Integrative Medicine

Integrative Medicine Research Review

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In this issue:

>>Cannabidiol as an adjunctive therapy in schizophrenia

>>Nutritional deficiencies and clinical

correlates in first-episode psychosis

>>Physical activity and incident depression >>Exercise and the prevention of depression >>Saffron for the treatment of youth anxiety and depression

>>Adjunctive bright light therapy for bipolar depression

>>Antidepressant effects of acute sleep deprivation

>>Mindfulness-based cognitive therapy

for unipolar depression in patients with chronic pain

>>Vitamin D supplementation in bipolar depression

>>Rosa Damascena oil improved methadonerelated sexual dysfunction in females

>>Modified African Ngoma healing ceremony for stress reduction

Abbreviations used in this issue: BLT = bright light therapy; CBD = cannabidiol; CGI-S = clinical global impressions scale; HDRS17 = 17-item Hamilton Depression Rating Sale; FEP = first-episode psychosis; MBCT = mindfulness-based cognitive therapy; PA = physical activity; QIDS-C16 = 16-item quick inventory of depressive symptomatology-clinician rated; PANSS = positive and negative syndrome scale; RCADS = revised child anxiety and depression scale; SIGH-ADS = structured interview guide for the Hamilton Depression Scale with atypical depression supplement; THC = Tetrahydrocannabinol.

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Issue 2 - 2018

Welcome to the latest issue of Integrative Medicine (Mental Health) Research Review. In this issue we review complementary adjunctive therapies for depression including saffron, bright light therapy, acute sleep deprivation and mindfulness-based cognitive therapy. We also review a large Norwegian cohort study investigating physical exercise as a modifiable risk factor for depression onset and a meta-analysis of longitudinal studies that quantifies the role of moderaters such as gender and age on the protective effect of exercise on depression onset. We also look at other interesting therapies such as cannabidiol, Vitamin D supplementation, Rosa Damascena oil and an African Ngoma ceremony amongst others. I hope you find these and the other selected studies interesting, and look forward to receiving any feedback you may have. Kind Regards, Professor Jerome Sarris [email protected]

Cannabidiol as an adjunctive therapy in schizophrenia Authors: McGuire P et al. Summary: This multi-centre, double-blind, randomised controlled trial followed on from promising animal studies to investigate the antipsychotic efficacy of cannabidiol (CBD) in schizophrenic patients. 88 patients were randomised 1:1 to receive either 1000mg/day CBD (n=43) or placebo (n=45) for 6 weeks in addition to their regular antipsychotic medication. Psychotic symptoms were quantified pre and post-treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia, the Global Assessment of Functioning scale and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S). CBD showed beneficial effects in patients with schizophrenia including decreased levels of positive psychotic symptoms (PANSS: treatment difference=−1.4, 95% CI=−2.5, −0.2) and increased physician-rated "not as unwell" scores (CGI-S: treatment difference=−0.3, 95% CI=−0.5, 0.0). CBD was well tolerated with no notable adverse effects. Comment: It may seem counter-intuitive to many clinicians that a constituent from cannabis may actually be a useful adjunctive treatment in schizophrenia, as consistent data has shown that there is an increased risk in some people of developing a psychotic disorder from cannabis use. It is important to note that this is primarily associated with Tetrahydrocannabinol (THC), THC analogues, and THC-rich strains of cannabis. There appears, however, to be a role for other cannabinoids such as CBD, which does not have a direct affinity with the psychotropic CB1 receptor. It is of note that this study revealed that CBD in fact reduced ‘positive’ symptoms of schizophrenia, which incidentally typify some of the symptoms that occur in high THC use (e.g. visual and auditory hallucinations, paranoia etc.). Further work is needed to assess this therapeutic approach in a longer-term study to assess whether a treatment effect is maintained. It is also of potential interest to see if other medicinal cannabis constituents may enhance this effect, and whether a low-THC full spectrum whole plant effect can achieve similar or more beneficial outcomes. Reference: The American Journal of Psychiatry 2018;175(3):225-31 Abstract

