I just read a potentially practice changing  article in Bipolar Disorders: Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial, by Dickerson et al.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bdi.12652

Sixty-six patients hospitalized for mania were randomized to either receive 1 probiotic tablet or placebo for 24 weeks. The results were dramatic. The 33 patients on placebo had 24 hospitalizations (average length 8.3 days)  versus 8 hospitalizations for the 33 on probiotics (average length 2.8 days).

As the authors note, probiotics are safe, tolerable, and cheap. The compound they used “is commercially available in Europe but is not commercially available in the USA”. They used one tablet “containing Lactobacillus GG and Bifidobacterium lactis strain Bb12 (>10⁸ colony forming units) in maltodextrin and microcrystalline cellulose…obtained from Chr. Hansen (Horsholm, Denmark).”

If this is replicated, it could be huge. As the authors put it, “The probiotic compound was well tolerated and had low levels of side effects. The adjunctive use of probiotics might represent a major addition to the therapeutic armamentarium for the management of mania and other mood disorders.”

It’s hard not to get excited about a result like this.

But, it hasn’t been replicated.

It reminds me of my enthusiasm 19 years ago for Andrew Stoll, MD et al.’s paper in the Archives of General Psychiatry in May, 1999, Omega 3 Fatty Acids in Bipolar Disorder: A Preliminary Double-blind, Placebo-Controlled Trial. This was “a 4-month, double-blind, (randomized)  placebo-controlled study, comparing ω3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder”, which found that “the ω3 fatty acid patient group had a significantly longer period of remission than the placebo group (P=.002; Mantel-Cox). In addition, for nearly every other outcome measure, the ω3 fatty acid group performed better than the placebo group.”

But, as you know, we don’t recommend omega 3 fatty acids to our patients with bipolar disorders because Stoll’s work wasn’t replicated.

For example, in Keck  et al’s Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder, “overall, there were no significant differences on any outcome measure between the EPA and placebo groups…this study did not find overall evidence of efficacy for adjunctive treatment with EPA 6 g/day in outpatients with bipolar depression or rapid cycling bipolar disorder.”

https://www.ncbi.nlm.nih.gov/pubmed/16814257b

So it’s probably too early  to start hunting for a facsimile of Faith Dickerson’s probiotic. One might eat  4 ounces of Straus yogurt/day, with its living yogurt cultures, including  Lactobacillus bulgaricus and Bifidobacterium lactis. But, as Dickerson et al remind us, “care is required in determining equivalence in terms of the quantity and viability  of the microorganisms in different preparations.”

Joseph Goldberg has written an important article for clinicians who treat patients with mood disorders. Goldberg JF. Should we reserve big gun antimanic drugs for only big gun manias? Bipolar Disord. 2018; 20:7–8. https://doi.org/10.1111/bdi.12597

He suggests, writing primarily about olanzapine, that following the guidelines (use the big gun drugs last, because of their side effects) can harm patients, while using the big guns first can rapidly improve them, even for patients with “mild or moderate symptom severity on a baseline mania rating scale”.

In my outpatient practice, using it primarily for patients with treatment-resistant or “mixed features” depression (most of whom failed to respond to several previous antidepressant trials of adequate dose and duration), it is amazing how fast it works, often within 3 days. (Antidepressants usually take 2-3 weeks to begin to work, and 4-6 weeks to have their full effect).

The big side effect with olanzapine is weight gain. But this is slow to develop, taking weeks to months. And there are ways to combat it, such as using low carbohydrate diets, and metformin.

As an “atypical” or “second generation” antipsychotic, or “serotonin dopamine antagonist”, olanzapine has the usual list of antipsychotic side effects, including tardive dyskinesia: again, slow to develop.

In the meantime, the patient and physician get a quick answer to the question of ‘does this medication work?’

