Expert: Ivan Goldberg, M.D. - 4/8/2004

Question
-------------------------
Followup To
Question -
My 12 year old daughter has just been diagnosed with BPD.  The psychiatrist is going to start her on depakote and eventually add an anti-depressant.  What is your experience with this combination, and is it usually effective?  I am a bit concerned about anti-depressants, with all of the bad press regarding them and teenage suicide.

Thank you.
Answer -
Hi . . .

I do not like to prescribe depakote for women, especially young women. Depakote can have detrimental effects on ovarian function.  See the abstracts below.

As it allows people with bipolar disorder to be treated with one rather than two or more drugs, I consider lamotrigine (Lamictal) to be the treatment of choice. See: http://www.psycom.net/depression.central.lamotrigine.html

Best regards . . .

Ivan
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1: Seizure.  2003 Sep;12(6):323-9.  

A study of anticonvulsant medication on ovarian function in a group of women
with epilepsy who have only ever taken one anticonvulsant compared with a group
of women without epilepsy.

Betts T, Yarrow H, Dutton N, Greenhill L, Rolfe T.

Birmingham University Seizure Clinic, Queen Elizabeth Psychiatric Hospital,
Birmingham B15 2QZ, UK. t.a.betts@bham.ac.uk

A group of 105 women (54 of whom were, and had only ever been, taking valproate
for at least a year, and 51 who had only ever taken either lamotrigine or
carbamazepine, for at least a year) were compared with a group of 50 women who
did not have epilepsy: any oral contraceptive taken at the time of testing was
recorded and blood levels of follicle stimulating hormone (FSH), luteinising
hormone (LH), testosterone and prolactin were estimated from days 2 to 6 of the
menstrual cycle (day 1 being the first day of bleeding) and an MRI scan made of
their pelvis. Women with epilepsy in general were significantly more likely to
exhibit evidence on MRI scanning, of polycystic ovaries (PCO): women taking
valproate but not an oral contraceptive were significantly more likely to have
clinical biochemical evidence of the polycystic ovarian syndrome (PCOS) with
raised LH and/or testosterone levels between days 2 and 6 of their menstrual
cycle than women who did not have epilepsy: this was not so for women taking
lamotrigine or carbamazepine. Since the polycystic ovary syndrome has
potentially serious consequences it is suggested that, where possible, valproate
is avoided in women of child bearing potential.

PMID: 12915077 [PubMed - indexed for MEDLINE]



2: An Pediatr (Barc).  2003 May;58(5):443-8.  

[Effects of valproate on sexual development]

[Article in Spanish]

Balaguer Martinez JV, Lopez Garcia MJ, Andres Celma M, Contell Villagrasa A,
Castello Pomares ML.

Servicio de Pediatria. Hospital Clinic Universitari. Universidad de Valencia.
Espana.

INTRODUCTION: Valproate use in young girls has been associated with the adverse
endocrinological effects of weight gain and hyperandrogenism. Furthermore,
polycystic ovaries and hyperinsulinism have been described in adult women. In
men and young boys, however, the possible adverse endocrinological effects of
valproate have scarcely been analyzed. OBJECTIVES: The aim of this study was to
evaluate the effects of valproate treatment on pubertal development, especially
the possible hyperandrogenic effects, in girls and boys with epilepsy. MATERIAL
AND METHODS: Twenty-three girls and 15 boys (aged 8-16 years old) who were
undergoing valproate treatment for epilepsy were compared with 15 control girls
and 10 control boys of the same age range. Anthropometric indexes, sexual
maturation, and hirsutism scores were evaluated. Serum concentrations of
follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone,
androstenedione, dehydroepiandrosterone, estradiol, and insulin were measured.
Ultrasound examination of ovaries and estimation of bone age through X-ray of
the left hand were also performed. RESULTS: Valproate did not affect pubertal
development in the study group. No hirsutism or polycystic ovaries were found.
Increases in weight, relative weight, and body mass index were observed in the
group undergoing valproate treatment, but no statistically significant
differences compared with the control group were found. Plasma testosterone was
higher in valproate-treated girls (0.71 0.51 ng/ml) than in control girls (0.35
0.15) (p 0.001). This finding was independent of valproate dose and treatment
duration. Hyperandrogenism was not found in valproate-treated boys. CONCLUSIONS:
Valproate may induce hyperandrogenism in epileptic girls but not in boys. This
is an early adverse effect and is independent of the dose used. No changes in
normal pubertal development or physical repercussions were found in epileptic
patients.

Publication Types:
   Evaluation Studies

PMID: 12724077 [PubMed - indexed for MEDLINE]



3: J Neurol.  2002 Jul;249(7):835-41.  

Polycystic ovaries, obesity and insulin resistance in women with epilepsy. A
comparative study of carbamazepine and valproic acid in 105 women.

