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Effects of a standardized extract of Withania somnifera (Ashwagandha) on depression and anxiety symptoms in persons with schizophrenia participating in a randomized, placebo-controlled clinical trial

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Background: Extracts of Withania somnifera (WSE), or Ashwagandha, has traditionally been used as an adaptogen in Ayurvedic medicine, and evidence suggests that it may have efficacy in the treatment of psychiatric disorders, including schizophrenia. This secondary analysis reviewed change in depression and anxiety symptoms in a study using WSE as an adjunctive treatment in patients with schizophrenia experiencing an exacerbation of positive symptoms. Methods: We enrolled patients with schizophrenia in a 12-week, randomized, placebo-controlled, double-blind study. Active treatment was with 1,000 mg of standardized WSE. This analysis reviewed outcomes for 66 patients with depression and anxiety symptoms by examining the singleitem depression and anxiety-depression cluster subscores extracted from the Positive and Negative Syndrome Scale. Results: Medium effect sizes of 0.683 (95% confidence interval [CI], 0.16 to 1.21) and 0.686 (95% CI, 0.16 to 1.21) favoring WSE over placebo were observed for depression single-item and anxiety-depression cluster scores, respectively. Adverse events were mild and transient. Conclusions: Our findings suggest that WSE may hold promise in the treatment of depression and anxiety symptoms in schizophrenia. While the mechanism of its clinical efficacy requires more exploration, the data suggest.
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ANNALS OF CLINICAL PSYCHIATRY
AACP.com Annals of Clinical Psychiatry | Vol. 31 No. 2 | May 2019 123
ANNALS OF CLINICAL PSYCHIATRY 2019;31(2):123-129 RESEARCH ARTICLE
BACKGROUND: Extracts of Withania somnifera (WSE), or Ashwagandha,
has traditionally been used as an adaptogen in Ayurvedic medicine, and
evidence suggests that it may have efficacy in the treatment of psychiat-
ric disorders, including schizophrenia. This secondary analysis reviewed
change in depression and anxiety symptoms in a study using WSE as an
adjunctive treatment in patients with schizophrenia experiencing an
exacerbation of positive symptoms.
METHODS: We enrolled patients with schizophrenia in a 12-week, random-
ized, placebo-controlled, double-blind study. Active treatment was with
1,000 mg of standardized WSE. This analysis reviewed outcomes for 66
patients with depression and anxiety symptoms by examining the single-
item depression and anxiety-depression cluster subscores extracted from
the Positive and Negative Syndrome Scale.
RESULTS: Medium effect sizes of 0.683 (95% confidence interval [CI], 0.16
to 1.21) and 0.686 (95% CI, 0.16 to 1.21) favoring WSE over placebo were
observed for depression single-item and anxiety-depression cluster
scores, respectively. Adverse events were mild and transient.
CONCLUSIONS: Our findings suggest that WSE may hold promise in the
treatment of depression and anxiety symptoms in schizophrenia. While
the mechanism of its clinical efficacy requires more exploration, the data
suggest that WSE may treat a broad spectrum of symptoms in exacerbated
schizophrenia.
Effects of a standardized extract of Withania
somnifera (Ashwagandha) on depression
and anxiety symptoms in persons with
schizophrenia participating in a randomized,
placebo-controlled clinical trial
CORRESPONDENCE
Jessica M. Gannon, MD
Western Psychiatric Institute and Clinic
University of Pittsburgh Medical Center
3811 O’Hara Street
Pittsburgh, PA 15213 USA
E-MAIL
gannonjm@upmc.edu
Jessica M. Gannon, MD
Western Psychiatric Institute and Clinic
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, USA
Jaspreet Brar, MBBS, MPH, PhD
Western Psychiatric Institute and Clinic
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, USA
Abhishek Rai, MD
University of Pittsburgh Medical Center
Northwest
Seneca, Pennsylvania, USA
K. N. Roy Chengappa, MD, FRCPC
Western Psychiatric Institute and Clinic
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, USA
WITHANIA SOMNIFERA, DEPRESSION, ANXIETY, AND SCHIZOPHRENIA
May 2019 | Vol. 31 No. 2 | Annals of Clinical Psychiatry124
INTRODUCTION
Depression and anxiety symptoms are common in
schizophrenia. Most patients with schizophrenia have
had an episode of depression, with up to 80% of patients
experiencing depression during the early course of ill-
ness.1 While depression can occur during the chronic
stages of schizophrenia, it may be most prevalent in
acute exacerbations, and the incidence of depression
in this stage is estimated to range from 22% to 80%.2
Anxiety, too, is common in schizophrenia, and nearly
40% of patients have a comorbid anxiety spectrum dis-
order.3 Anxiety can also accompany depressive symp-
toms in schizophrenia and is common in acute episodes
of psychosis.
While antipsychotics alone may relieve depression
and anxiety in acute and post-psychotic depressive epi-
sodes, especially when combined with psychosocial
interventions, antidepressant initiation is often recom-
mended if symptoms persist,2,4 although evidence to
support this practice is mixed.5-8 Limited evidence sug-
gests that treatment of anxiety disorders comorbid with
schizophrenia with selective serotonin reuptake inhibi-
tors (SSRIs) can be effective9; less is known about effec-
tive treatment of anxiety emerging in acute psychosis.
Treatment avenues for depression and anxiety symp-
toms in schizophrenia deserve further investigation.
