ALTERNATIVE TREATMENTS FOR

PERINATAL MOOD DISORDERS:

FOCUS ON TRANSCRANIAL
MAGNETIC STIMULATION
AND KETAMINE
Merrill Sparago MD

1500 West Olympic Blvd Suite 538

Los Angeles, CA 90064

•310-231-8905

•msparagomd@msparagomd.com
 LECTURE OBJECTIVES
• Provide a base framework for understanding:

• Treatment of Perinatal Mood Disorders (PMD’s)

• The definition and management of Treatment

Resistant Depression (TRD)

• Repetitive Transcranial Magnetic Stimulation

(rTMS) and Ketamine in Treatment Resistant
Depression and in PMD’s
 QUESTIONS
Question 1: In general, what is a safer medication to use
in pregnancy: A medication to treat Schizophrenia or a
medication to treat Nausea and Vomiting?

Answer: It’s the same medication.

Question 2: In general, what is a safer medication to use

in the Postpartum: A medication to treat Schizophrenia
or a medication to induce lactation?

Answer: It’s the same medication.

Take Home Point: Treating the brain of a pregnant or

postpartum woman is just fine as along as we believe
we are not treating their brain!
 CASE 1
• 41 y/o G3 P1 TAB1, Consultation at 4 weeks gestation, hx of
multiple failed medication trials for depression and plan for
TAB.
• First pregnancy complicated by severe depression, suicidal
ideation, panic, loss of function, and severe postpartum
depression, onset of sx at 8 weeks gestation.
• Adopted 3 children after 1st pregnancy.
• 2nd pregnancy onset of same sx as 1st pregnancy 8 weeks
gestation, suicidal and ended pregnancy in TAB.
• 3rd pregnancy, unplanned but wanted, plan for TAB second to
expectation of recurrence of sx.
 CASE 1 (Con’t)

• Prior Rx: Zoloft, Prozac, Lexapro, Wellbutrin,

Remeron, Seroquel, Abilify, Ativan, Klonopin.
• Presenting Sx and Rx:
• Anxiety, Panic, Insomnia, Guilt, Fear, Depression.
• Prior MD started pt on Seroquel for sleep, panic.
Are their options for treatment?
 CASE 2
• 36 y/o G1P0, 15 weeks gestation, planned pregnancy
• History of treatment with antidepressants with partial response,
last treatment Lexapro 15mg for the past 7 months
• Stopped medication at recommendation of obstetrician 2 months
before getting pregnant
• Treated for nausea with Ondansetron/Zofran then
Metoclopramide/Reglan from weeks 6-12
• Recurrence of depressive sx for 5 weeks including depressed
mood, crying, insomnia, loss of appetite, hopelessness, worthless
• Thought depressive sx would resolve with resolution of nausea.
• What are the treatment options given the patient states, “I would
never take a medication that works in the brain during
pregnancy.”
 PERINATAL MOOD DISORDERS
GENERAL TREATMENT GUIDELINES
• In PMD’s there is always an exposure.
• The mother and the developing baby are exposed to
the impacts of the illness, the treatment or both.
• The goal of treating PMD’s is to eliminate one exposure
whenever possible, therefore when we treat, we treat to
remission.
• When antidepressant medications are needed, they
should be combined with psychotherapy or other
adjunctive therapies.
• My practice guideline is, “All children deserve healthy
parents.”
• The only guarantees I’ll ever give are…
 PERINATAL MOOD DISORDERS
GENERAL TREATMENT GUIDELINES (Cont)
• Question: Is pregnancy a “feel good state” that treats depression
or protects women from having a recurrence of depression:
Answer: No!
• Women who require antidepressant or mood stabilizing
treatment (Bipolar Disorder) prior to pregnancy relapse at a much
more frequent rate when medications/treatment are
discontinued prior to pregnancy.
• The faster a woman is taken off medications correlates with the
severity and longevity of depressive symptoms in pregnancy,
which can lead to a postpartum depression.
• Delivery does not treat depression in pregnancy.
• Breastfeeding does not treat a postpartum depression.
 WHAT IS TREATMENT RESISTANT
DEPRESSION (TRD)
• Evolved from studies such as Sequenced Treatments and
Alternatives in Depression (STAR-D) and Texas Algorithm which
looking at algorithms for treating depression to remission.

