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Mood Disorders in Women During the Reproductive Years – Participants
Objectives:
1 – to improve the participants’ awareness of the impact of, manifestations of,
diagnostic criteria and treatment options for mood disorders in reproductive-
age women
2 – to review factors which increase suicidal risk
3 – to highlight specific mood disorders associated with or affected by hormonal
fluctuation during the menstrual cycle, pregnancy, postpartum and
perimenopause
4 – to define PMS, recognize its impact on health and society, review the
etiology and pathophysiology, highlight clinical assessment tools and explore
treatment options
5 – to apply learning pearls through case
DEPRESSIVE DISORDERS DSM-V Classification
Disruptive Mood Regulation Disorder
Major Depressive Disorder (MDD)
Persistent Depressive Disorder
PMS
Substance/Medication-Induced Depressive Disorder
Depressive Disorder Due to Another Medical Condition
Other Specified Depressive Disorder
Unspecified Depressive Disorder
MDD Definition:
depressed/irritable mood or a loss of pleasure in life for a period of at least 2
weeks duration (reported by the sufferer or by others) for most of the day,
nearly every day, and associated with…
…at least 4 of the following Sx…
Sleep disturbance
Interest decreased
Guilt/Worthlessness
Energy decreased
Concentration impaired
Appetite altered (increased or decreased)
Psychomotor agitation/retardation
Suicidal thinking
WHO IS AT RISK FOR MDD?
F>M 2:1
chronic insomnia/fatigue/pain/stress
multiple somatic complaints (thick charts)
chronic medical illnesses
acute cardiovascular events
trauma/childhood abuse/early loss of parent
concomitant psychiatric illnesses
family history of mood disorders
hormonal fluctuation
unusual associations - noise/cadmium exposure
Screening/Monitoring for MDD
HAMD-7
PHQ 9
MDQ
Edinburgh Postnatal Depression Scale – a 10 item self-rating scale; score >12
indicative of MDD; used cross-culturally, multilingual, easy, convenient,
sensitivity 86-100%; specificity 78-90% - validated for post- and peripartum use
PERSISTENT DEPRESSIVE DISORDER (used to be called dysthymia)
Depressed/irritable mood for most of the day, almost every day (reported by the sufferer
or by others) for at least 2 years, and associated with…
… 2 of the following Sx…
Appetite increased or decreased
Insomnia or sleeping more
Energy decreased or sense of fatigue
Self-esteem decreased
Concentration poor/difficulty deciding
Hopelessness
FUNCTIONAL ASSESSMENT
Sheehan Disability Scale
Brief self-report tool in which patient rates level of function in 3 domains –
1) work/school; 2) social; 3) home life and family responsibilities
0-10 points for each category with a score of “0” being unimpaired and “30”
being maximally impaired; scores greater than 5 in any area of functioning are
significant
Sensitivity 83%; specificity 69%
Suicide Screening Questions:
Have you ever thought that life is not worth living?
Do you ever wish you could just go to sleep and never wake up?
Is death something you have thought about recently?
Are things so bad that you’ve thought about harming yourself?
Suicidal Risk Factors include:
Anxiety/Panic Attacks
Impulsivity
Helplessness, hopelessness
Substance Abuse
Men 20-30 or >50
Women ages 40-60
Borderline personality disorder
Older age
Previous attempts
Family history of suicidal behaviour
Loss of pleasure
Insomnia (severe)
Neuroticism
Social isolation
Perimenopause and Depression
Evidence to support association is mixed
Recent studies supportive of association
Cause of depression likely multifactorial
Psychological, genetic and physiological influences
Perimenopausal women should be screened for depressive symptoms
SSRIs are considered first line treatment but hormonal therapy could be
considered particularly if vasomotor symptoms an issue
TREATMENT OF DEPRESSION
Resources and Source of Guidelines
CANMAT (Canadian Network for Mood & Anxiety Treatments)
Canadian Psychiatric Association
Psychotherapy
Pharmacotherapy
Lifestyle Changes
Light Therapy
Education of Depressed Individual and Family
Alternative Therapies
Stress Management
ECT (can also be useful in pregnancy)
Effectiveness of Rx: Psychotherapy = Drug Therapy
Psychotherapy + Pharmacotherapy works the best for moderate to severe illness
Rapid remission of the depressive symptoms is the most important predictor for
favorable long-term outcome; 2 yr. study; N=196 (Szadoczky et al. J Affect
Disord 2004)
Longer duration (>12 weeks) of the previous episode reduced the likelihood of
recovery by 37%; N=250; 2 yr. study (Spijker et al. J Affect Disord 2004)
Worse outcome if pain present (Bair et al. Arch Intern Med 2003)
Psychotherapy:
Cognitive Behavioural Therapy – changing negative to positive thought
patterns – Level 1
Interpersonal Psychotherapy – improving quality of relationships/addressing
social avoidance behaviour – Level 1
Behavioural Activation – Level 1
Supportive PsychoRx – helps adaptation to present life situation/reduces stress
Brief Dynamic PsychoRx – identifying/discussing internal conflicts often
involving dependency/intimacy
www.livinglifetothefull.com
www.moodgym.anu.edu.au
Pharmacotherapy - Antidepressants
Tricyclic Antidepressants (TCAs)
Serotonin Antagonist Receptor Inhibitor (SARI)
Monoamine Oxidase Inhibitors (MAOIs)
Reversible Inhibitor of Monoamine Oxidase (RIMA)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)
Noradrenaline Dopamine Modulator (NDM)
Serotonin Noradrenaline Modulator (SNM)
Serotonin Reuptake Inhibitor/Serotonin Modulator
Tricyclic Antidepressants (TCAs): amitriptyline, desipramine, doxepine,
imipramine, clomipramine (50-450 mg), nortriptyline (25-200 mg) etc.