Individuals with schizophrenia and depressive symp-
toms have poor outcomes in multiple domains, includ-
ing high utilization of mental health services as well as
increased rates of substance use and forensic involve-
ment.1,10 Depression is a known precursor to suicide in
patients with schizophrenia,11 and rates of completed
suicide in schizophrenia hover around 7%.12
Withania somnifera is a medicinal plant whose
extracts have been long used in Ayurvedic medicine, and
recent clinical trials suggest that extracts of this plant could
be useful in the treatment of mental illness, especially for
patients with anxiety or depression.13-15 We conducted a
randomized, double-blind, placebo-controlled trial of
a standardized extract of Withania somnifera (WSE) in
patients with schizophrenia who had experienced a recent
exacerbation in psychotic symptoms. Withania som-
nifera extract was well tolerated and resulted in signifi-
cant improvements for negative and general symptoms.16
This report represents an analysis of secondary outcomes
of this parent study, exploring our hypothesis that ben-
efits in general psychopathology (symptoms other than
positive and negative symptoms of schizophrenia) scores,
as measured by the Positive and Negative Syndrome Scale
(PANSS),17 with WSE are reflected by improvements in
depression and anxiety symptoms.
METHODS
We conducted secondary outcomes analyses of a
12-week, double-blind, randomized, placebo-controlled
trial of a standardized WSE (Sensoril), used as an adjunc-
tive treatment to antipsychotics, in 66 participants with
recent exacerbations in positive symptoms of established
schizophrenia spectrum disorders,16 focusing on the
potential antidepressant and anxiolytic effects of WSE.
Briefly, female or male outpatients age 18 to 75, of
any race, with a DSM IV-TR diagnosis of schizophrenia
or schizoaffective disorder were recruited and provided
written informed consent. Symptom exacerbation had to
extend ≥2 weeks but ≤1 year. Participants were enrolled
only if their PANSS total score was ≥60, with a score ≥5 on
any 1 item or ≥4 on any 2 items of the positive symptom
cluster or unusual thought content. Inclusion criteria
also specified that participants had to be receiving a sta-
ble dose of antipsychotic agents for ≥4 weeks. Exclusion
criteria included pregnancy or breastfeeding, illicit drug
use (marijuana and alcohol use were allowed on a case-
by-case basis), unstable medical disorders, and known
allergy to WSE.
The study comprised a 1- to 2-week screening period,
and a 12-week treatment period for each patient; it was
registered at ClinicalTrials.gov (Identifier: NCT01793935)
and approved by the Institutional Review Board of the
University of Pittsburgh. Participants were randomized
to WSE or placebo. The WSE capsules were standardized
and each contained 250 mg of the extract. The placebo
capsules had the same fill weight as the WSE but only
included inactive ingredients; the placebo capsules were
exposed to cloth pouches containing WSE powder to
make them smell like the WSE capsules.
The active group received 250 mg of WSE by mouth
twice a day for a total dose of 500 mg/d for the first week.
This was titrated to 500 mg twice daily (1,000 mg/d) at
Week 2 and then maintained for the duration of the study.
Medication dosage could be lowered based on patient
tolerability. Pill counts and medication reconciliation
were completed at each of the study’s 6 visits to monitor
for adherence. Any ongoing psychotropic medications
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ANNALS OF CLINICAL PSYCHIATRY
125
(eg, antidepressants, anti-anxiety and hypnotic agents)
were continued.
Primary outcomes were assessed using the PANSS
total, positive, negative, and general symptoms scores.
These assessments were conducted at each study visit.
For the secondary outcomes, the PANSS single-item
depression score was isolated to determine outcomes
for depressed mood, as was the PANSS anxious/depres-
sion cluster, which encompasses PANSS items of somatic
concern, anxiety, guilt feelings, and depression, similar to
work done by previous research groups studying depres-
sion and anxiety symptoms in patients with psychoses.18
Homogeneity of treatment groups at baseline for
demographic and illness variables, and for antipsy-
chotic and other psychotropic medications, was estab-
lished by examining the efficiency of randomization.16
Independent t-tests were used to examine differences
in the mean change scores from baseline to end of treat-
ment, for depression single-item score, and the anxiety-
depression scores between WSE and placebo groups.
Significance levels were estimated using an alpha set at
.05. The size of the treatment effect was computed using
Cohen’s d using the difference in means from baseline
to endpoint, between WSE and placebo, divided by the
pooled standard deviation.
RESULTS
None of the illness, demographic, or medication char-
acteristics differed significantly between the WSE and
placebo groups.16 The mean duration of symptoms
exacerbation was 16 weeks at the time of trial inclusion.
Patients were, on average, in their 40s, had ≥7 lifetime
hospitalizations over at least 20 years of illness, and
had a DSM-IV-TR diagnosis of schizophrenia (61%).
The remainder (39%) had a DSM-IV-TR diagnosis of
schizoaffective disorder. Most patients were prescribed
1 atypical antipsychotic agent; daily olanzapine equiva-
lents were similar between groups.19 Other psychiatric
medications, including antidepressants, mood stabiliz-
ers, anxiolytics, hypnotic/sedatives and anticholiner-
gic agents, were evenly distributed between treatment
groups. There were no significant changes in these med-
ications during the study period between groups.16 Two
participants randomized to WSE had SSRIs decreased
or stopped; no antidepressant changes were noted in
the placebo group. One placebo participant had their
anti-anxiety medication stopped, while another had
their medication increased, but no such changes were
made in the WSE group.
There were no significant differences at baseline
between the 2 treatment groups for either the depres-
sion single-item score or for the anxiety-depression
cluster score. At the end of WSE treatment, the mean
improvement score for the depression single-item was
significantly better at 0.71 ± 0.97 than for placebo, 0.06
± 0.93. Mean change anxiety-depression cluster scores
for patients who received WSE were also significantly
higher (2.86 ± 2.56) than were mean change scores for
patients who received placebo (1.19 ± 2.32) (TABLE and
FIGURE 1). Medium treatment effect sizes of 0.683 (95%
confidence interval [CI], 0.16 to 1.21) and 0.686 (95% CI,
0.16 to 1.21) favoring WSE over placebo were observed
for depression single-item and anxiety-depression clus-
ter scores, respectively.
