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