Side effects: anticholinergic (dry mouth, blurred vision, constipation, urinary
retention, sweating); CNS (drowsiness, insomnia, headache, confusion,
fatigue); weight gain; cardiotoxicity in overdose
Serotonin Antagonist Receptor Inhibitor (SARI): trazodone (25-600 mg)
Side effects: drowsiness, nausea, dry mouth, dizziness, constipation, headache
Monoamine Oxidase Inhibitors (MAOIs): phenylzine (15-90 mg),
tranylcypromine (10-80 mg)
Side effects: dizziness, drowsiness, headache, sleep disturbances, weakness,
fatigue, tremor, twitching, constipation, dry mouth, nausea, weight gain, edema,
sexual disturbances etc.
Special concerns: hypertensive crisis, dietary restrictions, drug interactions
OTC/prescribed
Reversible Inhibitor of Monoamine Oxidase (RIMA): moclobemide (150-900
mg)
Side effects: headache, diarrhea, insomnia, dry mouth, nausea, constipation,
agitation, drowsiness, dizziness, fatigue
Selective Serotonin Reuptake Inhibitors (SSRIs): fluoxetine (10-80 mg),
fluvoxamine (50-300 mg), paroxetine (10-60 mg), sertraline (25-200 mg),
citalopram (10-60 mg), escitalopram (5-40 mg)
S/E: the 9 d’s (dizziness, dry mouth, diarrhea, drowsiness, diaphoresis,
dyspepsia, dysfunction sexually, difficulty sleeping, dreaming), agitation,
constipation
citalopram 40 mg or more can cause QT interval prolongation (FDA Aug.
2011); ??? escitalopram
Serotonin Norepinephrine Reuptake Inhibitor (SNRI): venlafaxine XL (37.5-
375 mg); duloxetine (60 mg – 40 to 120 mg range); desvenlafaxine (50-150 mg)
Side effects: similar to SSRIs but SNRIs more likely to cause constipation;
more nausea/dizziness/yawning with duloxetine initially than with venlafaxine
but less discontinuation S/E with duloxetine
When switching between these 2 agents, venlafaxine 150 mg to duloxetine 60
mg is roughly equivalent using Global Benefit/Risk; venlafaxine 150 mg is
roughly equivalent to desvenlafaxine 50 mg
Serotonin Modulator/Reuptake Inhibitor:
Vortioxetine (10-20 mg/d; 5 mg if not tolerated)
Side effects include nausea, bowel changes, dizziness, sexual dysfunction
Special properties: reported to be better for cognitive dysfunction; same for
mood
Newer Agents:
Noradrenaline Serotonin Reuptake Inhibitor (NSRI)
Levomilnacipran (Fetzima)(starting dose 10 mgX 2d and increasing to 20 mg and then
40 mg/d; max. 120 mg/day)
Advantages: fairly weight neutral; noradrenaline effect occurring from starting dose
and up; Disadvantages: may increase pulse and BP
Serotonin Reuptake Inhibitor/5HT1A partial agonist
Vilazodone (starting dose 10 mg for a few days; increase to 20 mg; max. 40 mg/day
Advantages: improves anxiety; Disadvantages: GI side effects
Treatment-related sexual dysfunction:
<10% with bupropion, desvenlafaxine, mirtazapine, moclobemide
10-30% with citalopram, escitalopram, duloxetine, venlafaxine
>30% with fluoxetine, fluvoxamine, paroxetine, sertraline
***Kennedy SH et al 2007
Risks of treatment:
Observational data that there may be a link between SSRI use and the risk of
fractures – possibly up to 70% increase in relative risk
Depression is an independent risk factor for low bone mineral density
Depression in Pregnancy and Postpartum
14-23% of women experience MDD in pregnancy; highest risk 28-32 wks.