TABLE
PANSS depression and anxiety symptoms scores, baseline to end of treatment
WSE Placebo
Measure Baseline
n = 33
End of treatment
n = 28
Baseline
n = 33
End of treatment
n = 31
Statistics
Depression
single-item,a
mean ± SD
2.85 ± 0.94 2.25 ± 0.89 2.79 ± 0.93 2.71 ± 1.16 t = 2.62
df = 57
P = .011
Depression
anxiety cluster,b
mean ± SD
11.30 ± 2.82 8.89 ± 2.15 11.33 ± 2.59 9.97 ± 2.92 t = 2.62
df = 57
P = .011
aScore from the depression single-item of the PANSS.
bScore from the depression-anxiety cluster of the PANSS, which includes somatic concern, anxiety, guilt feelings, and depression.
PANSS: Positive and Negative Syndrome Scale; SD: standard deviation; WSE: standardized Withania somnifera extract (Sensoril).
WITHANIA SOMNIFERA, DEPRESSION, ANXIETY, AND SCHIZOPHRENIA
May 2019 | Vol. 31 No. 2 | Annals of Clinical Psychiatry126
Withania somnifera extract was generally well-
tolerated. Adverse effects, including somnolence,
loose stool/diarrhea, and epigastric discomfort/
stomach pain, were more commonly reported in the
WSE group. However, there were no statistically signifi-
cant differences between WSE and placebo for adverse
events.16
DISCUSSION
Our findings suggest that depression and anxiety
symptoms in exacerbated schizophrenia may be sig-
nificantly improved by adjunctive treatment with
WSE. Evidence from previously reported clinical tri-
als suggests that WSE has anti-anxiety properties in
participants who are stressed,15 participants reporting
anxiety,14 and in those with diagnosed anxiety disor-
ders.13 Withania somnifera extract has also shown to
have antidepressant effects.20 The effects of WSE in
schizophrenia have not widely been explored; to the
best of our knowledge, this study represents the only
report of WSE being of benefit for mood and anxiety
symptoms in schizophrenia.
Immune and inflammatory pathways likely play a
role in some depressive illnesses,21 anxiety disorders,22
and schizophrenia.23 In schizophrenia and depression,
antioxidants and anti-inflammatory agents have been
investigated as adjunctive treatments.24-26 Modern ani-
mal and human studies have confirmed WSE exhibits
potent anti-inflammatory, immunomodulating, and
antioxidant properties,27-30 making it a candidate for the
treatment of these major mental disorders. As noted in
the primary study,16 patients treated with WSE experi-
enced a lowering of 2 inflammatory markers that were
measured, high sensitivity C-reactive protein and S100
calcium binding protein B, relative to participants
who were treated with placebo, but the data were sig-
nificantly skewed and there were outliers in both
groups. The differences in both markers from study
entrance to completion were not statistically signifi-
cant between treatments. While further exploration of
WSE’s mechanistic actions is needed, it is possible that
restoration of disturbed immune-inflammatory homeo-
stasis and poor antioxidant defenses by WSE helps
remedy dysfunctional neural circuits and alterations
in neuro transmitters associated with depression and
anxiety symptoms in schizophrenia. As such, WSE may
FIGURE 1
Mean change scores in PANSS depression single-item and depression-anxiety cluster scores
PANSS: Positive and Negative Syndrome Scale; WSE: standardized Withania somnifera extract (Sensoril).
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
4
3.5
3
2.5
2
1.5
1
0.5
0
Depression single-item Depression-anxiety cluster
WSE (n = 28)
Placebo (n = 31)
Depression single-item improvement
Depression-anxiety cluster improvement
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FIGURE 2
Chemical structures of bioactive constituents present in the standardized Withania somnifera extract
(Sensoril) used in the study
Withaferin A Withanoside IV
R1 = palmitoyl
Sitoindoside VII
R1= palmitoyl
Sitoindoside VIII
WITHANIA SOMNIFERA, DEPRESSION, ANXIETY, AND SCHIZOPHRENIA
May 2019 | Vol. 31 No. 2 | Annals of Clinical Psychiatry128
represent a clinically well-tolerated treatment option
for depression and anxiety in schizophrenia, regardless if
these symptoms are related directly to the schizophre-
nia spectrum illness itself or if they are secondary to a
comorbid mood or anxiety disorder.
A few points regarding the standardized WSE used
in this study, the patented formulation Sensoril, are
pertinent. Sensoril is comprised of a combination of a
minimum concentration of the following bioactives:
Withanolide glycosides: ≥8% (including withanosides
and sitoindosides), carrier oligosaccharides: ≥32%, and
Withaferin A: ≤2%.31 FIGURE 2 shows the medicinal chemis-
try structures of some of these compounds. Furthermore,
in addition to ensuring batch-to-batch reliability of the
product, including appropriate ratios of withanolides to
aglycones, the lack of contaminants, toxins, microbes,
and toxic heavy metals are important for replication of
the clinical results of herbal botanical products.
Limitations
Our study was designed to recruit for individuals with
exacerbation of positive symptoms of schizophrenia
rather than for symptoms of depression and/or anxiety.
We did not use scales specific to elucidating depression in
schizophrenia (for example, the Calgary Depression Scale
for Schizophrenia32). Interestingly, negative symptoms
showed improvement under treatment with WSE, begin-
ning at 4 weeks and becoming more sustained and robust
at 12 weeks,16 whereas depression and anxiety symptoms
showed significant improvements in comparison with
placebo only at the end of the 12-week treatment period.
Further replication of our findings through a larger, pro-
spective study focusing on the treatment of anxiety and
depression in schizophrenia would be needed to validate
our results.
CONCLUSIONS
Our findings suggest that WSE may hold promise in the
treatment of depression and anxiety symptoms in schizo-
phrenia. While the mechanism of its clinical efficacy
requires more exploration, the data suggest that WSE
may treat a broad spectrum of symptoms in exacerbated
schizophrenia.
