an off-label manner to those patients who complained of excess abdominal obesity associated with their psychiatric medication. Only twenty-four were offered this option, and twenty-three elected the trial. Each had clear risk factors due to significant obesity.
All twenty-three began treatment with waists in excess of 35 inches for females and 40 inches for males. This simple and rapid measurement identifies people who have a high increased intra-abdominal accumulation of fat. Also, all patients had to have a waist measurement in excess of hip size. And all patients had a body mass index (BMI) greater than 30 (obese). None were active athletes, which might invalidate the BMI measurement due to significant muscularity. They also had to have failed weight loss interventions with their primary care physician.
The FDA basic informed consent for metformin treatment in diabetics includes education about lactic acidosis symptoms. Specifically, malaise, rapid breathing, shortness of breath and severe weakness. If present, these require prompt medical attention and the medication discontinued. Each patient was told about this risk and also that the estimated death risk was approximately 1/33,000 in diabetics according to the package insert which they received.
Summary of Results in Full Group
Our initial metformin group consisted of twenty-three patients age 33-62 years old, who believed their weight problem was excessive and had failed previous treatments. Fourteen achieved an average weight loss of approximately four pounds per month. All had reported past failures in "dieting and exercise," and none had engaged in either during the initial 3 months of treatment. All were started at 250 mg at diner and increased by 250 mg every week in 2-3 divided doses until they reported a clear and profound appetite suppression. Weight loss also began at this specific dose. Occasional onset nausea was treated with a daily dose decrease of 250 mg. The physicians did not predetermine a fixed dose, but in consultation with the patient, allowed them to determine their 250 mg. increases. None received a dose over 1000 mg at lunch and diner. All were weighed on a single scale without shoes with appointments between 1 and 8 weeks apart.
Results and Examination of Retrial Subgroup
Our major concern was to understand the reason for treatment failures. We found six reasons why some patients failed treatment. After these issues were addressed, their retrials were successful in this small sample of nine patients.
- Dose adjustments as little as 250 mg per day influenced tolerability or effectiveness. For example, two patients had unremitting nausea on only 250 mg am and diner per day and dropped out. Yet four had no benefit on 2000 mg per day. When we treated the sensitive patients with 250 mg for a month, instead of a week, they had benefits and could also handle a smaller increase to 500 mg a day. Four others were raised above our 2,000 mg cut off, and achieved weight loss on doses up to 2,750 mg a day in divided doses with meals. The later dose approximates maximum diabetes treatment dosing. Any non-diabetic protocol must allow for this wide range.
In one fixed dose study in adolescents on weight-gaining psychotherapeutics, metformin was given to nineteen adolescents and four did not lose weight. All were given 500 mg per meal or 1500 mg/day. Perhaps if these four were increased by 250 mg. increments above 1500 mg. they might have responded. 16
- Metformin decreases bio-available testosterone,17 thus its use in polycystic ovarian disease. Patients will reduce or end treatment because of new onset anorgasmia or erection problems. One 48 year-old man decided he felt "no benefit" and ended treatment. Yet his blood testing while on metformin showed a very low free serum testosterone level. After treatment with a bio-identical testosterone transdermal cream, he reported feeling much better and mentioned his sexual functioning was returning. We were unaware it had declined. He asked to retry the metformin, and while we increased his dose we also increased his testosterone approximately 33%. He lost weight and then explained he had previously stopped it, due to a sudden worsening of his troubled baseline sexual functioning.
- Metformin has been identified as a cause of vitamin B12 deficiency. Three patients had classic B12 induced painful paresthesias of the hands. They terminated treatment. On a retrial, they were given an aggressive B complex vitamin for 3 days before treatment. No paresthesias appeared. However, one patient stopped taking the B complex and after 5-10 days the paresthesias returned, and promptly disappeared with a return to the supplement. (Metformin also reduces folic acid, which increases homocystiene--a cardiovascular risk factor. Therefore, we lowered homocystiene by supplementing with a broader B complex (folate, B6 and B12). 18,19
- Two patients briefly decreased their dose on multiple occasions for psychological reasons. These include "grieving the loss of food, " "missing the pleasure of eating," and, "I feel like I lost a friend." Weight loss involves more than an effective medication. Successful weight loss requires comprehensive psychological treatment. When they were given regular intensive counseling, they wanted to stay at an effective dose, which also curbed their appetite.