Risk factors for depression in pregnancy include a history of depression;
positive FH of BPD or depression; childhood trauma or abuse; single
motherhood; smoking; low income; age <20; domestic violence; inadequate
social support; NEJM Oct. 2011
Screening tool Edinburgh Postnatal Depression Scale – also validated for use
in pregnancy
Perinatal period generally defined from onset of pregnancy until about 1 year
postpartum
Management should begin pre-conception with counseling for women with a
personal history of mental health problems
Untreated depression in pregnancy has been associated with a number of
adverse outcomes including an increased risk of miscarriage, low birth weight
and preterm birth (Grote et al. Arch Gen Psych 2010); mother may get less
prenatal care and be at higher risk for suicide
Babies of untreated depressed mothers found to have increased irritability;
higher cortisol levels; fewer facial expressions; risk of developmental delay
(Field et al. Infant Behav Dev 2006)
Potential impact of untreated mood disorders on mother, infant and family
Postpartum: poor attachment/parenting, delayed infant motor, language and
cognitive development, child behaviour problems, suicide/infanticide
Fava et al published 1 year study in Am J Psychiatry Sept. 2008 which basically
concluded that treating maternal depression until remission achieved decreased
psychiatric symptoms and improved function in the offspring
Pharmacotherapy in Pregnancy:
Depression occurs in up to 15% of pregnant women (12.7% NEJM 365;17 –
Oct. 27, 2011)
4% of those women will use antidepressants during the first trimester
Overall pregnancy loss rate at least 20%
Dr. Adrienne Einarson (assistant director of Motherisk) says that the increased
risk of miscarriage in depressed women could be related to the use of
antidepressants or to inadequately-treated depression itself
Study (nested case-control) by Drs. Nakhai-Pour, Broy and Berard CMAJ July
13, 2010 looked at Quebec Pregnancy Registry since 1997 and discovered that
there was a 5.5% miscarriage rate amongst women who had filled at least one
antidepressant prescription during pregnancy compared to 2.7% rate in
matched controls
When comparing SSRIs, 75% relative increased risk of miscarriage with
paroxetine (odds ratio (OR) 1.75) and doubling of risk with venlafaxine (OR
2.11); higher doses increased the risk
Slightly increased risks of maternal complications have been reported if the
woman received antidepressant during pregnancy including gest. DM, PROM,
preeclampsia, bleeding, requiring induction or a C-section (Reis et al. Psych
Med 2010)
Benefits of drug use > risks
TCAs have the most evidence – use of desipramine, nortriptyline give lowest
risk of orthostatic hypotension
Category C risk for fluoxetine, sertraline, paroxetine, citalopram, escitalopram,
trazodone, venlafaxine - overall, SSRIs have reasonable reproductive safety
especially fluoxetine and citalopram in 1st trimester
Jan. 2006 FDA advisory on paroxetine - flawed data suggesting minimally
increased cardiac abnormalities like ASD/VSD; possibly increased omphalocoel
Avoid MAO inhibitors - teratogenic, hypertensive crises
RIMA (moclobemide) - insufficient data to recommend
NEJM June 28, 2007 – 2 articles
“First Trimester Use of SSRIs and the Risk of Birth Defects” – U.S. study of
9849 infants with and 5860 infants without birth defects showed no increased
risks of craniosynostosis, omphalocoel or heart defects with the maternal use of
SSRIs overall; slightly increased risk of omphalocoel with sertraline and heart
defect with paroxetine
“Use of SSRIs in Pregnancy and the Risk of Birth Defects” population-based
case controlled Canadian study of 9622 infants with major birth defects and
4092 control infants from 1997 – 2002 showed no increased risks of birth
