Outcomes of Self-help Efforts in Anxiety Disorders

Amy J Morgan; Anthony F Jorm

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2009;9(5):445-459. 

In This Article

Supplements & Plant Remedies

5-hydroxy-tryptophan

Description 5-hydroxy-tryptophan (5-HTP) is an amino acid that is the immediate precursor of serotonin. It can be purchased as an over-the-counter dietary supplement in some countries.

Therapeutic Mechanism The therapeutic mechanism is not clear; however, it may be linked with an increase in serotonin synthesis.

Review of Efficacy One RCT has examined 5-HTP for anxiety disorders.[17] A total of 45 outpatients with agoraphobia with panic attacks, generalized anxiety disorder, panic disorder, or obsessive–compulsive disorder, were randomized to clomipramine, 5-HTP or placebo for 8 weeks. Patients treated with 5-HTP also received 150 mg carbidopa per day. Patients treated with 5-HTP showed a slight reduction in anxiety as assessed with the Hamilton Anxiety Scale; however, the effect was not significantly different from either placebo or clomipramine. However, five out of 15 treated with 5-HTP improved more than 50%, compared with only one out of 15 on placebo. Furthermore, an RCT of 24 patients with panic disorder found that 200 mg 5-HTP 90 min before a 35% CO2 challenge significantly reduced panic anxiety and symptoms compared with a placebo.[18]

Safety Issues The study by Kahn showed an initial and transient worsening of anxiety symptoms in those treated with 5-HTP before they started to improve.[17]

Conclusion 5-HTP shows promise for anxiety disorders but has yet to be adequately investigated.

Bach Flower Remedies

Description Bach flower remedies are a system of 38 flower extracts developed by Dr Edward Bach in the 1930s. The extracts of the flower are highly dilute, as they are made by dropping fresh flowers into water in the sun, removing the flowers after a few hours and then preserving the water with alcohol. A popular combination of five remedies is marketed as Rescue Remedy®, which is available in pharmacies and health food shops along with individual remedies.

Therapeutic Mechanism Bach flower remedies are believed to contain small amounts of the plant's life force energy, which heals emotional imbalances.

Review of Efficacy One small trial has evaluated the anxiolytic effect of Rescue Remedy, although the trial included participants with diagnoses other than anxiety disorders, such as depression or schizoaffective disorder.[19] In total, 98 patients were randomized to Rescue Remedy or placebo (water and alcohol drops) for 3 days and instructed to self-medicate at the onset of anxiety. There was no difference in effect on anxiety between the Rescue Remedy and placebo.

Safety Issues Bach flower remedies are devoid of toxicology due to their highly dilute nature.[20]

Conclusion Bach flower remedies for anxiety disorders have not been adequately investigated.

Combined Plant Preparations

Description Euphytose is a combination of six plant extracts: Hawthorn (Crataegus oxyacantha), Ballota foetida, passion flower (Passiflora incarnata), valerian (Valeriana officinalis), cola (Cola nitida) and guarana (Paullinia cupana), which is available in France as an over-the-counter anxiolytic. Sympathyl is a combination of Hawthorn (Crataegus oxyacantha), California poppy (Eschscholtzia californica) and magnesium, which is also available without a prescription in France.

Therapeutic Mechanism Euphytose is a combination of both mild sedatives and stimulants. Some components are thought to act on central benzodiazepine receptors and some are traditional remedies for anxiety. Hawthorn and California poppy in Sympathyl are reputed to have anxiolytic properties and magnesium deficiency can cause psychological disturbance.

Review of Efficacy Euphytose has been evaluated in one short, double-blind, placebo-controlled study.[21] A total of 181 adult outpatients with adjustment disorder with anxious mood were randomized to either euphytose or placebo for 28 days. A statistically significant effect was found for both reduction in symptoms and clinical response for Euphytose over placebo at the end of the trial. Sympathyl has been evaluated in one RCT in 264 adults with generalized anxiety disorder.[22] Participants were randomized to Sympathyl or placebo for 3 months. The Sympathyl group improved significantly more than the placebo group both in reduction in symptoms and number of responders.

Safety Issues Euphytose was well tolerated in the aforementioned trial with no difference in the number of adverse effects compared with placebo and no serious adverse effects. Adverse effects from taking Sympathyl were mostly digestive symptoms and were largely mild or moderate. Three severe adverse events were one case of muscular stiffness, one case of insomnia and one case of nausea that led to premature treatment discontinuation.

Conclusion Both combined preparations report positive effects from single RCTs; however, replication is required before firm conclusions can be made.

