Depression that occurs in someone who is bipolar is more complicated to treat than unipolar depression.    Optimal treatment often requires several medications—even 5 or 6 or more.  Rarely will one medication suffice.   Antidepressants should be avoided if at all possible:  they may initially help, but then the person is having more depressions than ever for the next year.

Bipolar patients include: 

#1: Bipolar I Disorder:   the highs (manias) are so severe that the patient was hospitalized for one, or should have been,

#2: Bipolar II Disorder:  the highs

[hypomanias] are not severe enough to cause hospitalization, but often cause severe financial and interpersonal problems.   They spend too much, argue too much, and engage in risky behavior.

#3:  Bipolar Spectrum Disorder:  the patient does not fit a classic pattern, but he/she is definitely cycling.   Some of these people may have frequent “mixed states,” where they are significantly depressed, but at the same time are “hyper”—energetically aggressive, talking rapidly, verbally obnoxious, and extremely anxious.

There are no definite rules about how to proceed with treatment.   A good place to start is a combination of three standard mood stabilizers:  Depakote/ divalproate,  Lamictal/ lamotrigine, and lithium.   All of these have significant antidepressant effects.



  • rTmsrTMS (Repetitive Transcranial Magnetic Stimulation), in my experience, is the most effective treatment of bipolar depression—as well as having the least side effects.  The benefit is also DURABLE—long lasting.   If and when the patient relapses, they only need a few treatments, not 20 or 30, to recover.  It is safer than ECT, just as effective, and more enduring.  It often changes whole course of the illness.   However, one must avoid standard  left excitatory treatment [on the DLPFC (dorsolateral prefrontal cortex], as that can be over-stimulating like a standard antidepressant and cause mania or increased cycling.   Instead, one does inhibitory treatment on the right dlPFC.

The only psychiatrists who are aware of  the benefit of TMS for bipolar disorder seem to be those who actually do the treatments.    I have two patients who at 22 y.o. had finished no college courses at all because of incapacitating rapid cycling bipolar disorder.   Now one is in her 4th year of college, making all A’s, and going to medical school.  The other the other is in his 3rd year of college, making mostly A’s.

  • Depakote / valproate: Joseph Goldberg, MD says the evidence is that Depakote is better at preventing depression than it is at preventing mania.    He never says anything without literature to back it up.  We think of it as anti-manic because it works so well in acute mania.  My experience over the years is that it is extremely good at preventing depression.  It also treats acute depression.    It can work immediately, or it can take a few months.  I have a few patients doing excellent for as much as 25 years on about 500 to 1250mg.   If I reduce the dose they began to descend into an agitated, angry depression—exactly as they were prior to Depakote.   They had forgotten what it was like.

—-and/or Tegretol/ Equetro/ carbamazepine; sometimes only Depakote/ divalproate  or only Tegretol/ carbamazepine works. Rarely, both are needed.  Tegretol/ carbamazepine seems to have efficacy close to Depakote’s, with the advantage of no weight gain.  (It has less research support because it went generic long ago.)  See Robert Post’s book, Treatment of Bipolar Illness: A Casebook for Clinicians and Patients. 