defects
Antidepressant Use in Pregnancy and the Risk of Cardiac Defects study –
Huybrechts et al – NEJM June 19, 2014
US population based cohort study of 949,504 pregnant women – 64,389 (almost
15%) used antidepressants during 1st trimester
72.3/100,000 infants in control group had cardiac defects and 90.1/100,000 in
the Rx group
Unlike previous studies no association was found with the use of paroxetine or
sertraline and cardiac defects in the infants of treated mothers
Population based study from Quebec from 1998 through 2010 published Am J
Obs Gyne Jan. 2015 looking at use of sertraline during the first trimester of
pregnancy was associated with an increased risk of atrial/ventricular defects
and craniosynostosis above and beyond the effect of maternal depression
Nonsertraline SSRIs were associated with an increased risk of craniosynostosis
and musculoskeletal defects as well
Kieler et al. BMJ 2011 Jan. examined use of SSRIs in pregnancy and the risk
of persistent pulmonary hypertension in the newborn
Absolute risk of PPH newborn roughly doubled from baseline risk 1.2/1000 to
3/1000 live births
Neonatal withdrawal symptoms observed in a small number of newborn babies
of mothers who took antidepressants in 3rd trimester of pregnancy – babies
jittery, self-limited respiratory difficulties, feeding issues; problem resolves
within a few days of birth with no lasting consequences
**Kalra S et al (Motherisk) CFP Aug. 2005
Alternative Rx in Pregnancy:
Evidence is insufficient to recommend acupuncture, hormone therapy, light Rx,
St. John’s wort for antenatal depression (NEJM 365;17 – Oct. 2011)
ECT reserved for severe, treatment-resistant cases, psychotic depression and for
pregnant women at high risk for suicide
Breastfeeding Motherisk data
Generally, drug excretion rates <10% in breast milk are considered safe by the
American Academy of Pediatrics
SSRIs - *fluoxetine (accumulates in serum) (7.7%); paroxetine (2.8%);
sertraline (2.2%); citalopram (3.6%); escitalopram (5.9%)
SNRIs - venlafaxine (6.4%); duloxetine (0.1%); desvenlafaxine (9.3%)
NDM - bupropion (1.9%)
sSNRI - mirtazapine (6.3%)
SARI - trazodone (2.8%)
Treatment of Depression Augmentation Strategies:
If first antidepressant not inducing remission, increase the dose, switch to a
different antidepressant, combine original with a second antidepressant or add
a non-antidepressant agent
Papakostas GI. Managing partial response or non-response: switching,
augmentation, and combination strategies for MDD. J Clin Psychiatry 2009;70
Suppl 6:16-25
For non-response or incomplete response:
1st line: switch to superior agent (duloxetine, escitalopram, mirtazapine,
sertraline, venlafaxine)
2nd line: add another agent (bupropion, mirtazapine, quetiapine, T3, another
antidepressant) or switch to superior agent with side effect limitations
(amitriptyline, MAOs, clomipramine)
3rd line: add another agent (bupropion, modafinil, stimulants, ziprasidone)
Level of Evidence for Augmentation Strategies:
atypical antipsychotics - A
omega-3 fatty acids- A-
lithium; modafinil; triiodothyronine - B
testosterone – B-
Pindolol; lamotrigine; methylphenidate - C
Helpful Lifestyle Changes:
Limit Alcohol
Avoid Street Drugs
Limit Caffeine
Exercise regularly especially outdoors
Stop Smoking
Winter Vacations closer to the equator
Sleep Hygiene
Stress Avoidance
Avoid Over-the-Counter Medicines unless sanctioned by your Physician
Light Rx:
Though light treatment was felt to be most helpful for seasonal affective
disorder, recent studies suggest it may be useful for other forms of depression
Sit under it for at least ½ hour/day in am upon arising and read whatever you
like, especially in the fall and winter months
Requires 10,000 lux of light intensity
Lieverse et al Arch Gen Psychiatry Jan. 2011;68(1):61-70.