Ginkgo Biloba

Description Extracts of the leaves of the Ginkgo biloba tree are used therapeutically. EGb 761® is a Ginkgo biloba extract registered in a number of countries for the treatment of dementia disorders. Some studies of EGb 761 treatment of these disorders have also observed beneficial effects on anxiety, suggesting the possibility that it may be effective for anxiety disorders.

Therapeutic Mechanism This is not understood. It has been hypothesized that suppression of corticotrophin-releasing hormone secretion may attenuate abnormal hypothalamic–pituitary–adrenal axis activation.[23]

Review of Efficacy One randomized, controlled, double-blind trial has been reported with EGb 761.[23] In total, 107 patients with either generalized anxiety disorder or adjustment disorder with anxious mood were randomized to daily doses of 480, 240 mg or placebo for 4 weeks. Improvement was significantly greater in the treated groups and there was a greater effect at the higher dose. A subgroup analysis showed that the treatment worked with the generalized anxiety disorder patients alone, but there were not enough adjustment disorder patients for a separate analysis of that group.

Safety Issues In the aforementioned trial, EGb 761 did not differ from placebo in adverse events.

Conclusion The Ginkgo biloba extract EGb 761 appears promising as a treatment for generalized anxiety disorder, but replication studies are needed.

Homeopathic Remedies

Description Homeopathy uses very small doses of substances to stimulate self-healing. Substances are selected that produce, in a healthy person, symptoms similar to those of the illness when used undiluted. Homeopathic remedies are prepared by diluting substances with water and alcohol, and shaking them. This process is then repeated many times until there is little or none of the substance left. Homeopathic remedies are usually provided by a practitioner but individual remedies are also available over the counter.

Therapeutic Mechanism Homeopathy is based on the principle of 'like cures like'. The diluting and shaking process is thought to have two functions. It removes any harmful effects of the substance, while the water retains the memory of the substance.

Review of Efficacy One systematic review focusing specifically on homeopathy for anxiety and anxiety disorders has recently been published.[24] Although it found a number of RCTs to review, only one was in a population with a diagnosed anxiety disorder. This trial included in 44 adults with generalized anxiety disorders and compared treatment with single homeopathic medicines prescribed on an individualized basis or placebo for 10 weeks. Anxiety symptoms significantly improved in both groups, but the study was underpowered to detect a difference in improvement between groups.

Safety Issues Although there may be under-reporting of negative reactions, reported adverse effects are relatively rare, mild and transient. They include temporary worsening of symptoms and reappearance of old symptoms.[24]

Conclusion Homeopathic remedies for anxiety disorders have not been investigated adequately.

Inositol

Description Inositol is an isomer of glucose. It is naturally present in the human diet and is available as a supplement.

Therapeutic Mechanism Myo-inositol (an inositol isomer) is a precursor in the phosphatidylinositol second-messenger system, which is used for several neurotransmitters, including some subtypes of serotonin receptors. Many mental disorders, including anxiety disorders, have been hypothesized to involve abnormalities of nerve cell myo-inositol levels or the phosphatidylinositol second-messenger system.[25]

Review of Efficacy A number of small, randomized, double-blind, placebo-controlled, crossover trials have been carried out. A study of patients with panic disorder found positive effects of 12 g/day over 4 weeks.[26] To investigate the mechanisms of action in panic disorder, a subsequent study was carried out in patients subjected to the panic-inducing drug, meta-chlorophenylpiperazine.[27] Acute inositol administration was found not to affect responses to this drug, suggesting that the time course of action for inositol may be longer and similar to that of antidepressants. Another trial compared inositol with fluvoxamine in panic disorder.[28] Similar overall effects were found for 18 g/day of inositol over 1 month compared with 150 mg/day of fluvoxamine. However, the inositol treatment reduced the rate of panic attacks more.

Inositol has also been tested with obsessive–compulsive disorder patients. A comparison with placebo found positive effects of 18 g/day over 6 weeks.[29] However, another study found that inositol did not augment the effects of selective serotonin reuptake inhibitor antidepressant treatment, even though the two treatments were hypothesized to have different sites of action.[30]

Finally, no effect was found in a double-blind, placebo-controlled, crossover trial of post-traumatic stress disorder patients who received 12 g/day over 4 weeks.[31]

Safety Issues In the aforementioned trials, few side effects have been reported.

Conclusion There is some preliminary indication that inositol may be effective for panic disorder and obsessive–compulsive disorder. Larger trials examining longer term effects are needed.

