The Gut-Brain Axis and Potential Roles of Probiotics in the Treatment

of Depression: “I’ve GUT a Feeling”

Pharmacotherapy Rounds

Bryan Sackey, PharmD, BCPS, AAHIVP

PGY2 Psychiatry Pharmacy Resident

South Texas Veterans Health Care System

The University of Texas at Austin College of Pharmacy

University of Texas Health Science Center San Antonio

April 7, 2017

Learning Objectives

1. Discuss the epidemiology, clinical features, diagnostic criteria, and pathophysiology of

depression

2. Identify conventional treatment options for patients with Major Depressive Disorder

3. Describe the physiological link between the gastrointestinal system and psychiatric

disorders, specifically depression

4. Evaluate the potential role of probiotics as a therapeutic option for depressive disorders in

concordance with literature evidence

2 | S a c k e y

Depression

I. Background1-3

a. Depression: a serious mood disorder characterized by a persistent feelings of sadness, loss of

interest (anhedonia), and other symptoms which are severe enough to interrupt daily activities

b. Though a treatable condition, depression remains a major public health concern

c. Various classifications of depression based on duration of symptoms, etiology, and severity

d. Major Depressive Disorder (MDD) is most severe form of

depression

II. Diagnosis and Clinical Presentation of MDD1-3

a. Based on Diagnostic and Statistical Manual of Mental

Disorders, Fifth Edition (DSM-5)

i. ≥5 of 9 symptoms present for 2 weeks

ii. At least one symptom has to be depressed mood or

anhedonia

iii. Must cause clinically significant distress or

impairment in important areas of functioning

iv. Not attributable to physiological effects of a

substance or other medical condition

b. Cannot be attributed to physiological effects of other

substance or medical condition

c. Not better explained by another psychiatric diagnosis

III. Epidemiology2-6

a. MDD affects ~15 million American adults (≥ 18 years) or about 8% of the U.S. population

b. 12-month prevalence: 5.3% - 6%

c. Lifetime prevalence: 13.25% - 16.2%

d. The World Health Organization estimates that depression will be the second highest medical

cause of disability by the year 2030, second only to HIV/AIDS

e. Accounts for 13.7 missed worked days per year

f. Total cost of depression in U.S. estimated to be $44 billion

i. $12 billion in direct costs of treatment

ii. $8 billion in premature death

iii. $24 billion in absenteeism and reduced productivity at work

g. Accounts for >60% of suicides in the U.S.

IV. Risk Factors/Etiological Factors5-7

a. Genetics Twin studies suggest a heritability of 40-50%

b. Life Stressors

c. Substances/Medications (appendix A)

d. Medical Conditions (appendix A)

e. Predisposing factors Female, middle-aged, widowed or separated/divorced, low income,

unemployment, comorbid psychiatric or personality disorders

Depressed mood Anhedonia

Appetite Changes

Diminished concentration

Sleep disturbances

Feelings of guilt or worthlessness

Fatigue or low energy

Psychomotor disturbances

Suicidal ideations

Figure 1. Symptoms of depression1

3 | S a c k e y

V. Screening and Assessment (Appendix C)3,10

a. Hamilton Depression Rating Scale (HAM-D)

b. Montgomery-Asberg Depression Rating Scale (MADRS)

c. Quick Inventory of Depressive Symptomatology (QIDS)

d. Patient Health Questionnaire-9 (PHQ-9)

e. Beck Depression Inventory (BDI)

f. Hospital Anxiety and Depression Scale (HADS)

g. Leiden Index of Depression Sensitivity-Revised (LEIDS-r)

•Depressive symptoms related to deficiencies in serotonin (5-HT), norepinephrine (NE), and dopamine (DA)

•Depressive symptoms improved with increased monomanine availability in synapse

•Does not account for delayed onset of effect on mood

Monamine Hypothesis

•Depression resulting from dysregulation of neurotransmitters which leads to alterations in both pre-and post- synaptic receptors

•Normalization of receptors in response to antidepressant therapy accounts for delayed onset of antidepressant activity

Dysregulation Hypothesis

•Stress effects on the hypothalamic-pituitary-adrenal axis secretion of glucocorticoids, cortisol and proinflammatory markers low brain-derived neurotrophic factor (BDNF) decrease neurogenesis in the hippocampus

•Antidepressants increase neuronal cell proliferation in hippocampus in animal models

Chronic Stress Model

Onset

•Average age is late 20s

•Sharp increase between ages 12-16 years; gradual increase with initial decline in early 40s

Duration

•Median time to recovery is 20 weeks with adequate treatment; untreated episodes can last ≥6 months

•Periods of remission generally longer early in the course and become shorter as illness progresses

Recurrence

•50% with single episode will recover without recurrence

•Three or more prior episodes: ≥90% recurrence

Suicide

•Increased risk of suicide especially if depression left untreated (20% lifetime risk)

•Risk of suicide becomes greater with each episode of depression

Figure 3. Clinical course of MDD3,8

Figure 2. Most common pathophysiological hypothesis for MDD1,3-9

4 | S a c k e y

VI. Conventional Treatment of MDD11-15

a. Non-pharmacologic Treatment

i. Psychotherapy

ii. Vagal Nerve Stimulation (VNS)

iii. Electroconvulsive Therapy (ECT)

iv. Bright Light Therapy

b. Pharmacologic Treatment (figure 4)

i. Goal of treatment – remission

ii. First line (table 2): SSRIs, SNRIs, bupropion, or

mirtazapine

Table 1. Important considerations of antidepressant (AD) therapy16-22

Treatment response definitions Time course of action Efficacy of medications

No response: ≤ 25% reduction in

baseline symptoms

Partial response: 26-49%

reduction in baseline symptoms

Full response: ≥ 50% reduction

in baseline symptoms

Remission: Return to normal

function

Relapse: Return of fully

symptomatic state after remission

~ 4-8 weeks to achieve full AD effects

a. First few days: ↓agitation,

improved sleep and appetite

b. 1-3 weeks: ↑activity, ↑self-care,

normalization of memory,

concentration, thinking, movement,

sleeping, eating

c. 2-4 weeks to 8 weeks: relief of

depressed mood, less hopelessness, ↓

thoughts of suicide

Overall efficacy ~50-60%

Effect size range from 0.34-0.41

More effective for severe symptoms

(NNT=4 for severe vs. 16 for mild)