Depression assocd. with circadian rhythm disturbances assocd. with impaired
functioning of the suprachiasmatic nucleus (biological clock)
Bright light therapy (BLT) studied in 89 elderly patients with non-seasonal
MDD using the Hamilton Depression Inventory
BLT enhanced mood, sleep efficiency even after discontinuation of therapy
Alternative Rx:
Nahas and Sheikh published review of complementary and alternative Rx of
MDD in CFP June 2011;57:659-63
St. John’s wort (watch for drug interactions) and regular exercise appeared
effective; acupuncture not found to be effective but had other health benefits;
promising Rx included SAM-e; omega-3 fatty acid; folate supplementation in
select groups
Premenstrual Syndrome (PMS)/Premenstrual Dysphoric Disorder (PMDD)
Natural History of PMS:
• Prevalence PMS 13-18 % (up to 30% reported)
• However, 30 % felt need for treatment
• Prevalence PMDD (severe PMS) 2-9 %
• Cumulative lifetime incidence 7.4 %
• Similar prevalence to persistent depressive disorder (previously called dysthymic
disorder) and only slightly less than major depression
• Prevalence PMS 13-18 % (up to 30% reported)
• However, 30 % felt need for treatment
• Prevalence PMDD (severe PMS) 2-9 %
• Cumulative lifetime incidence 7.4 %
• Similar prevalence to persistent depressive disorder (previously called dysthymic
disorder) and only slightly less than major depression
PMS Etiology:
Numerous theories re: etiology abound
Women who suffer from PMS seem to be inordinately sensitive to the natural
fluctuations of hormonal levels of estrogen and progesterone across the
menstrual cycle
There is no difference found in the gonadal steroid levels of women with PMS
vs. non-sufferers of the condition
Neurotransmitter levels in the brain are affected by the fluctuation of hormonal
levels throughout the menstrual cycle
Serotonin, gamma aminobutyric acid (GABA) and endorphins are primarily
implicated
Twin studies suggest genetic predisposition
Estrogen decreases MAO-A and MAO-B, involved in 5-HT degradation and
increases both tryptophan hydroxylase (TPH-1 and TPH-2), involved in
serotonin synthesis and availability
Estrogen also regulates 5-HT transport and reuptake from synaptic cleft to the
pre-synaptic neuron
Estrogen promotes down-regulation of 5HT1a auto-receptors and up-regulation
of 5HT2a receptors, increasing the amount of 5-HT in the synapse and the
amount available for postsynaptic transmission
Definition of PMS/PMDD:
Symptoms must present during the luteal phase (particularly during the last
week before the period); resolve during the first few days after menses begins
and be absent during the week after the period is finished
Psychological symptoms must be of sufficient severity to markedly interfere with
activities of daily living such as relationships, work, school and social activities
DSM-V:
Diagnosis rests on having 5 of the following 11 criteria including at least 1 of
the first 4 listed:
1) depressed mood; 2) anxiety; 3) mood lability; 4) anger/irritability
5) anhedonia (loss of pleasure in life activities); 6) concentration difficulties; 7)
lethargy/fatigue; 8) appetite changes; 9) sleep alterations; 10) sense of feeling
overwhelmed/loss of control; 11) physical symptoms like breast swelling or
mastalgia, headaches, joint/muscle pain, bloating, weight gain
Mortola Criteria for PMS 1990:
Patient must report at least 1 of the affective and somatic symptoms in 3 prior
menstrual cycles during the 5 days before the onset of menses
The Sx must resolve within 4 days of onset of menses and not recur until after
day 12 of cycle
Sx must be present in at least 2 cycles during prospective recording
Sx must adversely affect social or work-related activities
These symptoms must be cyclic in nature
PMS can be diagnosed using self-administered rating scales such as a PRISM
calendar, Daily Record of Severity of Problems (DRSP), Self-Assessment Disk,
Premenstrual Assessment Form, Calendar of Premenstrual Experience (COPE),
Prospective Record of the Impact and Severity of Menstrual Symptoms,
Premenstrual Syndrome Diary (OMSD), Visual Analog Scale or Penn Daily
Symptom Rating
PRISM calendar can be found on-line for you and patients to use. Get your patient to
chart at least 2 menstrual cycles.