Here’s some key points Dr Goldberg makes in his paper:

1. He cites the paper by Samara et al, which used “individual participant-level data” to determine that “high baseline symptom severity strongly moderated treatment outcome” (i.e. the sickest patients did the best, a common finding in psychiatric drug trials, since most trials have placebo response rates around 30%; “High baseline severity typically lowers placebo responsivity.”). In a fascinating aside, he notes that using mildly ill patients helped delay recognition of lamotrigine’s efficacy, since it appeared ineffective due to the high placebo response rate.
2. But “side effect burden was unsparing of lower severity patients”. So, Samara et al and the treatment guidelines recommend use of olanzapine mainly in severe presentations of mania.
3. Goldberg notes that “the concept of examining participant-level data is more than just a data analytic nuance; as a practical strategy for transforming group-based findings into more tailored, individualized treatment, it is a quantum leap toward the goal of personalized medicine.” This is the holy grail of psychopharmacology: customizing the treatment to the patient, and the psychopharmacologist’s work with a patient resembles a Savile Row tailor creating a bespoke suit. Goldberg suggests that at present, participant level data is more helpful in this endeavor than pharmacogenomics. One can use “individual participant-level data to broker a more bespoke fit”
4. One can also use “pairwise post hoc comparisons—statistical power permitting—between clinical subgroups of interest. For example, post hoc analyses have demonstrated olanzapine’s comparable antimanic efficacy in men and women, psychotic and nonpsychotic patients, manic and mixed episode patients, rapid cyclers and non-rapid
cyclers, patients with early and later age at onset, and subjects with and without comorbid substance use disorders.” These comparisons usually suggest, however, what patient characteristics worsen response rather than telling us who will respond. What is striking here is olanzapine’s broad spectrum of efficacy.
5. Goldberg argues that we may be mistaking a mistake by withholding big gun drugs like olanzapine from all but the most severely ill patients. “Because some high-risk/
high-gain medications have fast onset and robust breadth of spectrum, even their short-term use at potentially low doses has been shown to reliably temporize an evolving subsyndromal deterioration” (I recently saw this in a treatment-resistant depression patient, who had a dramatic response after 2 days of 2.5 mg olanzapine, which has persisted for several weeks after he discontinued it.) “Brief initial pulsed dosing with a “big gun”/high-risk agent might thus forestall hospitalization or prevent work or other role functions being jeopardized.”
6. Finally, often the alternative to using one high-risk, high gain medication is to cobble together, over time, a multi-drug combination, which combines limited efficacy with additive side effects. “Given that about 20% of “real world” bipolar patients receive extensive polypharmacy regimens (at least four medications)…. consider the potential hazards that low-efficacy/low-risk agents may pose with respect to incomplete remissions, relapse risk, cumulative adverse effects and poorer adherence in complex multi-drug regimens, and prolonged morbidity with psychosocial sequelae—despite the presence of only mild or moderate symptom severity on a baseline mania rating scale.”

Goldberg is writing about olanzapine use for manic patients. But I think the same arguments hold for patients with treatment-resistant depressions (who often turn out to have mixed states, or some form of bipolar disorder).

His article gives the clinician the intellectual rationale for trying the most efficacious intervention first, in appropriately selected patients, rather than last. Time is important, and a rapid response diminishes the time a patient remains ill.

Occasionally insurance companies make doctors fill out forms for  medications  not on their formularies, and on the form will be  a statement that asks the doctor to check a box if a ‘standard review timeline’ of 72 hours might seriously ‘jeopardize the life or health of the enrollee’.

In the past, I paused to wonder if such a delay would really matter.

Then I read “Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study” by Soren Dalsgaard et al, in the Lancet in 2015.  http://www.sciencedirect.com/science/article/pii/S0140673614616846

This study (with no pharmaceutical industry funding) followed 1.92 million Danish individuals for 24.9 million person-years, and found a mortality risk ratio of 2.07 for individuals with ADHD. Accidents were the most common cause of death. The rates were far higher in those diagnosed after the age of 18 than in those diagnosed from   6 to 17. The mortality risk, surprisingly, was higher in girls and women than in boys and men.

This was the first study to show that ADHD doubled a patient’s risk of death. As Stephen Faraone put it in his accompanying editorial: “Although no single study can be definitive, this one comes close. The data come from the medical registers of Denmark, where diagnoses of ADHD are conservative. The sample was large—1·92 million people, of whom 32 061 had ADHD—and the follow-up was long, with little missing data. Most importantly, the authors adjusted for potential confounders.”