• Remission is the standard as it lowers risk of relapse and

improves health outcomes.

• Studies can define TRD as failure of one, two, or more than two
trials of a single antidepressant, combinations of
antidepressants, or augmenting strategies.

• For STAR-D: 4 treatment levels, 1/3 reached remission with one

antidepressant, 2/3 reached remission at 4 levels, each level
resulted in lower rates of remission with a sharp decline in
response at each level.
 TREATMENT RESISTANT DEPRESSION
IN CLINICAL PRACTICE
• In clinical practice, TRD is often defined as failure of four trials
of antidepressants alone, in combination, and with augmenting
strategies (i.e., failure of 4th Star-D level).

• When a patient has TRD it is important to consider Bipolar

Disorder may be misdiagnosed as unipolar depression.

• The depression is caused by or complicated by personality

disorders (Borderline Personality Disorder)

• In my practice, where I treat patients with newer therapeutic

modalities like TMS and Ketamine, TRD can be looked at
standard treatment resistance, (STR) rather than treatment
resistance (TR), which opens hope through options and
alternatives.
 TREATMENT RESISTANT DEPRESSION IN
PERINATAL MOOD DISORDERS (PMDs)
• The reproductive years represent one of the greatest
vulnerabilities to depression.

• Many women have had episodes of depression prior to

pregnancy, the postpartum and may not respond to one or two
trials of an antidepressants.

• In clinical practice, TR in PMDs can apply to failed medication

trials as well as resistance to being treated based on fear,
stigma, etc.

• TRD in the perinatal period should not be confused with

“untreatable” illness and should be addressed with pre-
pregnancy counseling when possible, maximizing response to
treatment and consideration of alternative treatments…such as
TMS.
 What Is Repetitive
Transcranial Magnetic
Stimulation (rTMS)?

• FDA Approved in 2009.

 DEPRESSION TMS AND RHYTHM:
THE HEART AND THE BRAIN
Normal Heart Rhythm

Arrythmia

If we look at depression as an arrythmia of the brain which impairs function,

Then TMS is a rhythm generator that clears the arrythmia
 THE BRAIN AS A COMPUTER:
HEALTHY VS. DEPRESSED

The Non-Depressed Brain Functions Like a Mac Humming on All Cylinders

The Depressed Brain Functions Like A Mac Spinning in the Circle of Doom
 HOW DOES TMS WORK IN DEPRESSION?

• Stimulates and turns on the

rhythm generator or
operating system of the
brain: The left dorsolateral
prefrontal cortex

• Deeper brain regions (e.g.,

cingulate cortex) that also
create symptoms are then
regulated and function
properly

• The result is a brain that has

an intact operating system
and functions in rhythm

My Basic Operating Principle is: “Treat the Brain to Free the Mind”
 MY EXPERIENCE WITH TMS

• Initial training in applications of TMS at UCLA in 2006

• Started treating depressed patients in 2012 to provide
options other than/or in addition to medications
• Did I think it would work:
• No.
• Actually,
• It’s one of the best treatments I have seen for depression.
 ADVANTAGES OF TMS IN PMDs

• Free of typical antidepressant side

effects.

• Does not exposure mother and baby

to systemic effects of
antidepressants.

• Non-invasive; pulse only goes

several centimeters into the brain.

• No anesthesia or sedation.
 TMS
TREATMENT COURSE

• 5x/week for 4-6 weeks.

• 30-40 mins per treatment (3000-5000 pulses).
• Response typically begins around 2-3 weeks.
• For partial responders, medications can be
continued and TMS can bring pts. to remission.
• Side Effects:
• Mild to Moderate Discomfort at Site
• Seizure: Occurs in chair, treatment is stopped, lower
incidence than in antidepressants, I have never had a
patient seize with TMS.
 TMS IN PERINATAL MOOD DISORDERS
WHAT DOES THE DATA SHOW?
• Multiple studies using TMS to treat depression in pregnancy
and the postpartum.

• Studies span from case reports, observational studies,

randomized placebo-controlled trials.

• No adverse effects in neonates.