Self-assessment tools must be used over a period of 2-3 cycles to chart
symptoms during consecutive days of the menstrual cycle
There are no confirmatory laboratory tests/investigations to make a diagnosis
Other medical/psychiatric conditons in the differential diagnosis must be
excluded
Differential Dx:
Psychiatric: depression, dysthymia, anxiety, panic disorder, BPD, somatoform
disorder, personality disorder, substance abuse
Medical: anemia, autoimmune diseases, chronic fatigue syndrome, diabetes,
seizure disorders, hypothyroidism, endometriosis, allergies, ovarian cysts
Risk Factors for PMS:
Advancing age
Genetics
Previous psychological trauma especially in childhood
Co-morbidity with other psychiatric illness
More prevalent in Caucasians (PMDD in 2.9% of black women vs. 4.4% white
women), smokers, obese, lower educational level
Biopsychosocial Impact of PMS:
Obesity (BMI > 30) 3-fold ↑ in PMS population
Criminal activity
Nicotine addiction
Alcoholism
↓ work productivity
↑ # days work/school missed for ANY health reasons
Interference with hobbies, social life, relationships
Significant ↑ in healthcare provider visits/year
Significant $$$ to society, healthcare system, insurance, etc…
Average delay in diagnosis 5.3 years
Cronje (2004) PMS x 10 years prior to Tx, then delay of 3.5 years for referral
after failed Tx
Approximately 3.75 clinicians to diagnose PMS
Assessing and Monitoring Function: Sheehan Disability Scale
10-point self-rated scale in 3 spheres of function – work, home and social life
Maximum score 30/30; if completely functional 0/30
Pathophysiology of PMS:
Condition seems to be connected with more dramatic drop in the level of estradiol and
possibly progesterone fluctuations at certain times in the menstrual cycle ie. at
ovulation and in the pre-menstrual period
Genetics:
major twin studies
Condon 1993
Correlation coefficient: monozygotic 0.55; dizygotic 0.28
Kendler 1998
Heritability 56 % in large (1312 twins) 6 year study
Treloar 2002
Genetic correlation between PMS and neuroticism was 0.62 and
0.70 for lifetime major depression
Jahanfar Oct. 2011
Prevalence of PMS 43.0% and 46.8% in monozygotic and
dizygotic twins respectively
Treatment:
Many similarities to treatment for other depressive disorders
Treatment options include: counseling for patients and their families, lifestyle
modifications, medications, surgery in select cases
Lifestyle changes:
Decrease salt/carbs intake/drink ++ fluids – data limited
Limit caffeine/carbonated drinks/ETOH – no good trials
Avoid stress especially when Sx worsen
Consider light treatment/acupuncture
Exercise 30 minutes/d at least 5 days of the week/engage in relaxation therapy
Stop Smoking
CBT vs. placebo better after 4 weeks/effects lasted up to 18 months
Educate family/friends/co-workers re: PMS
EvidenceEvidence--based Treatments for based Treatments for PMDD and PMSPMDD and PMS
Steiner. J Psychiatry Neurosci. 2000;25:459-468.Jarvis et al. Ann Pharmacother 2008;42:967-78.
Antidepressants
• SSRIs*
• SNRI*
• Clomipramine†
Anxiolytics
• Alprazolam†
• Buspirone†
Ovulation Suppression
• Oral contraceptives*
• GnRH Agonists†
• Danazol
• Oophorectomy
Other
• Lifestyle changes (diet, exercise)
• Calcium†
• CBT*
*Efficacy in double-blind studies of PMDD†Efficacy in double-blind studies of PMS
SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin and norepinephrine reuptake inhibitor; GnRH =
gonadotropin-releasing hormone; NSAID = nonsteroidal anti-inflammatory drug; CBT = cognitive-behavioral therapy.
Vitamin B6
NSAIDs
Supplements:
Calcium carbonate/citrate – 1200 mg/d in divided doses – Nurses’ Health Study
II (B - level of evidence)
Mg – 200-400 mg/day decreases fluid retention; helps mood/migraine –
evidence mixed
Vit. B6 – 50-100 mg/d - mixed data re: effectiveness (B); too much associated
with peripheral neuropathy
Vit. E – mixed data; 400-600 I.U./day
Vit. D – 800-1000 I.U./d good for bones & PMS
***Can J Clin Pharmacol. 2009 – Whelan et al
Folate 1-5 mg/d a good idea for women in child-bearing years to prevent neural
tube defects but no data to support use in PMS
**effectiveness of other supplements questionable (including dong quai, black
cohosh, wild yam, St. John’s wort, kava, evening primrose); chasteberry?