ACKNOWLEDGMENTS: The authors thank Ms. Joan
Spinogatti for her assistance with manuscript prepara-
tion and submission, and for coordinating author col-
laboration and meetings. We also thank Ms. Patricia
Schlicht for coordinating the study. Some aspects of
this study were presented by Dr. Gannon as a New
Investigator Awardee at the Annual Meeting of the
American Society for Clinical Psychopharmacology
held in Miami, Florida, May 29 to June 1, 2018.
DISCLOSURES: The funding for this trial was provided
mainly by a grant from The Stanley Medical Research
Institute (SMRI Grant #12T-001, Principal Investigator:
K. N. Roy Chengappa). Dr. K. N. Roy Chengappa
declares that the University of Pittsburgh is pursuing
intellectual property protection for the technology dis-
cussed in this study. The other authors report no finan-
cial relationships with any companies whose products
are mentioned in this article, or with manufacturers of
competing products.
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... Powdered root extract has been reported to treat various health conditions like anxiety, fertility issues, inflammation, fatigue, pain, skin diseases, diabetes, arthritis and epilepsy or as a general tonic to increase energy and to decrease ageing process [6]. In addition to above conditions, it also improves sleep quality and bipolar disorder [7][8][9][10][11][12]. It is further reported to boost the immune system, increase the production of vital fluids, lymph blood, semen, cells, memory power and possesses immunomodulatory, hemopoietic, rejuvenation and antineoplastic effects [13]. ...
... Although melanin pig- Tousif et al. Process Biochemistry xxx (xxxx) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] ment protects the mammalian skin from harmful UV radiations, [53] but over production of melanin leads to hyperpigmentation and causes melasma, freckles, age spots, or senile lentigines [54]. Tyrosinase is a copper-containing enzyme that catalyzes melanin synthesis and is held responsible for hyperpigmentation in human skin [55][56][57]. ...
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Withania somnifera (L.) Dunal has been identified as a miracle herb, thus the present study was carried out to investigate W. somnifera growing in Cholistan Desert for its secondary metabolic profile and various biological activities. The WS-C fraction of methanolic extract (WS-M) of W. somnifera was found rich in phenolics (39.96±0.90 mg GAE/g extract), and it exhibited significant DPPH (30.69±0.78 mg TE/g extract) and ABTS (113.60±2.41 mg TE/g extract) free radical inhibitory activities, cupric (Cu⁺²) and ferric (Fe⁺³) reducing potential as 157.51±2.10 and 124.60±0.34 mg TE/g extract. The same fraction also exhibited strong total antioxidant capacity (1.39±0.01 mmol TE/g extract) in phosphomolybdenum assay. Other fractions displayed relatively lower potential. In metal-chelating assay, WS-M, WS-E and WS-B showed nearly equal potential with values of 22.35±0.62, 20.96±0.12 and 22.10±0.75 mg EDTAE/g of the extract, while in AChE, BChE and tyrosinase inhibitory assay, again WS-C fraction was most active (7.50±0.21, 8.01±0.53 mg GALAE/g extract and 36.81±0.20 mg KAE/g extract, respectively). In α-amylase and α-glucosidase inhibitory assay, WS-C showed significant potential with values as 0.74±0.01 and 1.14±0.004 mmol ACAE/g extract, respectively. UHPLC-MS analysis of WS-C fraction leads to identify 100 secondary metabolites of phenolic, withanolide, terpenoid, steroid, lignin, flavonoid and limonoid classes of compounds. This profile makes W. somnifera a fascinating plant. These findings were validated by computational studies, which revealed that selected compounds exhibited high binding free energy and inhibition constants with the enzymes tested. Pearson correlation analysis clearly established that the phenols in the tested extracts were the main players as antioxidants and enzyme inhibitors, which was also substantiated through Principal Component Analysis (PCA). These results suggest that chloroform might be suitable for preparing further applications with W. somnifera extracts, and this plant can be placed in the list of top-selling herbs, and may become source of commercial assets.
... 3-O-Acetyl-11-keto-β-boswellic acid (AKBA), an active compound isolated from Boswellia serrata, is widely used to treat inflammatory disorders, including arthritic diseases [26]. Withania somnifera, commonly known as Ashwagandha or Indian ginseng, is used in phytomedicine to treat various chronic diseases such as schizophrenia [27], obesity [28], and arthritis [20]. In several studies, beneficial effects of bisdemethoxycurcumin, curcumin, 3-O-Acetyl-11-keto-beta-boswellic acid and Withania somnifera (Ashwagandha) alone on arthritic diseases have been reported by reducing the ROS generation, mitochondrial depolarization and expression of TNF-α, IL-1β, IL-6, NF-κB [18,22,27]. ...
... Withania somnifera, commonly known as Ashwagandha or Indian ginseng, is used in phytomedicine to treat various chronic diseases such as schizophrenia [27], obesity [28], and arthritis [20]. In several studies, beneficial effects of bisdemethoxycurcumin, curcumin, 3-O-Acetyl-11-keto-beta-boswellic acid and Withania somnifera (Ashwagandha) alone on arthritic diseases have been reported by reducing the ROS generation, mitochondrial depolarization and expression of TNF-α, IL-1β, IL-6, NF-κB [18,22,27]. Yeh et al. reported that curcumin and bisdemethoxycurcumin inhibit macrophage inflammation and osteoclast differential activities [24]. ...