Luef G, Abraham I, Haslinger M, Trinka E, Seppi K, Unterberger I, Alge A,
Windisch J, Lechleitner M, Bauer G.

Department of Neurology, University Hospital Innsbruck, Anichstrasse 35,
Austria. gerhard.luef@uibk.ac.at

In order to investigate the possible role of valproic acid therapy in the
development of obesity, hyperinsulinism and polycystic ovaries (PCOs), we have
studied metabolic parameters and ovarian morphology in epileptic women. A total
of 105 women, who were treated for at least 2 years with valproate (n = 52) or
carbamazepine monotherapy (n = 53), were included in the examination. Menstrual
disturbances were reported by 29 (28 %) of the women, 12 (11 %) of the VPA
treated women, and 17 (16 %) in the CBZ group. On ultrasound scan polycystic
ovaries were found in 28 patients (27 %) of the whole study population, of whom
13 (12 %) received VPA and 15 (14 %) CBZ. The mean body mass index (BMI) was
significantly higher in the VPA group (24.4 kg/m(2) +/- 4.1) than in CBZ treated
patients (22.9 kg/m(2) +/- 2.4;p < 0.022), and serum triglycerides tended to be
increased, while total cholesterol values (178.9 +/- 30.5) and LDL-cholesterol
values (92.6 +/- 27.4) were significantly lower in the valproate group, than in
the carbamazepine group (207.1 +/- 43.0 vs 115.1 +/- 42.0; p < 0.001).
Postprandial insulin, C-peptide and proinsulin levels were significantly higher
in VPA treated patients compared with those treated with CBZ, while no
differences could be found in the fasting state. In conclusion we could thus
demonstrate that the frequency of PCOs in 27 % of epileptic women seems to be
similar to that in the general population with a frequency of 20-30 %. The
development of PCOs did not reveal a difference with the administration of VPA
or CBZ. With respect to the metabolic side-effects of VPA therapy our data
indicate that VPA increases glucose stimulated pancreatic insulin secretion,
which might be followed by an increase in body weight.

PMID: 12140666 [PubMed - indexed for MEDLINE]



4: J Clin Psychiatry.  2002 Apr;63(4):322-30.  

Menstrual abnormalities and polycystic ovary syndrome in women taking valproate
for bipolar mood disorder.

O'Donovan C, Kusumakar V, Graves GR, Bird DC.

Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
mcpar@is.dal.ca

BACKGROUND: Valproate treatment has been associated with high rates of menstrual
abnormalities, hyperandrogenism, and polycystic ovaries in women with epilepsy.
This pilot study investigated whether valproate treatment had the same
associations in women with bipolar disorder. METHOD: One hundred forty
outpatient women with a DSM-IV diagnosis of bipolar disorder (aged 15-45 years)
were surveyed on their medical, psychiatric, and reproductive health history.
Thirty-two women met entry criteria for the study and were divided into 2
groups: (1) those currently receiving valproate (valproate, N = 17) and (2)
those who were not currently taking valproate (nonvalproate, N = 15). These 2
groups were compared with a normal (never diagnosed with a psychiatric disorder)
control group of 22 women. Women in the valproate group with current menstrual
problems (N = 7) underwent further assessment for the presence of polycystic
ovaries and hyperandrogenism. RESULTS: The age at onset of menses, mean length
of menstrual cycle, and mean length of menses were not significantly different
between the groups. Significantly more women reported menstrual abnormalities in
the valproate group (47%) than women not receiving valproate (13%) and controls
(0%). Forty-one percent of women with bipolar disorder taking valproate had
polycystic ovary syndrome. CONCLUSION: These results suggest high rates of
menstrual disturbances and polycystic ovary syndrome in women with bipolar
disorder currently receiving valproate.

PMID: 12000206 [PubMed - indexed for MEDLINE]



5: Epilepsia.  2001 Mar;42(3):295-304.  

Comment in:
   Epilepsia. 2001 Mar;42(3):305-10.

On the association between valproate and polycystic ovary syndrome.

Genton P, Bauer J, Duncan S, Taylor AE, Balen AH, Eberle A, Pedersen B,
Salas-Puig X, Sauer MV.