***Can J Clin Pharmacol. 2009 – Whelan et al
Pharmacotherapy:
Ovarian suppression for broad range of behavioral and physical
symptoms
Psychotropic meds most effective for irritability and anxiety symptoms
Combination therapy with ovarian suppression and psychotropic meds
may be required
Ovarian suppression:
Goal is to abolish variability in circulating levels of reproductive steroids,
especially in luteal phase
May be accomplished by a multitude of hormonal manipulations
Choice should depend on:
Comfort, compliance, complexity, cost…
Need for contraceptive or wish for pregnancy
Tolerance of side-effects
Relative vs absolute contra-indications
Severity of symptoms
Hormonal Contraceptives
Monophasic
Continuous
Oral, patch, ring, injectable formulations
Careful selection of progestin
19-nortestosterone derivatives
Drosperinone (Cochrane Database 2009 Lopez found it
effective in combination with EE 20 ug)
60 % response rate
Broad range of behavioral and physical symptoms
Most efficient for PMS vs PMDD
Danazol
17 α ethinyl testosterone
Suppresses ovarian steroidogenesis
Masculinizing side-effects
Halbreich 1991
Prospective study
20/23 vs 6/32 cycles were symptom-free
P=0.0002
GnRH agonist
Pseudo-menopause
Side-effects
Cost
Eventually need add-back HT if long-term
Ideal as challenge test prior to BSO
Bilateral oophorectomy
Definitive therapy
Cronje 2004
TAH BSO
6 year prospective study
PMS x 10 years
93.6 % complete resolution
Treatment with E+T post-op
Cyclic progesterone
Replacement of luteal phase progesterone, to stabilize or increase
circulating metabolites
Baker 1995
200 mg micronized progesterone vaginal suppository
7 month double-blind placebo controlled study
Beck depression, Hamilton anxiety scales
No significant Δ overall BUT significant improvement related to
tension, irritability, mood swings, anxiety, lack of control
Magill 1995
400 mg BID vaginal or rectal progesterone suppository
Luteal phase x 14 days, 4 cycles
Double-blinded, placebo-controlled
Clinical and statistical significance in highest scoring PMS in
treated vs placebo
Cochrane 2006
17 studies, only 2 analysable
115 patients
Could not combine for analysis
Statistically significant improvement in progesterone treated vs
placebo
Antidepressant Rx: most SSRIs and SNRIs have data to support use for PMS;
however… However, in 2005, FDA gave paroxetine category D rating for
potentially causing congenital cardiac defects; it should be avoided in women of
childbearing age if they are not using reliable contraception
Cochrane Database review; Brown Jan. 2009 found all SSRIs were effective in
luteal phase only treatment or if used continuously
Daily use of SSRIs or SNRIs with increased dose during the luteal phase is
another alternative for treatment
9 D’s common S/E of SSRIs/SNRIs:
Dizziness
Drowsiness
Diarrhea/constipation
Dry mouth
Difficulty sleeping
Dysfunction sexually
Dyspepsia
Diaphoresis
Dreaming
***SNRIs tend to cause more constipation; citalopram and escitalopram
typically cause softer stools
Benzodiazepines – alprazolam (Xanax) studied for use in the luteal phase – I
am not a big proponent of this for obvious reasons
Buspirone used continuously decreases irritability as well as physical Sx (83%
vs. 54% compared to placebo)
Spironolactone improved mastalgia, bloating, weight gain and depressed mood
compared to placebo
BIPOLAR DISORDER (BPD) Subtypes
Bipolar I (classic manic-depressive disorder) – one or more manic or mixed
episodes; occurrence of depressive episode not required for diagnosis but
almost all patients experience depressive episodes, which are in fact more
common than manic episodes
Bipolar II – one or more major depressive episodes accompanied by at least 1
hypomanic episode
BPD Definitions:
Mania – elevated, expansive or irritable mood lasting at least 1 week (lesser
duration required if hospitalised) and associated with at least 3 of the following
symptoms: grandiosity, decreased need for sleep, talkativeness, flight of ideas
or racing thoughts, distractibility, increased goal-directed activity or
psychomotor agitation, excessive involvement in pleasurable but unwise
activities
Hypomania – elevated, expansive or irritable mood clearly different from usual
non-depressed mood but lasting at least 4 days and involving 3 or more
symptoms necessary to make a diagnosis of mania
Cyclothymia – fluctuating periods (lasting < 2 months) of hypomania and
depressive episodes not meeting the criteria for major depression and occurring
for at least 2 years
Bipolar Disorder not otherwise specified – rapid alteration between manic and
depressive symptoms that do not meet the duration criteria; recurrent
hypomania without intercurrent depressive symptoms; manic or mixed episode
superimposed on delusional or psychotic disorder; unable to determine if
bipolar disorder is primary, substance-induced or related to medical condition
BPD typically emerges in adolescence and is usually manifested as depression
Severe or psychotic symptoms in a teenager are a possible clue to emerging
BPD
If teenager has presented with hypomania or mania, mood will be irritable and
fluctuate between the extremes of mania and depression within days
ADHD major condition in the differential especially with pre-teens
Diagnosis may be delayed for > 20 years
15-30% of depressed patients may have BPD
Screen patients with depression for hypomanic/manic symptoms
Ask about family history of mood disorders
Ask about suicidal ideation
Get historical corroboration from family/friends
Consider alternative diagnoses
Use Mood Disorder Questionnaire (MDQ)
1. Has there ever been a period of time when you were not your usual self and...
...you felt so good or so hyper that other people thought you were not your
normal self or you were so hyper that you got into trouble?
...you were so irritable that you shouted at people or started fights or
arguments?
...you felt much more self-confident than usual?
...you got much less sleep than usual and found you didn’t really miss it?