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Osteoarthritis (OA) is a musculoskeletal disorder mainly found in elderly individuals. Modern treatment of OA, like nonsteroidal anti-inflammatory drugs, corticosteroids, hyaluronic acid injections, etc., is linked to long-term side effects. We evaluated the anti-osteoarthritic properties of a novel joint health formula (JHF) containing Bisdemethoxycurcumin enriched curcumin, 3-O-Acetyl-11-keto-beta-Boswellic acid-enriched Boswellia, and Ashwagandha in monosodium iodoacetate (MIA)‐induced knee OA in rats. Twenty-eight female rats were distributed into four groups: Control, OA, OA + JHF (100 mg/kg), and OA + JHF (200 mg/kg). JHF decreased the right joint diameters but increased the paw area and stride length compared to the OA group with no treatment. JHF significantly reduced the arthritic conditions after four weeks of supplementation (p < 0.05). JHF significantly decreased TNF-α, IL-1β, IL-10, COMP, and CRP in the serum of osteoarthritic rats (p < 0.0001). We observed reduced lipid peroxidation but increased SOD, GSH-Px, and CAT activities in response to JHF treatment in OA animals. JHF down-regulated MMP-3, COX-2, and LOX-5 and improved the histological structure of the knee joint of osteoarthritic rats. JHF demonstrated a protective effect against osteoarthritis, possibly due to anti-inflammatory and antioxidant activity in experimentally induced osteoarthritis in rats, and could be an effective option in the management of OA.
... The reduction in symptom severity was accompanied by a trend toward decrease in hsCRP, S100B, and IL-6 levels in the treatment arm and increase in these levels in the control arm, indicating an anti-inflammatory response to ASW that correlated with symptom amelioration. A follow-up paper by the same group of authors reported a reduction, also, in symptoms of depression and anxiety in the ASW arm, relative to the placebo arm [85]. ...
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Introduction Ashwagandha (ASW) is the extract of the plant Withania somnifera. It is widely used in complementary, alternative and integrative medicine (CAIM) but is little discussed in mainstream modern medical literature. Areas covered We performed a review of potential pharmacotherapeutic properties of ASW. Studies were sourced from relevant online and offline databases. In animal models, ASW displays antioxidant activity. It has GABAergic and other neurotransmitter modulatory effects. It reduces apoptosis and promotes synaptic plasticity. It improves cognition and reverses induced cognitive deficits. It attenuates indices of stress. In human subjects, ASW enhances adaptogenesis in healthy adults. It modestly benefits generalized anxiety disorder and obsessive-compulsive disorder, and symptom severity in schizophrenia, substance use disorders, and attention deficit hyperactivity disorder. It improves sleep quality. Expert opinion ASW may confer modest benefit in certain neuropsychiatric conditions. Its benefits may arise from induction of neuroplasticity, antioxidant and anti-inflammatory effects, and modulation of GABA and glutamate as well as other neurotransmitters. The antioxidant and anti-inflammatory actions may also benefit neurodegenerative states. Reports of clinical benefit with ASW must be interpreted with caution, given the paucity of randomized clinical trials (RCTs). Greater methodological rigor is necessary before clinical recommendations on ASW can be confidently made.
... Clinical trials have demonstrated various effects of ashwagandha, such as improved sleep quality [75][76][77]; improved cognitive performance [78], quality of life, and mental alertness [76] in elderly subjects; decreased HAM-A scores in subjects with anxiety [79,80] and high stress [81]; increased VO 2max in healthy adults and athletes [82,83]; decreased Perceived Stress Scale scores and serum cortisol in stressed adults [78,82,84]; and improved depression and anxiety scores [85] and Perceived Stress Scale scores [86] in individuals with schizophrenia or schizoaffective disorder. Due to its stress-reducing effects, ashwagandha is considered an adaptogen, a substance that helps the body respond and adapt to stress and environmental changes [84]. ...
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Herbal and dietary supplement (HDS) use has grown exponentially in the United States. Unfortunately, the incidence of HDS-related liver injury has proportionally increased. Despite the potential for certain HDSs to cause clinically significant liver injury, they are not regulated by the Food and Drug Administration. Recent efforts have been made to regulate HDSs but are far removed from the scrutiny of prescription medications. Scant literature exists on HDSs and their risks of causing liver injury. In this comprehensive review, we examine trends of HDS use in the United States and the pathophysiologic mechanisms of drug-induced liver injury (DILI) of certain HDSs. Finally, we review usage rates; benefits, if any; purported pathophysiology of DILI; and propensity for progression to fulminant hepatic failure of nine HDSs linked to clinically significant DILI.
... Multiple human trials have shown the capability of ashwagandha to treat anxiety (Pratte et al. 2014), and extracts of this herb were the most influential in this systematic review for improving aspects of social cognition, as shown in Table 4 and Figure 2. Ashwagandha has also been tested as an adjuvant pharmacological treatment for psychiatric disorders. For example, its use in schizophrenia patients led to a significant reduction in symptoms of depression and anxiety assessed in a 12-week, randomized, placebo-controlled, double-blind study administering 1000 mg of an ashwagandha standardized extract (Gannon et al. 2019). Similarly, this herb improved auditory-verbal working memory (as a measure of social cognition) in an 8-week, placebo-controlled, double-blind, randomized study with bipolar disorder patients with a dose of 500 mg/day of ashwagandha extract, taken together with psychopharmacological medication (Chengappa et al. 2013). ...
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Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research.
... The ethanolic root extract of WS showed neuroprotective activity in bisphenol A (BPA) induced loss of spatial learning and working memory in Swiss albino mice [57]. With mild and transient adverse effects, 1000 mg of standardized WS extract showed potent activity in the treatment of anxiety and depression caused by schizophrenia in a human trial [109]. ...
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Withania somnifera (L.) Dunal (Solanaceae) has been used as a traditional Rasayana herb for a long time. Traditional uses of this plant indicate its ameliorative properties against a plethora of human medical conditions, viz. hypertension, stress, diabetes, asthma, cancer etc. This review presents a comprehensive summary of the geographical distribution, traditional use, phytochemistry, and pharmacological activities of W. somnifera and its active constituents. In addition, it presents a detailed account of its presence as an active constituent in many commercial preparations with curative properties and health benefits. Clinical studies and toxicological considerations of its extracts and constituents are also elucidated. Comparative analysis of relevant in-vitro, in-vivo, and clinical investigations indicated potent bioactivity of W. somnifera extracts and phytochemicals as anti-cancer, anti-inflammatory, apoptotic, immunomodulatory, antimicrobial, anti-diabetic, hepatoprotective, hypoglycaemic, hypolipidemic, cardio-protective and spermatogenic agents. W. somnifera was found to be especially active against many neurological and psychological conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemic stroke, sleep deprivation, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, bipolar disorder, anxiety, depression, schizophrenia and obsessive-compulsive disorder. The probable mechanism of action that imparts the pharmacological potential has also been explored. However, in-depth studies are needed on the clinical use of W. somnifera against human diseases. Besides, detailed toxicological analysis is also to be performed for its safe and efficacious use in preclinical and clinical studies and as a health-promoting herb.