Reduces with each unsuccessful

attempt to achieve remission

Risk of relapse ranges from 20-85%

without continuation of medications

Up to 46% of patients do not

experience sufficient response

Table 2. Evidenced based approach for the treatment of MDD (American Psychiatric Association 2010)12

First line* Second line Third line Treatment Resistance

Mild to moderate depression

Psychotherapy +/-

pharmacotherapy: SSRI, SNRI,

mirtazapine, bupropion

Moderate to severe depression

Pharmacotherapy +/- psychotherapy

Severe depression

ECT (in addition to therapy)

Depression w/ psychotic features

AD + antipsychotic or ECT

Switch to different

medication from list

above as monotherapy

Augment with an AD

with a different

mechanism

Augment with atypical

antipsychotic

Augment with

psychotherapy

Switch to medication

with a different

mechanism of action

Augment with an

AD with a different

mechanism or a

TCA

Augment with

lithium or

triiodothyronine

MAOI

ECT

Figure 5. Phases of MDD Treatment18

Figure 4. Class of antidepressant agents11

Selective Serotonin Reuptake Inhibitors

(SSRIs)

Serotonin Norepinephrine

Reuptake Inhibitors (SNRIs)

Tricyclic Antidepressants

(TCAs)

Monoamine Oxidase Inhibitors

(MAO-I)

Atypical Antidepressants

*See appendix B for classification of depression

5 | S a c k e y

GUT-BRAIN AXIS

I. Gut Microbiome23

a. The gut or gastrointestinal (GI) tract provides the largest physical interface between the

environment (including the microbiome) and self

b. Commensal microbiome

i. Abundance: 10xe14

(10:1); more than 10,000 unique species (genetic load 150:1)

ii. Mass: 2-6 lbs

iii. Intestinal microbiota and its metabolites shown to be involved in modulating GI

function, immune function and activity in the enteric nervous system

iv. The whole is greater than its parts functional role of the bacterial community is more

important than the specific components

v. Microbiome shifts over a lifetime and is affected by various factors including nutrition,

antibiotics, stress, perinatal period, infections, and GI related disorders

vi. More dramatic effects expected in children (and perhaps elderly) who have less diverse

microbiota and more vulnerable to external influences

II. Physiology of Gut-Brain Axis23-25

a. Complex nervous system interfaces directly

with central nervous system (CNS) and allows

bidirectional information flow between the

microbiota and brain

b. Close interaction suggests aspects of brain

development, function, mood, and cognition

may be influenced by GI contents

c. Communications with CNS:

i. Systemic Communication

1. Hypothalamus-Pituitary Axis

2. Neurotransmitters

3. Bacterial metabolites

4. Cytokines

ii. Neural Communications

1. Vagal nerve

2. Sympathetic nervous system

Table 3. Neurotransmitter production

and associated microorganism28

Neurotransmitter Microorganism

Norepinephrine Escherichia coli

Bacillus

Saccharomyces

GABA Lactobacillus

Bifidobacterium

Serotonin Candida

Streptococcus

Escherichia

Enterococcus

Dopamine Bacillus

Serratia

Limitations of

conventional

MDD Treatment

High rates of disease relapse

Delayed onset of action

Medication tolerability

Figure 6. Limitations of current MDD treatment9,20-22

Up to 67% relapse in those

who respond but not remit

Up to 4-6 weeks for full

antidepressant effects

Includes sexual dysfunction,

GI disturbances, weight gain

6 | S a c k e y

III. Gut Brain Axis influence on CNS function25

a. GI is only organ to contain independent nervous system often termed “Second Brain”

b. Intricate network of 100 million neurons embedded in gut wall

c. 95% of all serotonin in the body is in the gut

IV. Gut Microbiota and CNS Interactions26-29

a. Production of signaling neurotransmitters (NT) from metabolites of gut microbiota

i. NT includes norepinephrine (NE), serotonin (5-HT), GABA, and dopamine (DA)

ii. Indigenous bacteria produce metabolites that signal to colonic enterochromafin cells

(ECs) ECs increase tryptophan hydroxylase 1 (Tph1) expression and 5-HT synthesis

iii. Short chain fatty acid metabolites induce tryptophan production which can influence

circulating serotonin levels and subsequently mood

b. Studies to suggest conditions which alter gut microflora (i.e. C. difficile infection, chronic

antibiotic use, Irritable Bowel Syndrome) associated with mood disturbances

c. Preclinical models raise possibility that mood symptoms may be influenced by intestinal

microbiota

d. Prevention/treatment of psychiatric disease by manipulating gut microflora

Probiotics

I. Probiotics at a Glance30-32

a. World Health Organization’s (WHO) definition: live micro-organism that when ingested in

adequate amounts, confers a health benefit on the host

b. Broad heterogeneous group of microbial species

c. Lactic acid bacteria and non-pathogenic yeasts most commonly used

d. General mechanism provides environment conducive for growth of commensal microflora

