Probiotics for Bipolar Disorder Mania

Relation

Dickerson, F., Adamos, M., Katsafanas, E., et al. Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: a randomized controlled trial.Bipolar disorder. 2018;20(7):614-621.

Objective

To determine whether adjunctive probiotic administration reduces rehospitalization of patients with bipolar disorder 1 following hospitalization for mania.

Draft

Randomized, double-blind, placebo-controlled 24-week intervention with in-person visits every 4 weeks. Statistics used intention-to-treat analysis.

intervention

Lactobacillus GGandBifidobacterium lactisStrain Bb12 combined probiotic (>10⁸colony forming units [CFUs]) or placebo, once daily.

Participant

Sixty-six patients aged 18 to 65 years admitted to psychiatric inpatient or day hospitals in Baltimore for mania were enrolled upon discharge. Fifty-two participants completed the study (26 in each group). All participants were enrolled with a diagnosis of Bipolar 1 (single manic episode, recent manic episode, or recent mixed episode) or schizoaffective disorder, bipolar type (manic or mixed state; DSM-IV-TR), confirmed by the Structured Clinical Interview for Diagnosis of DSM-IV Axis I Disorders (SCID). Participants continued their regularly prescribed medications and other psychiatric treatments as usual.

Exclusion criteria included:

• Substanzinduzierte oder medizinisch induzierte Manie
• HIV-Infektion oder andere Immunschwäche
• Erkrankung, die das Gehirn oder die kognitive Funktion beeinträchtigt und/oder Diagnose einer geistigen Behinderung
• Drogenmissbrauch oder -abhängigkeit innerhalb von 3 Monaten vor Studienbeginn
• Vorgeschichte eines intravenösen Drogenkonsums
• Teilnahme an einer Arzneimittelstudie innerhalb von 30 Tagen vor Studienbeginn
• Schwanger oder planen, während des Studienzeitraums schwanger zu werden
• Dokumentierte Zöliakie

Study parameters assessed

• Dauer bis zur Rehospitalisierung nach der Entlassung
• Gesamtzahl der Krankenhauseinweisungen in jeder Gruppe
• Durchschnittliche Anzahl der Krankenhaustage im Studienzeitraum
• Gesamttage des Krankenhausaufenthalts
• Psychiatrische Indikatoren alle 4 Wochen: Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS) und Montgomery-Åsberg Depression Rating Scale (MADRS)
• Entzündungs-Score unter Verwendung von Blut, das zu Studienbeginn und bei Abschluss der Studie/24 Wochen entnommen wurde. Der Entzündungs-Score verwendete diese Variablen: Immunglobulin (Ig)G-Antikörper gegen das NR2-Peptidfragment des N-Methyl-D-Aspartat (NMDA)-Rezeptors, Gliadin und das Gag-Protein des Mason-Pfizer-Affenvirus; und IgM-Klasse-Antikörper gegen Toxoplasma gondii.

Primary outcome measures

The primary endpoints measured were the effects of probiotics on:

• Entzündungspunktzahl
• Anzahl und Dauer der Rehospitalisierungen
• Relatives Risiko einer Rehospitalisierung
• Psychiatrische Bewertungsskalen

Key insights

• Insgesamt weniger Rehospitalisierungsereignisse in der Probiotika- vs. Placebogruppe (8 vs. 24; Hazard Ratio [HR]: 0,28, P=0,009)
• Geringeres Risiko einer ersten psychiatrischen Rehospitalisierung in der Probiotika- vs. Placebo-Gruppe (HR: 0,37; 95 % Konfidenzintervall [CI]: 0,15-0,91, P=0,029)
• Während des 24-wöchigen Studienzeitraums verbrachte die Probiotika-Gruppe insgesamt 182 Tage weniger im Krankenhaus, und der durchschnittliche Aufenthalt war kürzer (Mittelwert [SD] Aufenthaltsdauer = 2,8 Tage [6.3] gegenüber 8,3 Tagen [12.4], P=0,017)
• Die psychiatrischen Skalen (MADRS, YMRS, BPRS) unterschieden sich zwischen den Gruppen zu keinem Zeitpunkt der Nachuntersuchung in der Studie.
• Keine Studienabbrüche wegen Beschwerden über die Studienmedikation; Die gemeldeten unerwünschten Ereignisse waren in beiden Gruppen gleich

The following finding trended toward significance (P=0.0596): The higher the inflammation at baseline in all patients, the higher the risk of re-hospitalization.

Interestingly, the study neither quantifies the change in inflammation scores in the group as a whole nor compares the two groups. However, the authors noted that participants with higher levels of inflammation (determined to be above the 50th percentile of a separate control group without psychiatric symptoms from another study¹) were associated with the greatest reduction in rehospitalization risk. The authors comment: "For individuals [who experience mania] with relatively high rates of systemic inflammation, adjunctive probiotic treatment was associated with an approximately 90 percent reduction in the risk of rehospitalization."

Practice implications

This study is particularly interesting because it examines 2 questions simultaneously: 1) Are probiotics helpful in reducing hospitalizations for mania? and 2) if so, does the mechanism have anything to do with inflammation?

The answer to the first question was yes – in this study, additional probiotic treatment for 24 weeks after hospitalization for maniadidReducing the risk and length of stay of rehospitalization for mania. It's a seemingly straightforward finding that could potentially change the standard of care for bipolar disorder, schizoaffective disorder and other disorders. Even if hospital protocol does not change, outpatient physicians can use the results of this study to initiate long-term probiotic treatment for patients with a history of mania.

Patients in the probiotic group were hospitalized less, but were they symptomatically better?

The answer to the second question – is the benefit achieved by reducing inflammation? – is less clear. No data on the final inflammatory scores or their changes were published, nor was there a discussion about the significance between the two groups. Only 1 comment mentioned that people with higher levels of inflammation had a lower risk ratio associated with hospital readmission - perhaps meaning that the protective effect of probiotics was stronger in patients with higher levels of inflammation. Although encouraging and consistent with the studies cited in the paper's introduction, it would be helpful to flesh out this hypothesis a little more. Clinicians do not typically evaluate inflammation with specific tests, such as: B. the IgG and IgM markers for various pathogens used in this study. They rely more on C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in combination with physical symptoms to assess or estimate systemic inflammation levels.

Note that the probiotics used in the study are fairly low doses at 100 million CFU. Commonly used probiotics in naturopathy are 10 to 25 billion CFU per dose, and some intensive probiotics contain over 150 billion CFU per dose.

Finally, little attention is paid to the fact that the results at the psychiatric level do not differ at any point between the probiotic and placebo groups. Patients in the probiotic group were hospitalized less, but were they symptomatically better? We assume that hospital stay was the primary outcome measure of the study because it speaks the language of the medical establishment: money. Psychiatric hospitalization is very expensive, and often the cost is even higher than what hospitals advertise, with a 5.5-day hospital stay for treatment of bipolar disorder costing $4,356 ($7,593 for 9.4 days) in the United States.²This averages out to about $800 per day. If treating 66 people in this study saves 182 days of hospitalization (275 minus 93 days),that saves almost $145,600. That's about $4,400per patientin the 33-member probiotic group.

For those of us who treat patients on an outpatient basis, the financial numbers are less important than knowing that something as simple as probiotics could spare patients the major life disruption caused by hospitalizations. Physicians both in and out of hospitals should consider probiotic treatment due to its low risk profile and high potential for benefit. Continued large-scale studies will be helpful in evaluating symptomatic benefit.