Why the increased accidents? One possibility is that people with ADHD have increased sensation seeking (SS). “SS refers to a personality trait marked by the proclivity to seek out experiences that are novel, varied, complex, and intense” (page 180). Another is that they have problems with “effortful control” processes that result in lapses of concentration or working memory. http://www.sciencedirect.com/science/article/pii/S0140673614618225

A patient recently told me a story that brought the concept of ADHD-induced accidents  to life for me. He had started Adderall close to the age of 30, after his previous physician had advised him to take a low dose consistently. On the routine Adderall, he had  been able to finish his thesis, get married, and obtain a job, all in rapid succession. (He previously had used  Adderall intermittently to cram for exams.) When he tried to taper off Adderall, his list of incomplete chores grew, producing more anxiety and frustration.  He went back on it and has stayed on the same low dosage for the last 6 years.

At our first visit, about six years ago, he reported he had had surgeries on  both knees, his wrist, and his hand, due to accidents suffered doing vigorous outdoor sports such as  surfing, rockclimbing, and mountain biking.

I saw him again in early June, 2017. He continued to do well, and the Adderall continued to be helpful, at the same modest dosage: “If I don’t stay on it, work won’t happen”.

But, he reported, there had been a remarkable change in the frequency of his accidents and surgeries. “I had about one orthopedic surgery/year from my teens to my late twenties:  both knees, both elbows, multiple broken wrists, and multiple concussions, because of my risk-taking behavior. Now I’m less apt to carelessly throw myself off something”. His last major injury had occurred one year before he started Adderall,  when he broke his wrist.

He ascribes the difference to his ability to perceive risk.

“Wow,” I said. “That’s an amazing change. It’s really impressive. But please,” I begged, “please wear your helmet when you ride your bike.”

How lithium helps prevent suicide: a patient’s experience

Lithium is one of the most effective anti-suicide medications psychiatrists have to treat patients with mood disorders. http://www.bmj.com/content/346/bmj.f3646

How it works is unknown. [i]

Recently, a patient of mine with recurrent major depression had increasingly intense suicidal ideation.  She was already taking lurasidone (Latuda), escitalopram (Lexapro) 10 mg/day, and trazodone 50 mg at bedtime, but they weren’t helping.  She reported she was “terrible…desperately depressed…I can’t get out of this dark place…I go to bed early to escape the day…It would be easier if I wasn’t here.” She told me she was thinking of overdosing several times a day.

I started her on lithium 300 mg/day and met with her two weeks later. She reported she had been feeling so unsafe she had asked a series of family members to stay with her.

One week after she started the lithium, she was at home with her sister, standing in her living room, next to her couch, watching golf on television, when “it felt like a switch flipped, and the suicidal thoughts left me. It felt like a weight had been lifted. I knew it immediately.”

“Before this, the suicidal thoughts had been constant: how can I do it (which pills can I take), when can I do it, where should I do it (should I got go a hotel, so no one has to find me in the house?). It was overwhelming and very scary.”

“I still have the depression, I’m still feeling sluggish and sad, but I don’t have the suicidal thoughts. Things don’t seem as catastrophic. Before, everything seems like a dead end, hopeless”.

In a post about the Research Domain Criteria (RDoC), Thomas Insel notes  “that symptoms alone rarely indicate the best choice of treatment” and that “mental disorders are biological disorders involving brain circuits”. [ii]

In this case, a symptom (increasing suicidal ideation) suggested a treatment (lithium) that appeared to cause my patient’s suicidal ideation (and hopelessness) to turn off like a switch turning off an electrical circuit.

Psychopharmacology Made Simple: What’s it like when an SSRI[1] works?

What benefit can one expect from a medication? While it’s easy enough to find information online about side effects and diagnostic indications (approved uses), it’s much more difficult to learn how it feels, from the patient’s point of view, when a medication works well.

Numerically, there are drops in rating scales, like the GAD-7 or the PHQ-9. [2] But it’s more useful (and certainly more interesting) to hear a patient’s experience directly.

This patient had started on Lexapro (escitalopram) [3] three months earlier. Her primary

complaint was her irritability, which led her to make harsh, critical comments to coworkers that she always regretted.