(i.e. ↓ pH) and promote healthy microbiome

e. Sales of probiotic products have a rising trend from 2010 to 2014, increasing globally by 35%

from $23.1 billion to $31.3 billion

f. Food and Agricultural Organization (FAO)/WHO 2002 probiotic guidelines:

i. Probiotics have to be alive when administered

ii. Must be able to survive in intestinal ecosystem

iii. Must have undergone controlled tests documenting health benefits in target host

iv. Must be supplied in adequate amounts most reported benefits demonstrated after

ingestion of a concentration around 107 to 10

9 probiotic cells/gram, with a serving size

around 100 to 200 mg per day

g. Minimum safety requirements of probiotics (according to FAO/WHO 2002 guidelines)

i. Determination of antibiotic resistance patterns

ii. Assessment of certain metabolic activities (e.g., D-lactate production)

iii. Assessment of side effects during human studies

iv. Epidemiological surveillance of adverse incidents in consumers (after market)

v. Must be tested for toxin production and determination of hemolytic activity

II. Regulation30-32

a. Not manufactured using pharmaceutical standards or regulated by Food and Drug

Administration (FDA) claims of effectiveness have proliferated

7 | S a c k e y

b. FDA and WHO recommend product labeling to include minimum viable numbers of each

probiotic strain at the end of the shelf-life (however not enforced)

c. Very few “probiotic” preparations on the market today fulfil definition of a probiotic

III. Products30

a. Live probiotic cultures available in fermented dairy products and fortified foods

b. Freeze dried forms tablets, capsules, powders, and sachets

c. Microencapsulation techniques used to prevent destruction by acidic stomach conditions

IV. Safety33

a. Generally considered to be safe for consumption

b. Side effects mostly mild and digestive (i.e. gas, bloating)

c. Potential for allergic reactions mainly attributed to products used for probiotics

d. Severe side effects are rare and mostly seen in immunocompromised patients

i. Risk of fungemia and bacteremia in immunocompromised children and pregnancy

ii. Higher risk of severe ADEs observed in patients with central venous catheters,

cardiac valve disease, pancreatitis, short bowel syndrome and premature infants

V. Current proposed indications/health benefits34-36

VI. Psychobiotics37-46

a. Probiotics studied to manipulate gut microflora and improve psychiatric symptoms (figure 7)

b. Most commonly studied include various Lactobacillus species (i.e. helveticus, rhamnosus),

and Bifidobacterium species (i.e. longum)

c. Aizawa, et. al. demonstrated significantly lower quantities of bifidobacterium and

lactobacillus in MDD patients compared to controls

d. Preclinical studies demonstrate various probiotic species in improving mood symptoms in

mice (see appendix E)

e. Cross-sectional study suggested that those who consumed probiotics had a lower odds of

depression (OR=0.58, 95% CI=0.45-0.75); however not significant when adjusted for

patient characteristics (i.e. age, race, socioeconomic status)

Table 4. Proposed indications and

health benefits of probiotics35-36

Eczema

Antibiotic-associated diarrhea

Recurrent C. diff.

Bacterial Vaginosis

Hypertension

Immune function

GI-related infections

Irritable Bowel Syndrome (IBS)

Inflammatory Bowel Disease (IBD)

Lactose intolerance

Psy

cho

bio

tics

Promote neurotransmitter

production

Restore commensal microbiota

Attenuation of pro-inflammatory response

Clinical Question

Are probiotics a viable option as prevention, adjunct, or monotherapy treatment of depression?

Figure 7. Proposed mechanism of

psychobiotics in improving mood symptoms37

8 | S a c k e y

Literature Review

I. Meta-analysis conducted by Huang et al. (2016)47

a. Evaluated existing evidence on effect of probiotics-based interventions on depression

b. Included five randomized controlled trials (RCTs) from 2011 to 2015

c. Results showed probiotics significantly reduced depression scale score Mean Difference (MD

= -0.30, 95% CI [-0.51 to -0.09], p = 0.005) in the subjects (see appendix F)

Table 5. Characteristics of RCTs included for Huang et al. Meta-Analysis*

Study Subjects, Cases Dose; Duration Species, Dosage Depression scale

Mohammadi,

2015, Iran

20–60 years old

healthy

petrochemical

workers, 45

6 weeks Actobacillus casei 3 x103 CFU/g,

L. acidophilus 3 x107CFU/g,

L. rhamnosus 7 x109 CFU/g,

L. bulgaricus 5 x108 CFU/g,

B. breve 2x1010

CFU/g,

B. longum 1x109 CFU/g,

S. thermophilus 3 x108 CFU/g

Depression

Anxiety and

Stress Scale

(DASS)

Akkasheh,

2016, Iran

20–55 years old

patients with

MDD, 40

One capsule

per day; 8

weeks

L. acidophilus 2 x109 CFU/g,

L. casei 2x109 CFU/g,

B. bifidum 2x109 CFU/g

BDI

Steenbergen,

2015, The

Netherlands

Around 20 years

old; healthy young

adults, 40

One sachet per

day; 4 weeks

B. bifidum, B. lactis, L. acidophilus,

L. brevis, L. casei, L. salivarius,

Lactococcus lactis 2.5x109 CFU/g

BDI, LEIDS-r

Messaoudi,

2011, France

30–60 years old

healthy human

volunteers, 55

1.5 g/day; 30

days

L. helveticus, B. longum 3x109

CFU/g

HADS-D

Shinkai,

2013, Japan

Adults aged 65

years or older, 278

One capsule

per day, 20 wk

L. pentosus strain, low-dose =2 x109

CFU/g, high-dose =2x1010

CFU/g

Profile of Mood

States (POMS):

*See appendix F for forest plot of meta-analysis

II. Literature review of individual studies50-52

Table 6. Steenberg et al. A randomized controlled trial to test the effect of multispecies probiotics on

cognitive reactivity to sad mood. Brain, Behavior, and Immunity 2015;48:258-64.