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Integrative Medicine Research Review Focus on Mental Health

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Nutritional deficiencies and clinical correlates in first-episode psychosis Authors: Firth J et al. Summary: This systematic review and meta-analysis investigated the presence of nutritional deficits in first-episode psychosis (FEP). 28 studies analysing blood levels of 6 vitamins and 10 minerals from 2612 people (1221 with PEP and 1391 healthy controls) were included. Meta-analysis revealed that patients undergoing FEP had significantly lower blood levels of folate, vitamin D and vitamin C. Lower levels of folate and Vitamin D clinically correlated to worse psychiatric symptoms in FEP. Comment: Diet is increasingly recognised as being a potentially modifiable factor in a range of mental health disorders, and in particular depression. Emerging research is also showing that chronic schizophrenia is associated with various nutritional deficiencies. This meta-analysis explored whether this relationship also was found in people with early or ‘first-episode’ psychosis compared to healthy controls. The results expectedly revealed that Vitamin D, C, and folate levels were significantly lower compared to healthy counterparts. This mirrors some general chronic schizophrenia data, and is of particular note regarding Vitamin D, which has been shown to be significantly deficient in some mothers who’s offspring later were diagnosed with schizophrenia. While deficiencies may exist in higher prevalence in this cohort, it remains to be seen aside from adjunctive treatment with B Vitamins, whether treatment with Vitamin D and Vitamin C in prospective studies improves the mental health of those managing schizophrenia. Reference: Schizophrenia Bulletin 2017; epub ahead of print Abstract

Physical activity and incident depression Authors: Schuch F et al. Summary: This Brazilian group performed a meta-analysis of prospective cohort studies evaluating the relationship between physical activity (PA) and depression. A search of PubMed, PsycINFO, EMBASE and Sportsdiscuss databases identified 49 longitudinal cohort studies (n= 939, 47% male). Random effects meta-analysis of the data showed an inverse correlation between physical activity and odds of developing future depression. The protective effect of physical activity against developing depression was consistent across geographical locations around the globe and did not differ according to age or gender. Comment: Physical activity and formalised exercise are well-accepted as having a mood elevating effect, with data suggesting that a dose-dependent effect occurs (not-withstanding that more extreme levels of exercise may in fact be deleterious to mental and physical health). Recent meta-analyses have however shown that this effect may not be quite as robust when looking at diagnosed Major Depressive Disorder, and when a robust control comparator is used. This meta-analysis provides important data to show that longitudinally, baseline levels of PA may ‘predict’ the risk of developing depression (as opposed to cross-sectional data just showing a ‘temporal association’). It is further enhanced by the analyses showing that depression risk is greater in those who are sedentary, regardless of geography or age. More nuanced data collection in the future may ascertain which types of PA may be of more benefit, and the potentially additionally beneficial elements of a salubrious social setting or greenspace. Reference: The American Journal of Psychiatry 2018; ahead of print

Integrative Medicine Research Review

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Focus on Mental Health

Independent commentary by Professor Jerome Sarris, Professor of Integrative Mental Health and Deputy Director of NICM Health Research Institute at Western Sydney University. He holds an NHMRC Clinical Research Fellowship, in addition to an honorary position at the University of Melbourne, Department of Psychiatry as a Principal Research Fellow. He has a particular interest in anxiety and mood disorder research pertaining to integrative medicine, nutraceutical psychopharmacology and psychotropic plant medicines (such as kava and medicinal cannabis), and lifestyle medicine. His research also utilises genomic technology to examine the pharmacogenomics of individual responses to nutraceuticals in the treatment of psychiatric disorders. Professor Sarris has over 135 publications and has published in many eminent journals in the field including The American Journal of Psychiatry, Lancet Psychiatry, and World Psychiatry. He is currently involved in over a The International Network of Integrative Mental Health & an Executive Committee Member of the International Society of Nutritional Psychiatry Research.