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Clinical trial studies revealed conflicting results on the effect of Ashwagandha extract on anxiety and stress. Therefore, we aimed to evaluate the effect of Ashwagandha supplementation on anxiety as well as stress. A systematic search was performed in PubMed/Medline, Scopus, and Google Scholar from inception until December 2021. We included randomized clinical trials (RCTs) that investigate the effect of Ashwagandha extract on anxiety and stress. The overall effect size was pooled by random‐effects model and the standardized mean difference (SMD) and 95% confidence interval (CIs) for outcomes were applied. Overall, 12 eligible papers with a total sample size of 1,002 participants and age range between 25 and 48 years were included in the current systematic review and meta‐analysis. We found that Ashwagandha supplementation significantly reduced anxiety (SMD: −1.55, 95% CI: −2.37, −0.74; p = .005; I2 = 93.8%) and stress level (SMD: −1.75; 95% CI: −2.29, −1.22; p = .005; I2 = 83.1%) compared to the placebo. Additionally, the non‐linear dose–response analysis indicated a favorable effect of Ashwagandha supplementation on anxiety until 12,000 mg/d and stress at dose of 300–600 mg/d. Finally, we identified that the certainty of the evidence was low for both outcomes. The current systematic review and dose–response meta‐analysis of RCTs revealed a beneficial effect in both stress and anxiety following Ashwagandha supplementation. However, further high‐quality studies are needed to firmly establish the clinical efficacy of the plant.
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As pandemic hit the globe, stress in people increased drastically. Some people were losing their jobs while others were restricted to their homes due to precautionary measures against COVID-19 infection. Some were stressed about their living while others concerned about their families being affected. Many lost their dear ones. But one thing we learnt in this phase was ghting immunity and how immunity plays a vital role in prevention of disease. Ashwagandha (roots of Withania somnifera, fam. Solanaceae) is named generally as "Indian Winter cherry" or "Indian Ginseng" has been in use for medicinal purposes since more than 3000 years [1]. This herb is one of the main spices of Ayurveda (the customary arrangement of medication in India) consumed since centuries as a Rasayana (rejuvenator) for its larger spectrum of medical advantages. By increasing cell-mediated immunity, Ashwagandha boosts the body's resistance against disease. It also has powerful antioxidant properties, which help to protect cells from free radical damage. The bitter leaves are used to treat fevers and uncomfortable swellings. Aphrodisiac, astringent, depurative, diuretic and aphrodisiac are all properties of the owers. It can also help eliminate white spots from the cornea when combined with rock salt and an astringent. Hysteria, anxiety, memory loss, syncope, and other conditions are treated with Ashwagandharishta, which is made from it. It is also consumed for nervous exhaustion, insomnia, neurodegenerative diseases, memory loss [2]. It is also used as anti-inammation, anti-cancerous, general weakness, impotency and respiratory disorders [3]. A randomized controlled trial has suggested its role in the treatment of anxiety and depression in schizophrenia [4]. Its role in health and healing has also been observed [5]. As studies show its role on immunity so we should consume it in our daily lives for variety of benets.
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The Withania genus comes from the Solanaceae family and includes around 23 species, spread over some areas of the Mediterranean, Asia, and East Africa. Widely used in traditional medicine for thousands of years, these plants are rich in secondary metabolites, with special emphasis on steroidal lactones, named withanolides which are used as ingredients in numerous formulations for a plethora of diseases, such as asthma, diabetes, arthritis, impotence, amnesia, hypertension, anxiety, stress, cancer, neurodegenerative, and cardiovascular diseases, and many others. Among them, Withania somnifera (L.) Dunal is the most widely addressed species from a pharmacological and agroindustrial point of view. In this sense, this review provides an overview of the folk uses, phytochemical composition, and biological activity, such as antioxidant, antimicrobial, anti-inflammatory, and cytotoxic activity of W. somnifera, although more recently other species have also been increasingly investigated. In addition, their health-promoting effects, i.e., antistress, anxiolytic, adaptogenic, antirheumatoid arthritis, chemoprotective, and cardiorespiratory-enhancing abilities, along with safety and adverse effects are also discussed.
Chapter
Ageing is an innate indispensable physiological process largely conceived as general decline in body functions and defense mechanisms. While ageing per se is not a disease, there are many age-related pathologies, modulation of which is considered as anti-ageing in several ways. Chronic stress often triggers senescence-inducing mechanisms manifested as premature/rapid ageing. The latter is associated with a high incidence of stress-related disorders such as cancer, neurodegeneration, metabolic disorders and muscle/bone dysfunctions. Cell culture system provides an easy and convenient experimental system to study mechanisms of natural (replicative) and stress-induced ageing. We, over the years, have researched molecular mechanisms of ageing and age-related pathologies, and their modulation with natural compounds using cell culture as a model system. Among several others, bioactives from Ashwagandha (Withania somnifera) have emerged as useful natural compounds with a variety of activities and are hence predicted to assist in health care in stress and disease states. In this chapter, we describe highlights of our research work demonstrating the therapeutic potential of Ashwagandha leaves that offer advantage over roots in terms of availability, processing and being enriched with active compounds.