Study Design Randomized, placebo-controlled, triple blind, pre-and post-intervention study (The Netherlands)

Objective To test if a multispecies probiotic may reduce cognitive reactivity in non-depressed patients

Participants Inclusion criteria

Non depressed male and female subjects

Exclusion criteria

Psychiatric or neurologic disorders, family

history of depression or migraines

Smokers

Reported cardiac, renal, or hepatic conditions

More than 3-5 alcoholic units/week

Methods/

Intervention Participants received a 4-week food supplementation intervention of either placebo or probiotics

Pre and post intervention assessments were provided to each participant

Compliance was facilitated by reminding participants via daily text message

Probiotic

intervention Bifidobacterium bifidum, B. lactis, Lactobacillus acidophilus, L. brevis, L. casei, L. salivarius,

and Lactococcus lactis (multispecies product known as Ecologic Barrier® with 2.5x10

9 CFU/g)

Each sachet contained 2g freeze dried powder of probiotic mixture to consume daily

9 | S a c k e y

Outcomes Primary: assess change in cognitive reactivity after 4 week probiotic therapy

o Measured by cognitive reactivity: LEIDS-r

Secondary: assess effect on depression and anxiety

o BDI, Beck Anxiety Inventory (BAI)

Statistical

analysis Mean scores of assessments evaluated using ANOVA with time (pre- vs. post-intervention) as

within-subjects factor and group (placebo vs. probiotics) as between subjects factor

Alpha set at 0.05

Results

Baseline characteristics

o 40 patients were included

o No significant group differences were observed for age and gender distribution

(p=0.45 and 0.43 respectively)

Table 1. Patient demographics

Placebo Probiotics

N (M:F) 20 (3:17) 20 (5:15)

Age (years) 19.7 (1.7) 20.2 (2.4)

Body Mass Index (SD) 21.5 (2.0) 22.6 (2.3)

Outcomes

o Significant time by group interactions for LEIDS-r total score (p=0.019) and

aggression (p=0.032) and rumination (p=0.001) subscale for probiotic group

o BDI total score and BAI revealed no main effect of time, group, nor time by group

interaction for both placebo and probiotic groups

Table 2. Assessment score outcomes

Pre-intervention Post-intervention P-value

LEIDS-r (SD) Placebo 44.70 (3.24) 42.30 (3.51) 0.63

Probiotics 42.75 (3.24) 33.35 (3.51) 0.01

BDI (SD) Placebo 9.10 (1.00) 9.10 (1.19) 0.31

Probiotics 7.90 (1.00) 7.25 (1.19) 0.52

BAI (SD) Placebo 12.21 (1.70) 11.21 (1.69) 0.64

Probiotics 11.35 (1.66) 9.95 (1.65) 0.14

-40%

-30%

-20%

-10%

0%

10%

20%

30%

Per

cen

t C

han

ge

in B

ase

lin

e S

core

s

Subscales

Placebo

Probiotics

* *

*

*Significant change from baseline (p<0.05)

Figure 1. LEIDS-r percent change in baseline subscale scores

Table 6 continued.

10 | S a c k e y

Author’s

Conclusion

4-week administration of probiotics significantly reduced overall cognitive reactivity to

depression and in particular aggressive and ruminative thoughts

Critique Strengths

RCT with triple blinding

Assessed effects of probiotics

on pre-depressive symptoms

Viability and stability testing

conducted on probiotic mixtures

Weakness

LEIDS-r is not a well validated tool

Dietary measures were not included

Compliance was not confirmed

Not generalizable to males

Multiple species used; unclear which may have effect

Small sample size

Short duration of study

Limited baseline characteristics and statistical analysis

Take home

points

Mixed probiotic species (containing lactobacillus and bifidobacterium species) may have a

preventative role in non-depressed patients by reducing cognitive reactivity (specifically

aggressive and ruminative thoughts); unclear effects on patients with a diagnosis of MDD

Table 7. Akkasheh G, et al. Clinical and metabolic response to probiotic administration in patients with

major depressive disorder. Nutrition 2016;32(3):315-20

Study Design Randomized, double-blind, placebo-controlled trial (Iran)

Objective To investigate whether probiotics improved mood, stress and anxiety in a patients with MDD and

assess whether inflammatory and metabolic biomarkers would predict or impact treatment

Participants Inclusion criteria

Diagnosis of MDD (per DSM-IV criteria, ≥

15 on HAM-D 17 item)

Exclusion criteria

Age <20y/o or >55y/o

History of coronary infarction or angina

pectoris

Pregnancy or lactation

Substance abuse

Taking dietary supplements or probiotic

supplements during previous 2 months

Methods/

Intervention Placebo vs. probiotic treatment for 8 weeks

Patients requested not to change routine physical activity, usual diet, or consume outside

supplementation products (dietary and physical activity records taken at weeks 2, 4, and 6)

Compliance to probiotic and placebo capsules monitored by asking participants to return the

medication containers at end of study

Probiotic

intervention Daily capsule containing Lactobacillus acidophilus (2x10

9 CFU/g), L. casei (2x10

9 CFU/g), and

Bifidobacterium bifidum (2x109 CFU/g)

Provided by Tak Gen Zist (Iranian pharmaceutical company) and approved by Iranian FDA

Outcomes

and

Measurement

Primary: assess change in mood as measured by BDI administered at baseline and end of study