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Exercise and the prevention of depression

Adjunctive bright light therapy for bipolar depression

Authors: Harvey S et al. Summary: The Nord-Trøndelag Health Study (The HUNT Study) includes large total population-based cohorts from the 1980ies, covering 125 000 Norwegian participants. This analysis of HUNT data prospectively followed 33, 908 Norwegian adults (with no mental or physical health conditions) for 11 years to elucidate whether exercise, and what amounts, protect against new-onset depression and anxiety. Low levels of regular exercise were found to protect against future depression but not anxiety.

authors: Sit D et al. Summary: This randomised, double-blind, placebo-controlled trial assessed the efficacy of adjunctive bright light therapy (BLT) at midday for bipolar depression. The six-week trial randomised 46 adults with bipolar I or II disorder 1:1 to 7,000-lux bright white light or 50-lux dim red placebo in addition to their regular antimanic medication. The primary endpoints of remission rate, depression symptom level, and rate of mood polarity switch were assessed using the Structured Interview Guide for the Hamilton Depression Scale with Atypical Depression Supplement (SIGH-ADS) and the Mania Rating Scale. At 4-6 weeks, the treatment group showed significant increased remission rates (defined as SIGH-ADS score ≤ 8) (68.2% compared with 22.2%; adjusted odds ratio=12.6) and at the final visit lower depression scores (9.2 [SD=6.6] compared with 14.9 [SD=9.2]; adjusted β=–5.91).

Comment: As detailed above in the Schuch et al. publication which highlighted a strong prospective association between physical activity and a reduced risk of depression, this large cohort analysis revealed a similar link between the reduction of depression and physical activity. The fascinating finding of this study is that low levels of exercise were protective against depression, and in fact was preferentially beneficial as opposed to high intensity exercise. While some data has shown that exercise can elicit a dose-dependent effect, and acutely this makes sense, it is whether sustained long-term high-intensity exercise reflects a consistently beneficial effect on mood. The data from this present study suggests not, but encouragingly that ‘any movement is good movement’ where mood is concerned. This makes intuitive sense in terms of alleviating rumination and stimulating mental and physiological activity, a cornerstone of depression treatment. Reference: The American Journal of Psychiatry 2018;175(1):28-36 Abstract

affron®, a standardised extract from saffron (Crocus sativus L.) for the treatment of youth anxiety and depressive symptoms Authors: Lopresti A et al. Summary: This randomised, double-blind, placebo-controlled study analysed a saffron extract (affron®, 14 mg b.i.d) for effect on anxiety and depressive symptoms in youths aged 12-16 years. 80 youths with mild to moderate anxiety or depressive symptoms were given placebo or affron® tablets for 8 weeks. 68 participants completed the study. The primary outcome measure was self-reported Revised Child Anxiety and Depression Scale (RCADS) scores from the youth and their parents (parent-version). Analysis of the youth RCADS correlated affron® with improvement in depression and several anxiety scales (separation anxiety and social phobia, p = 0.003 and p = 0.023, respectively). Analysis of parental scores showed an overall improvement in the mean RCADS scores (p = 0.026) but no improvements on individual scales. Affron® was well tolerated and the authors noted a trend of decreased headaches in the treatment group. Comment: This study adds to a growing body of evidence that saffron may be beneficial for treating affective complaints. The vast majority of research has been conducted in Iran, and thus further research in other jurisdictions is advised. This is the first RCT to study a standardised saffron preparation in an adolescent cohort. This is greatly needed, with few youth nutraceutical clinical trials, and a growing recognition about the importance of early intervention. Plant-based medicines, if effective, would be of marked value as there is reluctance for both prescribing and consuming antidepressant medication in adolescents and children. While the self-report results were consistently positive in favour of saffron over placebo, it is curious to note that the parental observation did not corroborate this finding in respect to percentage of responders to treatment. Perhaps teenagers are correct in their common protests, that their parents “don’t really know them at all”. Reference: Journal of Affective Disorders 2018;232: 349-57 Abstract