- Two patients blamed metformin for decreased concentration, fatigue, and irritability. The irritability was most common in the late afternoon and early evening.
These non-diabetic patients were promptly removed from metformin, and measured their blood sugar 4x per day. Measurements were made with a virtually painless arm glucose meter (Freestyle), requiring only 1/30th of a micron of blood. In the absence of metformin, these patients had occasional blood sugars in the 63-77 range, with levels particularly low before dinner.
Their food diaries revealed minimal food intake at lunch and before dinner. Once these patients ate raw fruit or vegetables at 3:30 PM, and stopped their afternoon fasting, they had no more reports of concentration decline, fatigue or irritability. Therefore, they were restarted and successfully maintained on metformin. They lost abdominal weight with no reports of decreased concentration, fatigue or irritability.
- One patient reported no decrease in cravings and had two pounds of weight gain over two months, while on 750 mg of metformin with breakfast, 500 mg at lunch and 1000 mg with diner. Yet a relative questioned his consistency. With a pill bottle exam and a closer interview, the patient mentioned "forgetting" most morning and lunch doses. He attached his medication bottle to his toothpaste and bought a medication timer for his lunch dose, resulting in minimal missed doses, and then he experienced seven pounds of weight loss in nine weeks.
If metformin is worthy of a trial, our goal has been to show that effectiveness and compliance can be increased if our six retrial points are considered.
- Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76-9.
- Rabkin SW, Chen Y, Leiter L, Liu L, Reeder BA. Risk Factor correlates of body mass index. Canadian Heart Health Surveys Research Group. CMAJ 1997;157(S 1):S26-31.
- Rose DP, Gilhooly EM, Nixon DW. Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review). Int J Oncol 2002;21:1285-92.
- Lean ME. Obesity: Burdens of illness and strategies for prevention or management. Drugs Today (Barc). 2000;36:773-84.
- American Medical Association. Managing diabetes part 1: understanding type 2 diabetes. 2000, pg. 1.
- Werneke U, Taylor D, Sanders DA. Options for pharmacologic management of obesity in patients treated with atypical antipsychotics. Int Clin Psychopharmacol 2002;17:145-160.
- Kurzthaler I, Fleischhacker WW. The clinical implications of weight gain in schizophrenia. J Clin Psychiatry 2001;62:32-7.
- Birt J. Management of weight gain associated with antipsycotics. Ann Clin Psychiatry 2003;15:49-58.
- Morrison JA, Cottingham EM, Barton BA. Metformin for weight loss in pediatric patients taking psychotropic drugs. Am J Psychiatry 2002;159:655-7.
- Pfeifer SM, Dayal M. Treatment of the adolescent patient with polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2003;30:337-52.
- Molitch ME, Fujimoto W, Hamman RF, Knowler WC; Diabetes Prevention Program Research Group. The diabetes prevention program and its global implications. J Am Soc Nephrol. 2003;14:S103-7.
- Ibanez L, Ong K, Ferrer A, Amin R, Dunger D, de Zegher F. Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism. J Clin Endocrinol Metab. 2003;88:2600-6.
- Bell PM, Hadden DR. Metformin. Endocrine Metab Clin N Amer 1997;26:523-534.
- www.fda.gov/bbs/topics/ANSWERS/ANS00627.html. Accessed July 19, 2003.
- Wiernsperger NF, Bailey CJ. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs 1999;58(S1):31-9.
- Morrison, Ibid.
- Parsanezhad ME, Alborzi S, Zarei S, Dehbashi S, Omrani G. Insulin resistance in clomiphene responders and non-responders with polycystic ovarian disease and therapeutic effects of metformin. Int J Gynaecol Obstet 2001;75:43-50.
- Desouza C, Keebler M, McNamara DB, Fonseca V. Drugs affecting homocystiene metabolism: impact on cardiovascular risk. Drugs 2002;62:605-16.
- Saperstein DS, Barohn RJ. Peripheral neuropathy due to cobalamin deficiency. Curr Treat Options Neuro 2002;4:197-201.
James L. Schaller, MD, MAR
Community Bank Towers
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David Behar, MD
Assistant Clinical Professor
Drexel University Medical School
John Thomas, MD, MPH
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