Secondary: assess effect on metabolic and inflammatory components including:

o Fasting plasma glucose (FPG), homeostasis model of assessment in insulin resistance

(HOMA-IR), homeostasis model of assessment of β-cell function (HOMA-B), quantitative

insulin sensitivity check index (QUICKI), lipid concentrations, high-sensitivity C-reactive

protein (hs-CRP), total antioxidant capacity (TAC), and glutathione (GSH) levels

Statistical

analysis Power set at 80% (requiring 17 patients in each group); alpha set at 0.05

Intention-to-treat; missing values handled based on the last-observation-carried forward method

Independent sample t-test to detect differences in general characteristics and dietary intakes

One-way repeated measures analysis of variance was used to determine the effects of probiotic

administration on metabolic factors

Within-group comparisons (endpoint vs. baseline) were done using paired-samples t-test

Analysis of covariance was used to control for confounders

Table 6 continued.

11 | S a c k e y

Results Demographic characteristics

o 40 total patients evaluated (6 withdrew for personal reasons); compliance >90%

o Baseline and end of trial mean weight and BMI not significantly different in groups

o No significant differences in dietary intake between two groups

Table 1. General characteristics of study participants

Characteristics Placebo (n=20) Probiotics (n=20) P-value

N (M:F) 3:17 3:17 1.00

Age (y) 36.2 ± 8.2 38.3 ± 12.1 0.52

Baseline weight (kg) 68.7 ± 11.5 72.6 ± 11.3 0.21

End of trial weight (kg) 68.7 ± 10.5 72.5 ± 11.1 0.28

Weight change (kg) 0.7 ± 2.7 -0.1 ± 1.6 0.26

Baseline BMI (kg/m2) 26.3 ± 4.1 27.6 ± 6.0 0.42

End of trial BMI (kg/m2) 26.5 ± 3.9 27.5 ± 5.9 0.53

BMI change (kg/m2) 0.2 ± 1.0 -0.1 ± 0.6 0.23

Primary outcome (depression)

o Probiotic group had significantly decreased BDI total score compared to placebo

(-5.7 ±6.4 vs. -1.5 ± 4.8, p=0.001)

o BDI scores were not significantly different after controlling for confounders (p=0.05)

Secondary outcomes (metabolic)

o Those on probiotics had significant decrease in insulin resistance scores (HOMA-IR),

and hs-CRP, and increase GSH compared to placebo

o No significant change in FPG, cholesterol levels, TAC, and beta-cell function

(HOMA-B), and insulin sensitivity index (QUICKI)

Table 2. Adjusted changes in metabolic variables with MDD from baseline

Variables Placebo group Probiotic group P-value

BDI total score -1.8±1.2 -5.3±1.2 0.05

FPG (mg/dL) -1.5±1.7 -1.2±1.7 0.92

Insulin (μIU/mL) 2.5±1.6 -2.2±1.6 0.05

HOMA-IR 5.4±0.4 -0.6±0.4 0.04

HOMA-B 9.9±6.5 -7.2±6.6 0.08

QUICKI -0.001±0.005 0.007±0.005 0.17

Total Cholesterol (mg/dL) -2.8±4.6 -3.2±4.6 0.96

hs-CRP (ng/mL) 188.5±378.2 -1138.9±378.2 0.01

TAC (mmol/L) -21.1±22.9 -10.6±22.9 0.75

GSH (μmol/L) -101.6±33.2 -3.4±33.2 0.04

Author’s

Conclusion

Probiotic supplementation improved the BDI score, insulin function, and decreased oxidative

stress in patients with MDD

Critique Strengths

Double blind RCT

Power analysis

Assessed potential effects on

metabolic factors

Adjusted for confounders

Viability and stability testing

conducted on probiotics

Weakness

Did not characterize severity of depression at baseline

No information on current antidepressant treatment (i.e.

medications, psychotherapy)

Multiple species used; unclear which has direct benefit

May not be generalizable to males

Not generalizable to substance abuse patients

Small sample size; long term efficacy/safety not established

Take home

points Mixed probiotic species containing lactobacillus and bifidobacterium as adjunct to regular

therapy in MDD patients provide only modest reduction in depressive symptoms

Additional benefits on metabolic factors, inflammatory markers, and oxidative stress may

describe potential mechanistic pathway of probiotics in altering mood symptoms

Table 7 continued.

12 | S a c k e y

Table 8. Romijn A, et al. Lactobacillus helveticus and Bifidobacterium longum for the symptoms of

depression. Aust N Z J Psychiatry 2017 Jan 1:4867416686694.

Study Design Randomized, double-blind, placebo-controlled trial (Australian and New Zealand)

Objective To assess for potential favorable effects of probiotic monotherapy on symptoms of depression and

inflammatory markers in patients with MDD

Participants Inclusion criteria

Either ≥11 on the QIDS assessment or ≥14 on

the depression subscale of the Depression,

Anxiety and Stress Scale (DASS-42)

Age ≥16 at the time of screening

Free of any psychiatric medication for at least

4 weeks prior to trial

Exclusion criteria

Any neurological disorder, renal, hepatic,

cardiovascular or respiratory disease

Any serious medical condition with major

medical intervention anticipated in trial

Pregnancy or breastfeeding

Use of any supplement considered potentially

antidepressant (e.g. St John’s Wort, 5-HTP)

Serious risk of suicide or violence

Current or recent antibiotic use

Methods Placebo vs. probiotic treatment for 8 weeks

Patients were to avoid any probiotic supplements during trial

May continue psychotherapy if receiving for ≥6 months prior to trial

Compliance measured by post-study sachet counts

Probiotic Sachet containing freeze dried L. helveticus and B. longum (3x109 CFU per 1.5g)