She returned 3 months later for a follow-up visit and noted she felt much less stressed.

“Things don’t bother me nearly as much; it’s like water off a duck’s back”. [4]For example, “previously my husband would say things I found very irritating and I would debate with him to try to change his mind. Now, I realize we don’t have to feel the same way about everything. I’m much better about letting things go.” “It’s much easier to talk with people and care about how they feel, because I care less about how I’m feeling, because I feel less upset about things. It’s amazing. Everything seems so much easier.”

Annoying things are still annoying, but the annoyance doesn’t last as long, it’s easier to put it aside, and the pain caused is not as great.

Is a medication worth taking? No one knows before trying a new one. One weighs the benefits and the side effects, and decides.

Wellbutrin (bupropion) works quite differently from SSRIs such as Lexapro (escitalopram), the subject of a previous blog post.

How does it work? Per UpToDate[1], “like other antidepressants the mechanism of bupropion’s activity is not fully understood”. [2]

Clinically, it’s useful to think of it as a selective norepinephrine reuptake inhibitor, or SNRI. It helps depressed mood, low energy level, hypersomnia (sleeping too much), and anhedonia. [3] It’s quite different from the SSRIs, which help anxiety, rumination, and irritability.

Here is one patient’s experience with it. He reported chronic depression for many years that worsened in the last 12 months since he became clean and sober, and got even worse when he quit his lifelong smoking habit, which  increased his irritability. “I want to sleep all day. I have no passion to do anything I used to love doing. I’m not interested or excited by anything.” He had been attending AA meetings daily, then decreased for the last couple of months to 1 or 2 meetings/week. He had no sponsor. He hadn’t progressed beyond the third step because “I feel worn out when I think about picking up a book”.

He started Wellbutrin XL 150 mg/day for one week, and then increased to 300 mg/day, but after 3 days on the higher dosage, he called me to report he was “waking up at 4 AM, ready to go, with a lot of energy. I started to get racy, I felt like I couldn’t breathe, I had  little shocks, “air hiccups”, like I was out of breath. Last night I felt a lot of anxiety, panicky, my heart was heart racing.”

Dosing of Wellbutrin has to be individualized. Some people need 300 mg, some can’t tolerate it and do better on 150 mg. I told him to stop it for a day or two until his symptoms resolved, and then to restart on 150 mg/day.

I saw him one month after he reported the side effects.  “The Wellbutrin is doing good; I feel pretty normal, not elated. Before, I couldn’t get out of bed, I had very low energy, I wanted to sleep 18 hours/day, be horizontal, I felt worn out all the time”. Now, he reported he was going to more meetings, 2-3/day, and working his program.

For depression, one of the  most common conditions seen in outpatient practice, either the SSRIs or the SNRI bupropion are probably the most common first medications tried. [4]

Hypomanic states are rarely observed by the psychiatric clinician. Bipolar  patients are much more commonly depressed  (according to Judd et al, bipolar II patients spent only 1.3% of the time in hypomania over 13 years of follow-up).

http://jamanetwork.com/journals/jamapsychiatry/fullarticle/207252  accessed 1/14/17

The manifestations of hypomania are often quite subtle. By definition, in hypomania the patient is not psychotic, does not need hospitalization, and has no marked impairment in social or occupational functioning.

I am indebted to a patient, whom I have treated for 10 years, and who takes several mood-stabilizing medications, for providing a vivid example of hypomania, and the damage that can result.

Her hypomanic states are infrequent, once every 3 months. They occur 3 days before her period, and end when she gets her menses. First she has extra energy, then she stops sleeping for 1-2 days, then feels “light, happy, like I can do no wrong” for one day, and then crashes and goes back to normal.

She only recognizes her hypomania after the episode has ended. When her partner tries to point it out to her, she becomes irritable and can’t hear her. Earlier in her life, she went shopping when hypomanic.

Unfortunately, considerable damage can result from the impaired judgment typical of hypomanic states. In this case, the patient was involved in litigation. She decided to edit and “improve” a document which had already been submitted to opposing counsel “because I thought it didn’t look professional enough”, without  informing her attorney or asking his opinion. The unfortunate result was that her lawsuit, from which she was likely to get a substantial award, was thrown out, and she was fined a large sum for altering the document.