  • Lamictal/ lamotrigine –This must be increased slowly over 5 weeks because of the risk of a severe allergic reaction– SJS (Stevens Johnson Syndrome). Thus, one is not on an antidepressant dose until 5 weeks have passed. There is no weight gain, and usually no sedation.       
  • lithium 150mg–at most 300 to 900mg/day, not 1200 to 1500mg. [I am speaking generally; there are always special cases.]  Blood levels should be ≤ 0.6.    As of 5/21/2016, I have had 32 [26 women] patients  [unipolar as well as bipolar] who had a dramatic antidepressant effect within 1-2 weeks of adding only 150mg lithium.    Even if it seems no benefit, I leave them on it.  Perhaps because of its powerful effect on increasing Brain Derived Neurotrophic Factor (BDNF), over time it may transform the illness.  A few people may need 1200mg per day. I have a 41 y.o. patient with severe Bipolar I Disorder since her early teens.  I have treated her 10 years and it took over 7 or 8 years to stabilize her.  But she says she only became completely normal in mood when lithium was added [again] last summer.  She takes only lithium 150mg twice a week!  If she takes it once a week she is depressed, as well as cycling a little.  If she takes it 3 times a week, her mood is good, but she has a significant hand tremor.
  • A small dose of Wellbutrin–of all the antidepressants, it seems the least likely to cause cycling. Large doses are probably fairly safe if the patient is on sufficient mood stabilizer. Perhaps start with ½ of 75mg for a few days.
  • L-channel calcium channel blockersnimodipine, isradipine, nifedipine, and amlodipine—but the first two have the most evidence. See Robert Post’s book, as well as his papers on using these agents–especially nimodipine.
  • Atypical antipsychotics in low dosesg., Latuda (lurasidone), Abilify/ aripiprazole, Zyprexa/ olanzapine, Geodon/ ziprasidone , and Seroquel/ quetiepine. Two new ones may have no weight gain: Rexulti (brexpiprazole) and Vraylar (cariprazine). Use at the lowest dose for 1-2 weeks, unless agitation requires a rapid increase.
  • Sulperide 150mg = ¾ of a 200mg tablet – this is an atypical antipsychotic that is not available in S.; we obtain it from England.   Above 150mg it usually stops working as an antidepressant, and then works mainly as a mood stabilizer or anti-manic medication.
  • Mirapex/ pramipexole –effective and safe in bipolar depression. It does not cause significant cycling.  Joseph Goldberg, MD is a proponent.
  • Amantadine is both an anti-viral and an anti-Parkinsonian medication.  It is thought to help depression by its pro-dopamine effect—but it could also be because of its anti-viral effect [e.g., against Borna virus, which is usually quiescent, and very difficult to measure; it is neurotoxic and was discovered in horses in Borna, Austria a century ago; some people postulate some agitated psychiatric states are precipitated by an outbreak of Borna virus].  It seems to be a relatively safe antidepressant in bipolar disorder.
  • Minocycline 100mg b.i.d. : This antibiotic is approved for chronic use for acne in adolescents.  It has an anti-inflammatory effect in the brain, which is why it helps depression.
  • THROID HORMONES: Cytomel (liothyronine)/ T3 25-50mcg.   If rapid cycling, very high doses of the other thyroid hormone, Synthroid (levothyroxine)/T4,   may help [Whybrow and Bauer].

NUTRIENTS for bipolar depression –these all have evidence.

  • fish oil 6 to 7 one gram pills per day –extremely effective;   40% of the cell wall of neurons is made from omega-3 fatty acids if the brain can obtain enough.   Another mechanism may be the anti-inflammatory effect.  The brand Omegavia is a small 500mg/pill with 500mg of EPA in it, so 3 to 4 pills may be enough for depression.  EPA is the only omega-3 fat that helps depression.
  • NAC (N-acetyl cysteine) 4 grams per day. This is often extremely effective.  Because of  providing cysteine, the body can make at least 50% more glutathione, which the main antioxidant in the body.  The glutathione cleans out free radicals [poisons] in  the brain and improves mood.
  • Vitamin D3: 5000 I.U. per day.    This is not a vitamin.  It is a steroid hormone.  We manufacture it, but one step in it production requires significant UVB light from the sun to strike the skin.  One can make 10,000 to 15,000 I.U. per day if one sunbathes in a bathing suit for 45 minutes in the middle of the day in the summer.  But we are not in the sun much in modern life.
  • Inositol : a sugar:  14 grams:  7 grams two times a day  (~3 tsp twice a day).  This is an intracellular substance involved in a positive cascade in neurons.   I have only had one home run with this, and it only lasted a few months.  That patient had never been euthymic in his life.  {Subsequently he received TMS [#50 over one year] and, at 62 y.o., remained completely euthymic for 3½ years, which was quite astonishing.}

Deplin/ L-methylfolate 15mg/dayespecially if they are homozygous for the MTHFR gene C677T.   However, L-methylfolate can help depression in anyone.  For years I used L-methylfolate in bipolar Chassidic patients, as Medicaid would pay for a 7.5mg pill.  It rarely seemed to help much—unless the patient increased to 2 pills/day, which they could not afford.    Then the company brought out a 15mg pill.  Then I began having many responders.   Two good double blind studies showed the same thing:  7.5mg did not help and 15mg did.   One patient came to me on 30mg—she is depressed if she lowers it to 15mg.   I never put patients on 30mg, but her physician did, and it worked.

Ø   EXERCISE:  minimum of 5 hours per week; –extremely effective.  5 to 10 minutes a day of EXTREMELY vigorous activity [such as running up stairs] may be just as good as an hour of moderate activity.

  • SLEEP: a regular, normal 8 hour sleep schedule. –extremely effective
  • LOSE WEIGHT—get a normal BMI. Not so easy without a lap band.