Stability and viability testing conducted on probiotic species

Outcomes

and

Measurement

Primary

o MADRS and improved Clinical Global Impressions (iCGI) at baseline and week 8

o QIDS-SR16 score at baseline and every 2 weeks

Secondary

o Global Assessment of Functioning (GAF) at baseline and week 8

o DASS-42 at baseline and week 8

o Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS) at baseline and week 8

o Inflammatory biomarkers (hs-CRP, IL-1β, IL-6, TNF-α, BDNF)

o Vitamin D at baseline and week 8

Statistical

analysis Power was set at 80% (requiring 40 patients in each group); alpha set at 0.05

Baseline variables compared between treatment groups using t-tests, chi square analysis, and

Mann–Whitney U tests

Changes from baseline to the end of treatment compared using analysis of covariance

(ANCOVA), with the baseline level as the covariate

Changes in assessment scales (i.e. iCGI) using ANOVA

Primary analysis conducted with intent-to-treat approach

Secondary analyses through per protocol (requires ≥80% compliance)

13 | S a c k e y

Results Baseline characteristics

o 79 total patients evaluated (7 dropped from probiotic group; 3 dropped from placebo)

o Significantly higher self-report of antidepressant use in probiotic group (70%) vs.

placebo (46%) p < 0.05

o Probiotic group with significantly higher IBS-SSS at baseline than placebo (p < 0.05)

o No significant differences in other baseline characteristics including socioeconomic

status, education, ethnic origin, psychiatric history and baseline MADRS score

Table 1. Selected general characteristics of study participants

Characteristics Probiotic (n=40) Placebo (n=39)

Age, years, mean (SD) 35.8 (14) 35.1 (14.5)

Male, n (%) 8 (20) 9 (23)

Baseline MADRS score, mean (SD) 28.3 (6.1) 27.0 (6.3)

Chronic low mood, n (%)a,b 31(78) 24 (62)

Alcohol/substance misuse or dependence, n (%)b

Current

Past

4 (10)

6 (15)

1 (3)

8 (21)

Any co-occurring psychiatric disorder, n (%)b

Current

Past

23 (57)

24 (60)

18 (46)

21 (54)

History of antidepressant use, n (%)b 28 (70) 18 (46)*

aChronic depression defined as >2 years continuous symptoms of current episode of low mood bEstablished using self-report and retrospective chart review

*significant differences (p < 0.05)

Primary outcome (mood and psychological functioning)

o No significant group differences on any outcome measure with intent-to-treat analysis

(n=79) and per-protocol sample (n=69)

o After 8 weeks, 9 (23%) in probiotic group showed a ≥60% change on MADRS compared to

10 (26%) in placebo group (p = 0.62)

Secondary outcomes (inflammatory biomarkers)

o No significant group differences observed in change of any biomarkers over trial period

o Significant interaction between vitamin D and QIDS-SR16, iCGI, and GAF for probiotic

group only high vitamin D level = greater improvement in mood

Significant group differences in number of adverse events (sleep disturbance, dry mouth), with

both occurring in placebo group (p < 0.05); 3 suicide attempts by one patient in placebo group

Overall 97% compliance rate; similar rates observed between groups

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

MADRS iCGI QIDS-SR16 GAF DASS

Per

cen

t C

han

ge

from

Base

lin

e

Assessment Scale*

Probiotics

Placebo

*No significant differences observed

Figure 1. Percent change of assessment scores from baseline

Table 8 continued.

14 | S a c k e y

Conclusions

I. Summary1-9, 31, 47-52

a. Depressive disorders, specifically MDD, continue to be a cause of high morbidity in the U.S.

and limitations exist with conventional pharmacotherapy

b. Physiological link between GI and CNS allows for evaluation of probiotics in the

management of depressive disorders

i. Lactobacillus and bifidobacterium species most implicated

ii. Probiotics may have preventative role in depressive symptoms (specifically cognitive

reactivity) and as adjunct to conventional therapy in MDD, however limited role as

monotherapy in MDD patients

iii. Mechanism may involve metabolic and inflammatory pathways with influences by

vitamin D levels

c. Limitations to probiotic use

i. Regulation of products

ii. Identification of specific species and optimal combination

iii. Long term safety and efficacy in depression not evaluated

iv. Unclear of effects in elderly population

v. Paucity of data current studies not robust

II. Recommendations

a. Probiotics cannot be recommended as monotherapy for MDD patients at this time

b. May consider probiotics containing ≥2.5x109/g of lactobacillus and bifidobacterium species

in the following scenarios:

i. As adjunct with conventional pharmacotherapy in individuals with MDD who

experience inadequate response to an adequate trial of agent (see table 1 & figure 5)

1. May particularly consider in individuals with suspected dysbiosis due to

chronic conditions (i.e. IBS/IBD, chronic antibiotic use, diet)

2. Trial of probiotics should be at least 8 weeks

ii. If probiotics is indicated for a patient (i.e. chronic C. diff) then consider species

containing ≥2.5x109/g of lactobacillus and bifidobacterium in those who may be at-

risk for depression (i.e. family history)

Author’s

Conclusion

No evidence that the probiotic formulation is effective in treating low mood, or in moderating

the levels of inflammatory and other biomarkers

Critique Strengths

Double blind RCT

Power analysis

More comprehensive baseline characteristics

Included substance abuse patients

Evaluated baseline psychiatric status

Assessed safety

Viability and stability testing conducted

Weakness

Dietary intake and physical activity was not

accounted for

Recruited via self-referrals, MDD diagnosis

not confirmed at baseline

Long term efficacy/safety not established

Higher proportion of previous AD use in

probiotic group (↑ treatment resistance?)