Centre Saint Paul, Marseille, France. PIERGEN@aol.com

Recent studies by Isojarvi et al. have raised the issue of an increased
incidence of polycystic ovary syndrome (PCOS) in women with epilepsy treated
with valproate (VPA) and have proposed replacement with lamotrigine (LTG).
Polycystic ovaries (PCO) are a common finding, with a prevalence >20% in the
general population, and are easily detected by pelvic or vaginal
ultrasonography, whereas PCOS is comparatively rare: few women with PCO have
fully developed PCOS, which includes hirsutism, acne, obesity, hypofertility.
hyperandrogenemia, and menstrual disorders. From an extensive review of the
current literature, it appears that there are no reliable data on the actual
prevalence of PCOS in normal women and in women with epilepsy. The pathogenesis
of PCO is multifactorial, including genetic predisposition and the intervention
of environmental factors, among which weight gain and hyperinsulinism with
insulin resistance may play a part. The roles of central
(hypothalamic/pituitary), peripheral, and local ovarian factors are still
debated. PCO and PCOS appear to be more frequent in women with epilepsy, but
there are no reliable data showing a greater prevalence after VPA. The recent
studies by Isojarvi et al. may have been biased by the retrospective selection
of patients. To date, there is no reason to contraindicate the use of VPA in
women with epilepsy. However, patients should be informed about the risk of
weight gain and its consequences.

Publication Types:
   Review
   Review, Tutorial

PMID: 11442143 [PubMed - indexed for MEDLINE]



6: Bipolar Disord.  2000 Mar;2(1):37-41.  

Comment in:
   Bipolar Disord. 2001 Feb;3(1):50-1.

Valproate treatment and the risk of hyperandrogenism and polycystic ovaries.

Soares JC.

Department of Psychiatry, Western Psychiatric Institute and Clinic, University
of Pittsburgh School of Medicine, PA, USA. soares+@pitt.edu

Long-term administration of valproate to women with epilepsy has been suggested
to result in increased risk of hyperandrogenism and polycystic ovaries. In
preliminary reports involving patients treated for several years, the reported
rates were as high as 43% for polycystic ovaries and 17% for hyperandrogenism.
In particular, when therapy started before the age of 20 years, the rates of
either one of these complications were as high as 80%. Surprisingly, these
reports have been relatively ignored in the psychiatric literature to date. As
increasing numbers of bipolar patients are in long-term treatment with
valproate, there is an important need for further research that clarifies the
relationship between long-term administration of valproate and other mood
stabilizers and the potential development of reproductive endocrinologic
abnormalities, and for increased awareness among clinicians and patients of the
unknown potential for these worrisome side-effects.

Publication Types:
   News

PMID: 11254018 [PubMed - indexed for MEDLINE]



7: Ann Pharmacother.  1999 Nov;33(11):1211-6.  

Is valproate pharmacotherapy associated with polycystic ovaries?

Chappell KA, Markowitz JS, Jackson CW.

Rutgers University, Piscataway, NJ, USA.

OBJECTIVE: To review and evaluate the published data associating the use of
valproate with the development of polycystic ovaries. DATA SOURCES: A
computerized search of MEDLINE (1966-May 1999) and Current Contents was
performed. Also, bibliographies were cross-referenced to yield additional
pertinent publications. All articles written in English were considered for
review. STUDY SELECTION AND DATA EXTRACTION: All pertinent clinical studies and
review articles associating valproate with polycystic ovaries and other
endocrinologic disorders were evaluated. DATA SYNTHESIS: Valproate is among the
most commonly used medications today effective in the treatment of a variety of
neurologic and psychiatric disorders. An accumulating body of literature has
suggested an increase in the incidence of polycystic ovarian syndrome among
women treated with valproate. The syndrome is characterized as hyperandrogenism
and chronic anovulation in the absence of identifiable adrenal or pituitary
pathology. It is a highly prevalent syndrome, affecting 2-22% of women in the
general population. CONCLUSIONS: Although a number of studies have found clear
evidence of neuroendocrine perturbations in patients treated with valproate,
there are presently limited data from large controlled studies involving
valproate monotherapy. Nonetheless, there appears to be a greater incidence of
polycystic ovaries associated with valproate use in comparison with other
anticonvulsants. The mechanism by which valproate may induce polycystic ovarian
syndrome is unknown, but could possibly be secondary to valproate-induced weight
gain or direct interference with steroid metabolism. Further study of the
potential association of valproate treatment with the development of polycystic
ovarian syndrome is warranted. Until the issue is clarified, clinicians should
at least be aware of the possibility of valproate-induced polycystic ovarian
syndrome and monitor patients accordingly.

Publication Types:
   Review
   Review, Tutorial

PMID: 10573322 [PubMed - indexed for MEDLINE]



8: J Endocrinol Invest.  1997 Oct;20(9):519-26.  

Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic
therapy.

Murialdo G, Galimberti CA, Magri F, Sampaolo P, Copello F, Gianelli MV, Gazzerro
E, Rollero A, Deagatone C, Manni R, Ferrari E, Polleri A, Tartara A.

Department of Endocrinological and Metabolic Sciences, University of Genova,
Italy.