It is much easier for patients to recognize their depressions than their hypomanias. In hypomania, they feel good and often become irritable when others try to inform them something is not right. Perhaps the best approach is to learn what your hypomanic symptoms look like and to work out in advance what your significant others can say or do to get through to you.

The English have a somewhat more relaxed attitude towards drinking in pregnancy than we do in the States.

From the RCOG:

“It is recommended that you do not drink alcohol during the first three months of pregnancy. Drinking small amounts of alcohol after this time does not appear to be harmful for the unborn baby, but you should not:

• drink more than one or two units, and then not more than once or twice per week

• binge drink (which for a woman is when she has six units or more of alcohol on any one occasion).”

https://www.rcog.org.uk/globalassets/documents/patients/patient-information-leaflets/pregnancy/pi-alcohol-and-pregnancy.pdf

Vs the CDC:

“Every woman who is pregnant or trying to get pregnant – and her partner – want a healthy baby. But they may not be aware that drinking any alcohol at any stage of pregnancy can cause a range of disabilities for their child,” said Coleen Boyle, Ph.D., director of CDC’s National Center on Birth Defects and Developmental Disabilities. “It is critical for healthcare providers to assess a woman’s drinking habits during routine medical visits; advise her not to drink at all if she is pregnant, trying to get pregnant or sexually active and not using birth control; and recommend services if she needs help to stop drinking.”

http://www.cdc.gov/media/releases/2016/p0202-alcohol-exposed-pregnancy.html

Ian McEwan’s latest novel, Nutshell (“Oh God, I could be bounded in a nutshell and count myself a king of infinite space – were it not that I have bad dreams.” Shakespeare, Hamlet), is told from the point of view of a rather sophisticated fetus 2 weeks prior to a full-term birth, during an English summer, using the plot of Hamlet as a frame: his mother Trudy (Queen Gertrude in Hamlet), and his uncle, Claude (King Claudius in Hamlet) are scheming to murder his father (a poet, in the novel).

Here are 3 excerpts from the novel portraying the fetus’s view of drinking:

“I like to share a glass with my mother. You may never have experienced, or you will have forgotten, a good burgundy (her favorite) or a good Sancerre (also her favorite) decanted through a healthy placenta. Even before the wine arrives – tonight, a Jean-Max Roger Sancerre – at the sound of a drawn cork, I feel it on my face like the caress of a summer breeze. I know that alcohol will lower my intelligence. It lowers everyone’s intelligence. But oh, a joyous, blushful Pinot Noir, or a gooseberried Sauvignon, sets me turning and tumbling across my secret sea, reeling off the walls of my castle, the bouncy castle that is my home. Or it did so when I had more space. Now I take my pleasures sedately, and by the second glass my speculations bloom with that license whose name is poetry. My thoughts unspool in well-sprung pentameters, end-stopped and run-on lines in pleasing variation. But she never takes a third, and it wounds me.

“I have to think of baby,” I hear her say as she covers her glass with a priggish hand. That’s when I have it in mind to reach for my oily cord, as one might a velvet rope in a well-staffed country house, and pull sharply for service. What ho! Another round here for us friends!

But no, she restrains herself for love of me.”

Ian McEwen, Nutshell, pages 6-7, 2016, Nan A. Talese/Doubleday

“A few minutes ago the radio told us it was four o’clock. We’re sharing a glass, perhaps a bottle, of Marlborough Sauvignon Blanc. Not my first choice, and for the same grape and a less grassy taste, I would have gone for a Sancerre, preferably from Chauvignol. A degree of flinty mineral definition would have mitigated the blunt assault of direct sunlight and oven blast of heat reflected off the cracked façade of our house.

But we’re in New Zealand, it’s in us, and I’m happier than I’ve been in two days. Trudy cools our wine with plastic cubes of frozen ethanol.”

Nutshell, page 31.