Ethics? (multiple suicide attempt in a patient)

Take home

points Probiotics (specifically containing bifidobacterium and lactobacillus species) may not be

effective in improving mood as monotherapy for patients with MDD

Potential moderating effect of vitamin D on treatment response (↓ levels = ↓ response)

Table 8 continued.

15 | S a c k e y

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17 | S a c k e y

Appendices

Appendix A. Drug and disease induced depression3,5

Disease-Induced Depression Drug-Induced Depression

Hypothyroidism

Diabetes (2 folds ↑ odds)

Severe anemia

Parkinson’s Disease

HIV/AIDS

Alzheimer’s Disease

Multiple Sclerosis

Wernicke’s Encephalopathy

CHF

Chronic Pain

Interferons

Barbiturates

Opioids

Stimulant withdrawal (i.e. cocaine)

Reserpine

Clonidine

Efavirenz

Methyldopa

Varenicline

Steroids HIV/AIDS= Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

CHF=Congestive Heart Failure

Appendix B. Classification and specifiers of MDD3,8

Classification/Current Status

A. Severity of episode a. Mild = 5-6 depressive symptoms and minimal functional impairment

b. Moderate = 7-8 depressive symptoms and moderate functional impairment

c. Severe = nearly all symptoms (≥7) with significant impairment in functioning

B. Presence of psychotic features a. Episode characterized by delusions or hallucinations (usually auditory)

b. Mood-congruent (during depressive moods) or mood-incongruent (no association with mood)

C. In remission a. Full remission = absence of significant symptomatology for ≥ 2 months

b. Partial remission = continued presence of some symptoms but still criteria not met or symptoms no longer

present but duration <2 months

D. Chronic a. Full criteria for major depressive episode met for ≥ 2 years

Descriptive Specifiers

I. With Anxious Distress present with symptoms of anxiety (i.e. tension, restlessness, etc.)

II. With Mixed Features at least 3 symptoms of mania for most days but does not meet criteria for bipolar

III. With Catatonic Features present with profound purposeless psychomotor changes and abnormal movements

IV. With Melancholic Features severe form characterized by lack of reactivity to pleasurable stimuli

V. With Atypical Features characterized by unique features such as mood reactivity, hypersomnia, ↑appetite

VI. With Peripartum Onset onset of symptoms occurs during pregnancy or within 4 wks after childbirth

VII. With Seasonal Pattern Recurrent MDD w/ mood episodes occurring repeatedly at specific times of the year

18 | S a c k e y

Appendix C. Depression rating scales3,8-10

Scale Name Assessment

Type

Description/Clinical Pearls Depression Severity Scoring

None/Minimal Mild Moderate Severe/Very Severe

Hamilton Depression

Rating, 17 item Scale

(HAM-D)

Clinician rated Commonly used in clinical trials to assess symptom

severity over past week (including somatic symptoms)

Gold standard for clinical research

0-7

8-13

14-19

20-25 (severe)

≥26(very severe)

Montgomery-Asberg

Depression Rating Scale

(MADRS)

Clinician rated Commonly used in clinical trials; less emphasis on somatic

symptoms than HAM-D

May be more sensitive to drug treatment than HAM-D

0-8

9-17

18-34

≥35

Quick Inventory of

Depressive

Symptomatology (QIDS)

Clinician

rated; self-

rated version:

(QIDS-SR)

Used in both clinical trials and clinical practice

Assesses 9 core DSM-5 depressive symptom domain

Results highly correlated with HAM-D

Most common is 16-item Self rated version (SR-16)

<6

6-10

11-15

16-20 (severe)

≥21 (very severe)

Patient Health

Questionnaire-9

(PHQ-9)

Self-rated Used in both clinical trials and clinical practice

Report of symptom frequency over past 2 weeks

Can be used as diagnostic tool for MDD

1-4

5-9

10-14

15-19 (mod. severe)

20-27 (Severe)

Beck Depression Inventory

(BDI)

Self-rated Used in both clinical trials and clinical practice

Patient symptoms and attitudes over past 2 weeks

0-9

10-18

19-29

30-63

Other rating scales

Scale Name Description/Clinical Pearls Scoring

Hospital Anxiety and

Depression Scale (HADS)

Clinician rated Used in clinical trials as measure of psychological distress

in non-psychiatric patient populations

Developed to distinguish mood symptoms (anxiety and

depression) from somatic symptoms

Not intended to diagnose depression or anxiety

Less validated than aforementioned rating scales

Total Scoring conducted for both anxiety & depression subscale

o 0-7 = Normal

o 8-10 = Borderline abnormal

o 11-21 = Abnormal Case

Leiden Index of

Depression Sensitivity-

Revised (LEIDS-r)

Self-rated Found to predict depression incidence in multiple

longitudinal studies and correlate with depression risk

factors (i.e. depression history, genetic markers, reaction to

tryptophan depletion)

Not intended to diagnosis or assess severity of depression

but rather predict development of clinical depression or

disease relapse (↑ scores = ↑ risk)

Relatively new scale and less validated

34 item with 6 subscales

5 point likert scale (max score of 24 for each scale)

Higher scores for each subscale indicate worse prognosis

o Aggression

o Control

o Hopelessness

o Risk Aversion

o Rumination

o Acceptance

19 | S a c k e y

Appendix D. Conventional antidepressant agents11,12

Agents Common ADEs Treatment Considerations

SSRIs: Increase synaptic 5HT through inhibition of serotonin transporter (SERT)

