Herbal and Complementary Medicine in the Treatment of Depression and Anxiety

Background: Mood and Anxiety disorders have a profound personal and socioeconomic impact. Response and remission rates from orthodox pharmacotherapies currently have moderate efficacy: more options are needed. Herbal and complementary medicines offer promise for the treatment of depression and anxiety, however research in this area is still in its infancy. Aims: To research the current evidence for herbal and complementary medicines in the treatment of mood (specifically unipolar depression) and anxiety disorders. To identify areas of interest where there are gaps in the literature, and to subsequently conduct two clinical trials in these areas. The research design aimed to create a thesis ‘by publication’, detailing 13 publications that pertain to the area of herbal and complementary medicine and mood and anxiety disorders. Process: Initial literature reviews on herbal medicine and psychiatric disorders, nutritional medicine and major depression, and exercise and depression were conducted to develop knowledge in the area and ascertain the gaps in the literature. Results revealed that in respect to nutritional medicines, varying levels of supportive evidence exists for using omega-3, folate, Sadenosyl methionine (SAMe), and L-Tryptophan as monotherapies and with synthetic pharmacotherapies to treat unipolar depression. A review of exercise in the treatment of depression revealed robust evidence for the use of physical activity as a mood elevating intervention. In regards to herbal interventions, Hypericum perforatum (St John’s wort: SJW) and Piper methysticum (Kava) were found to have the most evidence in the herbal treatment of depression and anxiety, respectively. A subsequent literature review was conducted on these herbal medicines. SJW was revealed via review of randomised controlled studies and meta-analyses to be equally effective to antidepressants in treating major depressive disorder. This activity is posited to occur via modulation of neurotransmission and neuroendocrine pathways, including non-selective inhibition of re-uptake of serotonin, dopamine, norepinephrine, decreased degradation of neurochemicals and sensitisation and binding to various neuroreceptors, dopaminergic activity (prefrontal cortex) and cortisol/hypothalmic pituitary adrenal -axis modulation. Kava was also revealed to have meta-analytic evidence in support of anxiolytic activity. This is postulated to occur via GABA membrane modulation, weak GABA binding and blockage of voltage-gated channels, and β-adrenergic downregulation. From this review a deficit in the area of treating comorbid depression and anxiety was identified, and no studies were found using SJW and Kava concomitantly. Due to this, the first study was formulated and conducted, hypothesising that a combination of SJW and Kava may be more effective in reducing participants’ co-occurring depression and anxiety than placebo. First clinical trial: A world-first randomised, placebo-controlled, crossover pilot trial was conducted, involving SJW and Kava in the treatment of major depressive disorder and comorbid anxiety. Twenty eight adults with major depressive disorder and co-occurring anxiety were recruited. After a placebo run-in of two weeks, the trial had a crossover design testing SJW and Kava against placebo over two controlled phases, each of four weeks. The primary analyses used intention-to-treat and completer analyses. On both intention-to-treat (p = 0.047) and completer analyses (p = 0.003), SJW and Kava gave a significantly greater reduction in selfreported depression on the Beck Depression Inventory II over placebo in the first controlled phase. However in the crossover phase, a replication of those effects in the delayed medication group did not occur. Nor were there significant effects on anxiety or quality of life. Possible explanations for the absence of anxiolysis may include a potential interaction with SJW, the presence of depression, or an inadequate dose of Kava. Furthermore, the high dropout significantly reduced the statistical power of the study, precluding firm conclusions. Second clinical trial: The next study sought to determine if the presence of depression affected participants’ anxiolysis from Kava by using a sample of people with chronic anxiety and varying levels of depression. The hypothesis was that higher levels of depression may truncate the anxiolytic effect from Kava. A supplementary aim of the study was to use an aqueous extract of Kava, which in light of hepatotoxic effects from acetone and ethanol based preparations (and incorrect plant parts and cultivars) may be potentially safer. No previous clinical trials had used a traditional aqueous extract. The Kava Anxiety Depression Spectrum Study (KADSS) was a 3-week placebo-controlled, doubleblind, crossover trial in participants with elevated generalised anxiety. Piper methysticum (Kava) has been withdrawn in European, British, and Canadian markets due to concerns over hepatotoxic reactions. The WHO recently recommended research into ‘aqueous’ extracts of Kava, which may be a safer formulation of the herb (as opposed to non-traditional acetone or ethanol extracts). Sixty adult participants currently experiencing one month or more of generalised anxiety were prescribed 5 tablets per day of Kava containing 50mg of kavalactones (250mg/day). Results revealed the pooled effect of Kava vs. placebo across phases was highly significant (p < 0.0001), with a substantial effect size (d = 2.24, ηp2 = .428). Pooled analyses also revealed highly significant relative reductions on the Beck Anxiety Inventory. A previously undiscovered antidepressant effect was revealed with highly significant reductions of depression scores occurring on the Montgomery-Asberg Depression Rating Scale (p = 0.003, d = 0.75 ηp 2 = .223). The aqueous extract was found to be safe, with no serious adverse effects, and no clinical hepatotoxicity. The aqueous Kava extract appears equally effective in cases where anxiety is accompanied by depression. This should encourage further study and consideration of globally reintroducing aqueous rootstock extracts of Kava for the management of anxiety. Conclusions: A review of the literature revealed that in the area of herbal and nutritional treatments of depression and anxiety, strong evidence exists for SJW in the treatment of depression, and for Kava in the treatment of generalised anxiety. Other herbal medicine monotherapies in the treatment of depression or anxiety or other psychiatric disorders currently have insufficient evidence to firmly recommend use. In respect to nutritional interventions, SAMe, L-Tryptophan, omega-3 and folate have limited evidence as monotherapies, while as adjuvants to antidepressants they have evidentiary support. Aside from exercise and relaxation interventions, other complementary medicine interventions currently possess limited evidence in the treatment of mood and anxiety disorders. The conclusions from the first study indicate that use of SJW and Kava concomitantly appears to not be an effective treatment of anxiety with or without co-occurring depression. The second study supports that an aqueous extract of Kava is an effective acute anxiolytic and tentatively demonstrates antidepressant properties. Possible future steps involve further exploration and clinical studies of promising medicinal plants in the treatment of depression or anxiety as monotherapies (or as augmenting agents with pharmacotherapies), while a larger and longer phase III Kava clinical trial is required to confirm the results of KADSS