Comment: This is a very interesting and somewhat courageous study, as there has been concerns over bright light therapy in Bipolar Disorder potentially ‘switching’ people into a hypomanic or manic phase. The use of a placebo light low lux control is commendable and offers some confidence that there was a true treatment effect for 7,000 lux of bright light over 6 weeks of midday treatment (which contrasts with other studies using early morning light). With results revealing a significant effect in favour of the bright light therapy with strong relative depression score reductions and remission rates, this cheap therapy holds novel promise. Randomisation was stratified (and analyses controlled) for seasonality effects. Clinicians are advised to be sure no significant upcycling is occurring prior or during treatment, and that patients with bipolar disorder commencing the therapy are taking mood stabilisers or other appropriate medication. Reference: American Journal of Psychiatry 2018;175(2):131-39 Abstract

Meta-analysis of the antidepressant effects of acute sleep deprivation authors: Boland E et al. Summary: This meta-analysis quantified the antidepressant effect of sleep deprivation. A search of PubMed and PsycINFO databases identified 66 studies that conducted experimental sleep deprivation independently of other therapies in patients with depression. Meta-analysis of proportions and a Poisson mixed-effects regression model found the overall response to sleep deprivation therapy to be 45% (trials with a randomised control group) and 50% (trials without a randomised control group). Factors such as age, gender, medication status or type of sleep deprivation had no significant effect on response rate to sleep deprivation. Comment: The use of sleep deprivation is often not known or not employed by the public as a mood elevating technique. Aside from it baring no financial cost, it can be modified according to patient preference and any important clinical concerns. Chronic sleep deprivation has been consistently shown to negatively affect work performance and productivity, and may be a risk factor for a range of diseases and disorders (curiously in this context- depression). Regardless, as the data from this meta-analysis shows (with depression response rates between 45-50% depending on control group), if used judiciously as an acute intervention, potential mood-elevation may occur. While the meta-analysis covered a decent volume of studies (66 clinical trials), marked heterogeneity is of concern, and there needs to be a clearer understanding as to the most appropriate way of restricting sleep, the ideal length of time, and whether restriction should primarily occur at the waking end. Reference: The Journal of Clinical Psychiatry 2017;78(8): e1020-34 Abstract

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Mindfulness-based cognitive therapy for unipolar depression in patients with chronic pain authors: de Jong M et al. Summary: This randomised, controlled pilot study aimed to determine the efficacy of mindfulness-based cognitive therapy (MBCT) for the treatment of depression in patients with chronic pain. 40 depressed patients (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) score ≥ 6) with chronic pain (≥ 3 months) were randomised to receive an adapted-MBCT treatment (n= 26) or waitlisted (n = 14). 19 patients completed the program. Primary outcome measures were changes on the QIDS-C16 and 17-item Hamilton Depression Rating Sale (HDRS17). The HDRS17 scores did not differ significantly between groups. Repeated-measures analyses of variance for the per-protocol sample (n = 33) revealed a significant treatment × time interaction (F1,31 = 4.67, P = .039, η2p = 0.13) for QIDS-C16 score and the authors concluded that MBCT shows potential as therapy for depression in patients with chronic pain. Comment: The incorporation of mindfulness into CBT programs has grown in interest in the last decade, with increasing applications being found for a range of psychiatric disorders. Raised depression levels are common in those suffering with chronic pain. This small-scale study sought to address this comorbidity and found an encouraging signal that MBCT may be beneficial in addressing depression co-occurring with chronic pain. The study was unfortunately not sufficiently powered to determine a clear result, however, it does support a future larger scale trial. This technique may also be beneficial in assisting with the management of pain (especially in light of concerns regarding the over-use of opioids), although clinician cost and compliance can be a potential issue. Reference: The Journal of Clinical Psychiatry 2018;79(1) Abstract