Impaired reproductive function is thought to frequently affect women with
epilepsy, mainly when seizures originate in the temporal lobe. In this study, we
evaluated menstrual cycle features and assessed ovulation by determining luteal
progesterone (Pg) levels in 101 consecutive women with epilepsy (36 with
idiopathic generalized epilepsy -IGE; 65 with partial epilepsy -PE), aged
between 16 and 50 years, treated with various antiepileptic drugs (AED). PE
originated in the temporal lobe (TLE) in 40 subjects, in the frontal lobe in 13,
in the parietal lobe in 2, while the origin of focal seizures remained
undetermined in 10 patients. In all patients, menstrual and reproductive
history, body mass index, hair distribution and hormonal pattern were assessed.
Suprapubic ovary ultrasound (US) examination was carried out in 83 patients (28
with IGE, 55 with PE). Three patients with IGE and one with PE were amenorrheic.
Oligomenorrhea occurred in 16 patients, polymenorrhea in 2. Changes in menstrual
cyclicity were independent from epilepsy type (19.4% in IGE; 23.1% in PE) and
from origin of focal discharges (22.5% of patients with TLE; 20.0% with origin
in other brain areas). Luteal Pg levels remained below 2 ng/ml in 30 patients
independently of epilepsy type. Corpus luteum dysfunction was combined with
hyperandrogenism in 15 of these patients. In the other cases different
alterations of hypothalamus-pituitary-ovary axis were observed. Valproic acid
blunted luteal Pg surge more frequently than other AED. Polycystic ovaries (PCO)
were observed in 14 (16.9%) patients (21.0% with IGE: 14.5% with PE). These
prevalences are not higher than those reported in the general population. Among
PE patients, PCO was found in 1 case with undetermined focal origin and in 7 TLE
cases, who also had ovary volume significantly larger than patients with
seizures originating from the frontal or parietal lobe. Epileptic women
exhibited an increased occurrence of multifollicular ovaries (MFO) found in 12
cases (14.4% vs 5% in the general population). However, no defined hormonal or
clinical pictures were associated with this US alteration in most patients.
These findings reappraise the impact of ovary alterations in women mainly
affected by mild to moderate epilepsy, on differing AED regimens, with the
exception of more frequent ovulatory dysfunction and PCO occurrence in patients
taking VPA.

PMID: 9413805 [PubMed - indexed for MEDLINE]



9: N Engl J Med.  1993 Nov 4;329(19):1383-8.  

Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy.

Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV.

Department of Neurology, University of Oulu, Finland.

BACKGROUND. Reproductive endocrine disorders are more common among women with
epilepsy than among normal women. These disorders have been attributed to
epilepsy itself, but could be related to antiepileptic-drug therapy. METHODS. We
studied 238 women with epilepsy who were seen regularly at the Outpatient
Department of the University Hospital, Oulu, Finland. Their mean age was 33
years (range, 18 to 45), and the mean duration of therapy was 9 years (range, 0
to 31). Twenty-nine (12 percent) were treated with valproate, 120 (50 percent)
with carbamazepine, 12 (5 percent) with valproate and carbamazepine, and 62 (26
percent) with other medications; 15 (6 percent) were untreated. Vaginal
ultrasonography was performed to determine ovarian size, and serum sex-hormone
concentrations were measured in 41 women with epilepsy and menstrual
disturbances, 57 women with epilepsy and regular menstrual cycles, and 51 normal
women. RESULTS. Menstrual disturbances were present in 13 of the women receiving
valproate alone (45 percent), 3 of the women receiving valproate in combination
with carbamazepine (25 percent), 23 of the women receiving carbamazepine (19
percent), and 8 of those receiving other medications (13 percent). Forty-three
percent of the women receiving valproate had polycystic ovaries, and 17 percent
had elevated serum testosterone concentrations without polycystic ovaries; 50
percent of the women receiving valproate and carbamazepine had polycystic
ovaries, and 38 percent had elevated serum testosterone concentrations without
polycystic ovaries. Eighty percent of the women treated with valproate before
the age of 20 years had polycystic ovaries of hyperandrogenism. CONCLUSIONS.
Menstrual disturbances, polycystic ovaries, and hyperandrogenism are often
encountered in women taking valproate for epilepsy.

PMID: 8413434 [PubMed - indexed for MEDLINE]


Thank you for your response, Dr.  That is some very disturbing news.  I have faxed your answer over to her therapist asking her opinion as to whether I should fax same to her psychiatrist for comment.  
What is your experience with the anti-depressant in combo with mood stabilizer of some sort?  She has been quite depressed and has mentioned "killing" herself on a number of occasions.  She has also been cutting herself (twice as far as I know).  Thank you again.
Graylynn Thrift


Answer
Hi . . .

While the combination of a mood stabilizer and an antidepressant is one approach to the treatment of patients with bipolar depression, I prefer to use lamotrigine (Lamictal).

Best regards . . .

Ivan
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