Fluoxetine

Citalopram

Escitalopram

Sertraline

Paroxetine

GI discomfort (esp. sertraline),

insomnia (esp. fluoxetine),

sexual dysfunction, weight

gain, platelet aggregation,

headache, SIADH

Little difference in efficacy between agents

Best balance of tolerability and efficacy amongst all ADs

May experience anxiety/agitation during initial therapy

Risk of withdrawal syndrome correlated with t1/2

Risk of QTc prolongation (highest with citalopram)

SNRIs: Increase synaptic 5HT and NE through inhibition of Norepinephrine (NET) and SERT

Duloxetine

Venlafaxine

Desvenlafaxine

Levomilnacipram

Similar to SSRIs, additionally:

increased sweating, more

cardiovascular concerns

NE activity provides analgesic properties

Monitor BP with dose escalation

Avoid duloxetine use in ESRD and liver disease

TCAs: Increase synaptic 5-HT and NE primarily through SERT and NET activity; additional α-adrenergic receptor blockade

Amitriptyline

Clomipramine

Desipramine

Doxepin

Imipramine

Anticholinergic ADEs (dry

mouth, constipation), sexual

dysfunction, sedation,

orthostatic hypotension,

cardiotoxicity, seizures

Evidence to suggest highest efficacy compared to other

antidepressants however poor tolerability

Mostly used for other indications (i.e. analgesia, insomnia, enuresis)

All contraindicated with a recent myocardial infarction

Risk of lethal overdose due to cardiotoxic effects

MAOIs: Irreversibly inhibit MAOs, allowing norepinephrine, serotonin, and dopamine to accumulate in the synaptic cleft

Isocarboxazid

Phenelzine

Selegiline

Tranylcypromine

Hypoglycemia, headache

dizziness, tremors, insomnia,

agitation, liver toxicity, GI

discomfort, seizures

Considered 3rd

or 4th

line due to tolerability concerns and interactions

Risk of hypertensive crisis with use of other sympathomimetic

amines (OTC decongestants, antidepressants, stimulants) and

tyramine containing foods (i.e. aged cheese, alcoholic beverages)

Aminoketone: Inhibits DA and NE reuptake & minimal effects on 5-HT

Bupropion GI disturbance, weight loss,

insomnia, headache, anxiety,

hypertension, dry mouth,

seizures (0.1-0.4%)

Contraindicated in patients with seizure disorders, history of

bulimia/anorexia

May improve sexual dysfunction

Decreases tobacco cravings

Beneficial in patients with concentration issues

Triazolopyridines: Weak SERT and NET inhibitors, weak α1 antagonism; 5-HT2A antagonism, partial agonism at 5-HT1A

Trazodone

Nefazodone

Orthostasis, nausea,

constipation, dry mouth,

blurred vision, headache

Trazodone mainly used at low doses (50-200mg) for insomnia and

sleep disturbances in patients with depression

Higher doses of trazodone (400-600mg) for sufficient AD activity

Nefazodone black box warning for life-threatening liver failure

Priapism rare but serious (particularly at higher doses)

Tetracyclics: Antagonize presynaptic increase NE and 5-HT; inhibits 5-HT2A, 5-HT3, and 5-HT2C; agonizes 5-HT1A

Mirtazapine Sedation, increased appetite,

weight gain, dry mouth

hypertriglyceridemia

Evidence to suggest AD activity observed only at doses ≥15mg

Little to no risk of sexual dysfunction

Weight and triglycerides monitoring at baseline & periodically

Serotonin modulators: SSRI with partial 5-HT1A agonism; vortioxetine also partial 5-HT1B agonist & antagonist at 5-HT3

Vilazodone

Vortioxetine

Similar to SSRIs, nausea and

diarrhea common (19-36%),

dry mouth

Lack of data suggesting superior efficacy over SSRIs

Vilazodone associated with more GI concerns (nausea, vomiting)

than vortioxetine

20 | S a c k e y

Appendix F: Forest Plot from Huang et. al Meta-Analysis on probiotics and depression47

Appendix E. Behavioral changes following probiotic treatment in pre-clinical studies40-45

Reference Model Used Behavioral Tests Conclusions

Desbonnet, et al.,

2010

Probiotic trial in mouse

model of maternal

separation (B. infantis)

compared to citalopram

Forced swim test B. infantis reversed behavioral deficits

caused by maternal separation,

normalization of immune response and

monoamine levels; outcomes similar to

citalopram

Messaoudi, et al.,

2011

Probiotic trial in rats and

humans (L. helveticus and

B. longum)

Rats: Conditioned defensive burying

test; Humans: Hopkins Symptom

Checklist; Hospital Anxiety and

Depression Scale; Perceived Stress

Scale; Coping

Probiotic combination of L. helveticus

and B. longum reduced anxiety-like

behavior in rats and had a beneficial

effect on signs of anxiety and depression

in humans

Bravo et al.,

2011

Probiotic trial in mice (L.

rhamnosus)

Stress-induced hyperthermia;

elevated plus maze; fear conditioning;

forced swim test; open field test

Administration of L. rhamnosus reduced

anxiety and depression-related behaviors

Ait-Belgnaoui,

et al.,2012

Probiotic treated in rat

model (L. farciminis)

Partial restraint stress test Probiotic treatment attenuated the HPA

response to acute stress

Ohland, et al.,

2013

Probiotic trial in mice on

standard chow or Western

diet (L. helveticus)

Barnes maze Efficacy of L. helveticus on the

reduction of stress and anxiety is

dependent on diet

Ait-Belgnaoui,

et al., 2014

Probiotic treated mouse

model (L. helveticus and

B. longum)

Water avoidance stress test Pretreatment with probiotics can reduce

chronic-stress induced abnormal brain

plasticity and reduce neurogenesis