Vitamin D supplementation in bipolar depression Authors: Marsh W et al. Summary: This double blind, placebo-controlled trial assessed the impact of adjunctive Vitamin D supplementation for the treatment of bipolar depression. Bipolar adults with vitamin D deficiency (< 30 ng/ml) were randomised to 0.125mg oral Vitamin D 3 daily (n=16) or placebo (n=17) for 12 weeks. Over the 12 weeks, the treatment group’s Vitamin D levels increased from 19.2 ± 65.8 ng/ml to 28 ng/ml but no significant difference in reduction of depressive symptoms was observed compared to controls on any of the scales assessed (Montgomery-Åsberg Depression Rating Scale, Hamilton Anxiety Rating Scale, Young Mania Rating Scale). Comment: This interesting study sought to establish whether Vitamin D may be effective as an adjunct treatment for bipolar depression, based on its pharmacological action and the link with increased deficiency in those with depressive disorders. The inclusion of Vitamin D deficient people is a thankful design element in this clinical trial, as many nutrient studies include people with ‘sufficient’ nutrient levels. While results showed no significant difference between 12 weeks of 5000IU of Vitamin D and placebo, it should be noted that the study was severely underpowered, and the raw score reduction did favour the active intervention. Previous data has revealed that Vitamin D may be of benefit as an adjunctive treatment in unipolar depression, but may not be beneficial in once off mega-dosing as a seasonal prophylactic for winter-onset depression. A curious additional finding from this study is that even with the large doses of Vitamin D given, serum levels did not rise past deficiency in many participants. Reference: Journal of Psychiatric Research 2017;95: 48-53 Abstract

Rosa Damascena oil improved methadone-related sexual dysfunction in females with opioid use disorder under methadone maintenance therapy Authors: Farnia V et al. Summary: This double-blind, randomized, and placebo-controlled trial assessed the use of Rosa Damascena oil to treat sexual dysfunction in female patients undergoing methadone maintenance therapy for opioid use disorder. 50 patients were randomised to receive Rosa Damascena oil or placebo for 8 weeks. Sexual function and happiness were assessed by questionnaires at baseline, 4 and 8 weeks and blood samples collected at baseline and 8 weeks. Both the treatment and placebo groups showed increases in happiness and sexual function over the trial however the treatment group’s increase was greater. Comment: Damask Rose has a gloriously sweet aromatic scent that is used in many perfumes. It is rich in volatile components such as citronellol, geraniol, nerol, quercetin, kampferol, and linalool, all of which have shown to possess biologically therapeutic activity. This study reflected in the present sample of females, the group’s previous work showing that the essential oil used orally may be of potential benefit in improving male sexual function in those using methadone maintenance therapy. It can be considered however that the methods in this study were poorly described in respect to the dilution and mode of administration of the oil (it appeared to be delivered in an oral liquid via a dropper). Further, the 2mL dose used in the study is extremely expensive considering the volume of rose petals needed for 1mL of the pure oil. Finally, while it was said to be blinded via a non-active aromatic placebo oil, it is hard to escape the obviously known therapeutic effect from direct inhalation. It is puzzling why it wasn’t administered in a soft gel capsule for blinding purposes. Reference: Journal of Psychiatric Research 2017;95: 260-68 Abstract

Modified African Ngoma healing ceremony for stress reduction Authors: LaVonne V et al. Summary: This pilot study investigated the use of a modified African tribal Ngoma drum and dance ceremony for stress reduction in women. 21 women completed an 8 -week program of a weekly session of either Ngoma or mindfulness-based stress reduction. Depression, anxiety and social functioning were assessed by self-completed questionnaires. The authors concluded that Ngoma ceremony participation resulted in a decrease in stress levels comparable to MBSR but should be tested in larger trials. Comment: There are various forms of indigenous healing ceremonies throughout the world, and these have profound physiopsychosocial effects. It is heart-warming to see these traditions continue, and to be studied using robust scientific methodology. While this particular study had some short-comings, the results of the pilot are encouraging, and provide the basis for future similar work. Cultural sensitivities need to be respected in the delivery of such interventions, however if handled in an appropriate manner, may also have a greater benefit in providing a vector for fellow humans to connect and share their cultural blessings. Reference: The Journal of Alternative and Complementary Medicine 2017;23(10) Abstract

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