• Response rates and remission rates vary by study, but show

TMS is effective in PMDs and in patients with prior TR who have
PMDs

• In my practice all women who have been treated with TMS for
PMDs have responded or remitted in pregnancy and the
postpartum witho adverse effects in neonates exposed to TMS.
 KETAMINE IN TRD
WHAT IS KETAMINE?
• Ketamine is an anesthetic that was first used in the 1960’s and has a
prominent role in veterinary medicine as well as in humans for
surgery and pain management.

• Ketamine blocks the NMDA receptor which is associated with pain,

alertness, learning, information processing and signal transmission.

• Ketamine’s psychoactive effects include hallucinations, dissociation,

altered states of consciousness making it a recreational drug with
abuse potential.

• Unlike opiates, Ketamine does not cause respiratory depression and

lower blood pressure at analgesic doses.

• Like people medications include two arms/sides and some are

Lefties (S’s) and Righties (D’s) : Ketamine is a Leftie: Es-Ketamine.
 HOW DOES KETAMINE TREAT DEPRESSION?
• Many theories have been developed to explain Ketamine’s antidepressant
effects including effects on Glutamate, GABA, AMP, etc..

• To me the Depressed Brain can look like a freeway where the interchanges are all
blocked.

Treatment with Ketamine removes the blocks and information can flow freely
 KETAMINE AS A TREATMENT
FOR DEPRESSION AND SUICIDALITY

• Ketamine provides a rapid and robust antidepressant effect and decrease

suicidal thoughts after a single administration.

• Like people medications include two mirror image sides where some are
Lefties (S’s) and Righties (D’s) : Ketamine is a Leftie: Es-Ketamine which is
about 4x as potent as the Righty.

• Ketamine can be administered intravenously (IV), intramuscularly (IM),

subcutaneously (SC) orally (PO) and Intranasally (IN).

• Subsequent studies over the course of 40+ years led to the FDA approval of
the intranasal form of es-ketamine (Spravato) in 2019, to treat a Major
Depressive episode in patients who are not responding to an antidepressant.

• Es-Ketamine is also indicated to treat acute suicidality in depressed patients.

 KETAMINE TREATMENT COURSE
• IV Ketamine is usually given as a course of 6-12 sessions over 2-
4 weeks.

• Starting dose is .5 mg/kg infused over 40 minutes, where the

psychoactive effects last approximately 1 hour.

• Some research shows dissociative effects during treatment are

important in the antidepressant effects.

• Es-Ketamine is given 2x a week for 4 weeks, then 1x a week for

4 weeks in the acute phase of treatment, effects last about the
same as IV Ketamine.

• Maintenance treatment is every 2-4 weeks which has been

shown to prevent relapse into a Major Depressive Episode.

• Patients can not drive home after ketamine treatment and are
encouraged not to work etc.
 KETAMINE IN PERINATAL MOOD DISORDERS
• Pregnancy: Ketamine is not approved for/or currently used as a treatment
for depression during pregnancy.

• Animal studies suggest neurotoxic effects on the developing fetus and there
are no controlled studies in humans.

• Ketamine in Delivery: Studies of Ketamine come from use for

anesthesia/analgesia in C-Sections to prevent or delay the onset of
Postpartum Depression (PPD).

• Include single doses and infusions over 2 days in the initial PP. Mother’s were
able to BF.

• Ketamine does not appear to have an adverse effect on neonates and may
delay the onset of PPD for 1 week- 1 month depending on the study.

• Current studies are ongoing to evaluate ketamine as a treatment for PPD.

• I have not treated PPD with ketamine.

 BACK TO THE CASES
• Case 1: 4 weeks pregnant, terminated prior pregnancy secondary to severe
depression/suicidality. Expected would terminate current pregnancy

• The patient started TMS at week 6 (2 weeks prior to onset of symptoms in

prior pregnancies).

• TMS prevented the recurrence of depression in pregnancy. Was used to treat

sx of PPD, and then a subsequent pregnancy from week 6 on, with no sx of
depression

• Case 2: The patient completed a course of TMS in that and one subsequent
pregnancy. The patient's depression remitted in both pregnancies.

• A 2-week booster was given for a DSTIL:

• (Depression Secondary to In-Laws)