And finally (and best of all):

“Trudy and I are getting drunk again and feeling better, while Claude, starting later and with greater body mass, has ground to cover. She and I share two glasses of the Sancerre, he drinks the rest, then returns to his plastic bag for a burgundy. The grey plastic bottle of glycol (which will later be used to poison his father) stands next to the empty, sentinel to our revels. Or memento mori. After a piercing white, a Pinot Noir is a mother’s soothing hand. Oh, to be alive while such a grape exists! A blossom, a bouquet of peace and reason. No one seems to want to read aloud the label so I’m forced to make a guess, and hazard an Echezeaux Grand Cru. Put Claude’s penis or, less stressful, a gun to my head to name the domaine, I would blurt out la Romanee-Conti, for the spicy cassis and black cherry alone. The hint of violets and fine tannins suggests that lazy, clement summer of 2005, untainted by heatwaves, though a teasing, next-room aroma of mocha, as well as more proximal black-skinned banana, summon Jean Grivot’s domaine in 2009. But I’ll never know. As the brooding ensemble of flavours, formed at civilisations’s summit, makes its way to me, through me, I find myself, in the midst of horror, in reflective mood.”

Nutshell, pages 51-52.

But, beyond illustrating trans-Atlantic cultural differences, I have one other reason for sharing these excerpts with you. A patient lamented yesterday that the pressures of her work for a famous tech company  left her longing for a break, which she wouldn’t have until an island vacation that was months away. And likewise we doctors need to have a  healthy way to relieve the pressures of our work. I  would argue that, for those who love and appreciate great writing, literary fiction can provide a break from the stress of work and daily life that is more readily available, more mentally refreshing, and more spiritually rejuvenating than even the banal pleasures of a resort holiday.

An important review article and meta-analysis, Early Treatment Responses of Selective Serotonin Reuptake Inhibitors (SSRIs) and clomipramine in pediatric OCD was published in the Journal of the American Academy of Child and Adolescent Psychiatry (October, 2016, p 851-859). http://www.jaacap.com/article/S0890-8567(16)31160-1/fulltext

The most important finding was that “more than 85% of the improvement observed on SSRI compared to placebo in pediatric OCD trials was observed by week 2”. The current guidelines state that an 8 to 12 week trial of SSRIs is necessary, for both children and adults, although adults have a similarly rapid response.

Also, in answer to patients’ common question, “which SSRI is the best?”, there was no “significant differences among individual SSRI agents” (fluoxetine, fluvoxamine, sertraline, paroxetine).

There was no effect of maximum SSRI dosing (previously, it has been posited that OCD response required higher dosages, than, say, depression, and previous adult meta-analyses showed greater therapeutic response with higher SSRI dosages).

Clomipramine, a tricyclic antidepressant, also showed a rapid response (75% of benefit by week 2), and was more effective than SSRIs, compared to placebo (there were no direct drug-drug comparisons). However, clomipramine is not viewed as the first choice, due to its higher side effect burden of “weight gain, anticholinergic side effects, and arrhythmias”.

The major clinical implication of this article is that if there is no or minimal response after 2 weeks of SSRI treatment  in pediatric OCD, one should start seriously thinking about changing medications. It also suggests that the follow-up visit should be 2 weeks after starting the new medication, and not 4.

Apparently this is the case not only in OCD, but in major depression, and in both children and adults.

Too often, when I ask patients if they smoke cigarettes, I hear, “Oh, only 2 or 3 a day”, as if, not a problem, no big deal, like saying, “when I play Russian roulette, there’s only one bullet in the gun”.

There was a nice little article in JAMA recently explain why sometimes even a little bit matters.

http://jama.jamanetwork.com/article.aspx?articleid=2443580

If you plot relative risk of mortality on the y-axis, and number of cigarettes/day on the x-axis, you see a simple linear association. Each cigarette smoked increases mortality risk. So with  1-4 cigarettes/day, the relative risk is 1.5, 5-9 cigarettes 2.0, 20-24, 3.0.

In contrast, alcohol, measured in drinks/day, has a j shaped curve. “Consumption of up to 2 drinks/day in women and 4 drinks/day in men was associated with lower mortality than zero consumption, with about one-half drink per day associated with the lowest mortality risk.”

So, better not to smoke.