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Schizophrenia and major depression (MD) have been associated with immune system dysfunction. One example of this is the altered level of cytokines—important inflammatory mediators—in blood, and a proinflammatory immune state has been described in some subgroups of patients. A knock to the immune system in early life might trigger a life-long increased immune reactivity, and infections and autoimmune disorders are now known to be risk factors for development of schizophrenia and MD. Pro- and anti-inflammatory cytokines mediate indoleamine 2,3-dioxygenase activity; this enzyme drives metabolism of tryptophan and kynurenin in the central nervous system and degrades serotonin. Alterations of serotonergic, noradrenergic, and glutamatergic neurotransmission have been associated with low-level neuroinflammation, and anti-inflammatory compounds have a therapeutic benefit in MD and schizophrenia, as shown in meta-analyses. Moreover, antidepressants and antipsychotics have intrinsic immunomodulatory effects. With evidence pointing to the role inflammatory processes play in the pathogenesis of major psychiatric disorders, this review will look at various immunological aspects of treatment of such disorders.
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Full text: http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/sbw097? ijkey=HnnjCz8Mgb4ItNC&keytype=ref The presence of depression in schizophrenia has been a challenge to the Kraepelinian dichotomy, with various attempts to save the fundamental distinction including evoking and refining diagnoses such as schizoaffective disorder. But the tectonic plates are shifting. Here we put forward a summary of recent evidence regarding the prevalence, importance, possible aetiological pathways and treatment challenges that recognizing depression in schizophrenia bring. Taken together we propose that depression is more than comorbidity and that increased effective therapeutic attention to mood symptoms will be needed to improve outcomes and to support prevention.
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Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.
Article
Objective: To determine if adjunctive treatment with a standardized extract of Withania somnifera (WSE), with known anti-inflammatory and immunomodulating properties, improves psychopathology and stress in patients with schizophrenia or schizoaffective disorder (DSM-IV-TR). Methods: Patients experiencing an exacerbation of symptoms were assigned to WSE (1,000 mg/d) or placebo for 12 weeks, added to their antipsychotic medication, in a random-assignment, double-blind, placebo-controlled study conducted from April 2013 to July 2016. Primary outcomes were change from baseline to end of treatment on the Positive and Negative Syndrome Scale (PANSS total, positive, negative, and general symptoms) between treatment groups. Secondary outcomes evaluated stress and inflammatory indices using the Perceived Stress Scale (PSS), S100 calcium-binding protein B (S100B), and C-reactive protein (CRP). Results: Sixty-six randomized patients (n = 33 per group) provided efficacy data. Beginning at 4 weeks and continuing to the end of treatment, WSE produced significantly greater reductions in PANSS negative, general, and total symptoms (Cohen d: 0.83, 0.76, 0.83), but not positive symptoms, when compared to placebo. PSS scores improved significantly with WSE treatment compared to placebo (Cohen d: 0.58). CRP and S100B declined more in the WSE group but were not significantly different from placebo. Adverse events were mild to moderate and transient; somnolence, epigastric discomfort, and loose stools were more common with WSE. No significant between-treatment differences were noted in body weight, vital signs, or laboratory measures, which remained stable. Conclusions: This early study suggests that adjunctive treatment with a standardized extract of Withania somnifera provides significant benefits, with minimal side effects, for negative, general, and total symptoms and stress in patients with recent exacerbation of schizophrenia. Trial registration: ClinicalTrials.gov identifier: NCT01793935.
Chapter
Bipolar Disorder is a mood disorder that can be quite severe for subgroups of patients, and often such patients manifest deficits in attention, concentration, memory, and executive functions that persist even when they are relatively well. Cognitive concerns can impair daily life functioning and impact employment, education, and interpersonal relationships. Main line treatments for bipolar disorder typically do not address cognitive impairments, and some treatments may actually worsen cognitive deficits. Treatment development for cognitive impairments in bipolar disorder is truly in its infancy; extracts of Ashwagandha (Withania somnifera) may hold promise as a potential treatment option. The bioactive constituents of Ashwagandha, including withanolides, indosides, Withaferin A, and others, possess anti-inflammatory-immunomodulatory, anti-oxidant, cortisol lowering, anti-stress, pro-cholinergic, anti-glutamatergic and neuroprotective properties, the very processes that are thought to underlie cognitive impairments not only in in bipolar disorder but also in other psychiatric disorders like schizophrenia and major depression. This chapter reviews this in detail and highlights the preliminary randomized controlled study assessing an extract of Ashwagandha for improving cognition in bipolar disorder. The chapter also explores the potential role of Ashwagandha extracts in the treatment of other neurocognitive disorders, and it concludes by summarizing additional future research needed to realize the potential of this ancient medicinal plant for the treatment of human ailments.
Article
Background Dose equivalents of antipsychotics are an important but difficult to define concept, because all methods have weaknesses and strongholds. Methods We calculated dose equivalents based on defined daily doses (DDDs) presented by the World Health Organisation’s Collaborative Center for Drug Statistics Methodology. Doses equivalent to 1mg olanzapine, 1mg risperidone, 1mg haloperidol, and 100mg chlorpromazine were presented and compared with the results of 3 other methods to define dose equivalence (the “minimum effective dose method,” the “classical mean dose method,” and an international consensus statement). Results We presented dose equivalents for 57 first-generation and second-generation antipsychotic drugs, available as oral, parenteral, or depot formulations. Overall, the identified equivalent doses were comparable with those of the other methods, but there were also outliers. Conclusions The major strength of this method to define dose response is that DDDs are available for most drugs, including old antipsychotics, that they are based on a variety of sources, and that DDDs are an internationally accepted measure. The major limitations are that the information used to estimate DDDS is likely to differ between the drugs. Moreover, this information is not publicly available, so that it cannot be reviewed. The WHO stresses that DDDs are mainly a standardized measure of drug consumption, and their use as a measure of dose equivalence can therefore be misleading. We, therefore, recommend that if alternative, more “scientific” dose equivalence methods are available for a drug they should be preferred to DDDs. Moreover, our summary can be a useful resource for pharmacovigilance studies.