...you were much more talkative or spoke much faster than usual?
...thoughts raced through your head or you couldn’t slow your mind down?
...you were so easily distracted by things around you that you had trouble
concentrating or staying on track?
...you had much more energy than usual?
...you were much more active or did many more things than usual?
...you were much more social or outgoing than usual, for example, you
telephoned friends in the middle of the night?
...you were much more interested in sex than usual?
...you did things that were unusual for you or that other people might have
thought were excessive, foolish, or risky?
...spending money got you or your family into trouble?
2. If you checked YES to more than one of the above, have several of these
ever happened during the same period of time?
3. How much of a problem did any of these cause you – like being unable to
work; having family, money or legal troubles; getting into arguments or fights?
Please circle one response only.
No Problem Minor Problem Moderate Problem Serious Problem
4. Have any of your blood relatives (i.e. children, siblings, parents,
grandparents, aunts, uncles) had manic-depressive illness or bipolar disorder?
5. Has a health professional ever told you that you have manic-depressive
illness
or bipolar disorder?
THE MOOD DISORDER QUESTIONNAIRE
Instructions: Please answer each question to the best of your ability.
© 2000 by The University of Texas Medical Branch. Reprinted with permission.
This instrument is designed for screening purposes only and is not to be used as
a diagnostic tool.
If the patient answers:
1. “Yes” to seven or more of the 13 items in question number 1;
AND
2. “Yes” to question number 2;
AND
3. “Moderate” or “Serious” to question number 3;
you have a positive screen. All three of the criteria above should be met. A
positive screen should
be followed by a comprehensive medical evaluation for Bipolar Spectrum
Disorder.
BPD Management:
Mania with acute agitation – treated emergently with atypical/conventional
antipsychotics (oral as effective as IM) +/- benzodiazepines for sedation and
more rapid onset of action
Acute mania – 1st line Rx with lithium, valproate or atypical antipsychotic
monotherapy or combination of lithium or valproate + atypical antipsychotic
(risperidone, quetiapine or olanzapine); 2nd line Rx includes carbamazepine,
oxcarbazepine, ECT or lithium + valproate
Dosing for Mood Stabilisers: measure serum levels
Lithium: 900-1800 mg/day in 2 divided doses of sustained release; start with
300 mg bid (capsules of 150/300/600 mg)
Valproate: 750-1500 mg/day in 2-4 divided doses (250 mg capsules; 125 mg
sprinkles; 250 mg/5 ml syrup)
Dosing for Atypical Antipsychotics:
Risperidone: 1-6 mg/day; 2-3 mg starting dose for mania; .5, 1.0, 2.0 mg
dosages
Olanzapine: 10-15 mg od starting dose; max. dose 20 mg/day; maintenance 5-
20 mg/day; dosages 2.5, 5, 7.5, 10, 15, 20 mg; orally disintegrating tabs Zydis 5,
10, 15, 20 mg
Quetiapine: start with 50 mg bid, increase by 100 mg/day up to typical dose of
400-800 mg/d within 1 week; 25, 100, 200, 300 mg formulations
***Warning re: hyperglycemia April 2004
Women in reproductive years need to be on adequate family planning method to
avoid inadvertent exposure of a fetus to some drugs used for BPD
> 3 months before planned pregnancy discuss risks of maintenance medications,
risks of relapse without Rx, management plans during pregnancy
Consider stopping drug(s) before trying to conceive and during first trimester
Women needing meds may need dose adjusted
FDA Mood Stabiliser Teratogenicity
Lithium - Class D (overall risk 4-12%; Epstein tricuspid valve
malformation .1%)
Divalproex - Class D (11%)
Topiramate – Class D (newer data in Neurology July 08 shows 11% increased
risk cleft lip/palate; hypospadias)
Carbamazepine - Class D (5.7%)
Lamotrigine - Class C (2.9%)
Gabapentin, Olanzapine, Risperidone, Quetiapine - Class C (no good data)
***Base Rate (no drugs) - risk is 2-4%
Lithium therapy is associated with increased risk of reduced urinary
concentrating ability, hypothyroidism, hyperparathyroidism (monitor Ca levels)
and weight gain
Risk of end-stage renal failure is low; risk of congenital malformations
uncertain
McKnight et al. Lancet Jan. 2012
Geddes JR et al. Lamotrigine for treatment of BPD. Br J Psychiatry 2009
Jan;194(1):4-9. review article
Lamotrigine has beneficial but modest effect on depressive Sx in BPD, although
advantage over placebo larger in more severely depressed patients