Article
Objective: The authors examined the safety and efficacy of antidepressants added to antipsychotic drugs in the treatment of schizophrenia. Method: Multiple databases and previous publications were searched through June 2015 to identify all randomized controlled trials of any add-on antidepressants compared with placebo or no-treatment in schizophrenia. Depressive and negative symptoms (primary outcomes), overall symptoms, positive symptoms, side effects, exacerbation of psychosis, and responder rates were examined. Subgroup, meta-regression, and sensitivity analyses were performed, as well as investigations of publication bias and risk of bias. Results: Eighty-two randomized controlled trials with a total of 3,608 participants were included. Add-on antidepressants appeared more efficacious than controls for depressive symptoms (standardized mean difference: -0.25, 95% CI=-0.38 to -0.12), negative symptoms (standardized mean difference: -0.30, 95% CI=-0.44 to -0.16), overall symptoms (standardized mean difference: -0.24, 95% CI=-0.39 to -0.09), positive symptoms (standardized mean difference: -0.17, 95% CI=-0.33 to -0.01), quality of life (standardized mean difference: -0.32, 95% CI=-0.57 to -0.06), and responder rate (risk ratio: 1.52, 95% CI=1.29 to 1.78; number-needed-to-treat-to-benefit: 5, 95% CI=4 to 7). The effects on depressive and negative symptoms appeared more pronounced when minimum thresholds of these symptoms were inclusion criteria (standardized mean difference: -0.34, 95% CI=-0.58 to -0.09 and standardized mean difference: -0.58, 95% CI=-0.94 to -0.21, respectively). There were no significant differences between antidepressants and controls in terms of exacerbation of psychosis, premature discontinuation, and the number of participants with at least one adverse event. More patients taking add-on antidepressants suffered from abdominal pain, constipation, dizziness, and dry mouth. Conclusions: Analysis of primary outcomes (depressive and negative symptoms) suggests small, beneficial effects of adjunctive antidepressants. It would appear that this augmentation can be accomplished with a low risk of exacerbation of psychosis and adverse effects. However, secondary and subgroup analyses should be interpreted cautiously and considered exploratory.
Article
Anxiety symptoms can occur in up to 65 % of patients with schizophrenia, and may reach the threshold for diagnosis of various comorbid anxiety disorders, including obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). We review the clinical presentation, diagnosis, neurobiology, and management of anxiety in patients with schizophrenia, with a particular focus on pharmacotherapy. The prevalence of any anxiety disorder (at syndrome level) in schizophrenia is estimated to be up to 38 %, with social anxiety disorder (SAD) being the most prevalent. Severity of positive symptoms may correlate with severity of anxiety symptoms, but anxiety can occur independently of psychotic symptoms. While anxiety may be associated with greater levels of insight, it is also associated with increased depression, suicidality, medical service utilization, and cognitive impairment. Patients with anxiety symptoms are more likely to have other internalizing symptoms as opposed to externalizing symptoms. Diagnosis of anxiety in schizophrenia may be challenging, with positive symptoms obscuring anxiety, lower levels of emotional expressivity and communication impeding diagnosis, and conflation with akathisia. Higher diagnostic yield may be achieved by assessment following the resolution of the acute phase of psychosis as well as by the use of screening questions and disorder-specific self-report instruments. In schizophrenia patients with anxiety, there is evidence of underactive fear circuitry during anxiety-provoking stimuli but increased autonomic responsivity and increased responsiveness to neutral stimuli. Recent findings implicate the serotonin transporter (SERT) genes, brain-derived neurotropic factor (BDNF) genes, and the serotonin 1a (5HT1a) receptor, but are preliminary and in need of replication. There are few randomized controlled trials (RCTs) of psychotherapy for anxiety symptoms or disorders in schizophrenia. For pharmacotherapy, data from a few randomized and open trials have shown that aripiprazole and risperidone may be efficacious for obsessive-compulsive and social anxiety symptoms, and quetiapine and olanzapine for generalized anxiety. Older agents such as trifluoperazine may also reduce comorbid anxiety symptoms. Alternative options include selective serotonin re-uptake inhibitor (SSRI) augmentation of antipsychotics, although evidence is based on a few randomized trials, small open trials, and case series, and caution is needed with regards to cytochrome P450 interactions and QTc interval prolongation. Buspirone and pregabalin augmentation may also be considered. Diagnosis and treatment of anxiety symptoms and disorders in schizophrenia is an important and often neglected aspect of the management of schizophrenia.
Article
OBJECTIVES: Withania somnifera has been in use for several thousand years in Ayurveda to treat various neurological disorders. There is, however, not much scientific data on its protective role in neuronal pathology specifically against brain oxidative stress. Hence, an attempt is made in this work for systematic review and meta-analysis of W. somnifera on neurobehavioural disorders induced by brain oxidative stress in rodents. METHODS: A systematic search of the effect of W. somnifera on brain oxidative stress-induced neuronal pathology was performed using electronic databases. The systematic review was performed on neurobehavioural parameters, whereas meta-analysis of W. somnifera effect was done on oxidative stress markers (superoxide dismutase, catalase, glutathione peroxidase, glutathione and lipid peroxidation), nitrite, protein carbonyl, AchE, ChAT and Ach of rodent brain. Data were analysed using Review Manager Software. KEY FINDINGS: Twenty-eight studies were selected based upon the inclusion and exclusion criteria. W. somnifera appreciably inhibited the neurological abnormalities due to oxidative stress in rodent brain produced by different physical and chemical stimuli. W. somnifera also significantly restored the altered oxidative and other stress markers in different parts of rodent brain. SUMMARY: The systematic review provides scientific evidence for the traditional claim of W. somnifera use in different neurological aliments. However, future clinical trials are mandated to establish the therapeutic efficacy and safety in human beings. KEYWORDS: Indian ginseng; antioxidant; meta-analysis; neuropathology; oxidative stress