Kava (Piper Methysticum)

Description Kava is a herb from the South Pacific that has been used as a social drink and in ceremonial rituals for hundreds of years. Extracts are obtained from the dried root and rhizome. Products containing kava have been banned in Germany, France, Switzerland, Canada and Australia.[32] It is available in the USA, but the US FDA has issued warnings to consumers and doctors.

Therapeutic Mechanism Kavalactones are thought to be the active components. A number of mechanisms have been proposed, including blockading voltage-gated ion channels and facilitation of GABAergic transmission.[33]

Review of Efficacy A Cochrane review of placebo-controlled RCTs found 12 trials to review, but only seven provided data for the meta-analysis.[34] Participants had generalized anxiety disorder (one trial), nonpsychotic anxiety according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R; four trials), nonpsychotic anxiety syndrome according to International Statistical Classification of Diseases and Related Health Problems (ICD-9; one trial) or anxiety owing to climacteric syndrome (one trial). All except one of these trials used the same preparation, WS1490, which is standardized to 70% kavalactone content and is produced by the same manufacturer. Imputation was used in most trials to calculate the variance of the pre-intervention to postintervention change. Weighted mean difference between kava and placebo on the Hamilton Anxiety Scale (HAM-A) was 3.9 (95% CI: 0.1–7.7; n = 380). The five studies not included in the meta-analysis largely supported the findings from the meta-analysis. The authors concluded that kava extract is an effective symptomatic treatment for anxiety, but that the size of the effect seems to be small.

Since the Cochrane review, another meta-analysis has been published.[35] This restricted trials to those that used the extract WS1490 in nonpsychotic anxiety disorder patients and used the HAM-A as the outcome measure. Although it did not find any new trials, no imputation was performed as individual patient data was obtained from the manufacturer. The meta-analysis of six trials found patients in the kava group significantly more likely to improve by 50% or more (odds ratio: 3.3; 95% CI: 2.09–5.22); however, the meta-analysis of continuous HAM-A outcome data was nonsignificant (5.94; 95% CI: -0.86 to 12.8).

Since these meta-analyses were published, another two RCTs have been published.[36] These had small samples (11 patients treated with kava in total) and included patients with generalized anxiety disorder of moderate severity. There were no significant differences in remission rates and only a trend in favor of the kava group on the HAM-A in one of the studies.

Safety Issues Kava has been implicated in a number of cases involving liver damage, although this remains controversial and the mechanism by which this occurs is not yet clear.[32] Use of kava at frequent high doses causes kava dermopathy, a reversible skin rash. The Cochrane review found no reports of hepatotoxic events and seven of the trials measured liver enzyme levels as safety parameters but reported no clinically significant changes.

Conclusion Although the evidence is not entirely consistent, it appears that kava extract may be effective for some anxiety disorders. However, there are concerns regarding its safety profile that are yet to be resolved.

Omega-3 Fatty Acids (Fish Oils)

Description Omega-3 fatty acids are long-chain polyunsaturated fatty acids. The two most studied in mental disorders are eicosapentanoic acid (EPA) and docosahexanoic acid, which are found in fish, are made in the body from α-linolenic acid, or are available to buy as supplements.

Therapeutic Mechanism The therapeutic mechanism is not known; however, omega-3 fatty acids affect membrane composition and influence cellular function. Given their possible efficacy in affective disorders, they have been proposed as potentially effective in obsessive–compulsive disorder, which also responds to antidepressants.[37]

Review of Efficacy One small, crossover trial has been conducted on EPA for obsessive–compulsive disorder.[37] Patients with diagnosed obsessive–compulsive disorder who were stable on serotonin reuptake inhibitors were randomly allocated to 6 weeks of placebo (2 g liquid paraffin oil per day) followed by 6 weeks of 2 g of EPA or EPA followed by placebo. Both groups significantly improved their symptoms, but EPA was not more effective than placebo.

Safety Issues No clinically relevant side effects were reported in the aforementioned study.

Conclusion Limited evidence suggests that adjunctive EPA is ineffective against obsessive–compulsive disorder. It has not been adequately researched for other anxiety disorders.

Passionflower (Passiflora Incarnata)

Description Passionflower is a plant native to the Americas used as a folk remedy for anxiety and insomnia. For therapeutic use, it is available in tablet, dried herb or liquid extract form.

Therapeutic Mechanism The therapeutic mechanism is not understood, but could be related to activation of benzodiazepine receptors.[38]

Review of Efficacy A systematic review found two randomized trials that compared passion flower with benzodiazepines over a 4-week period.[39] One trial involved the treatment of generalized anxiety disorder and the other involved neurosis/anxiety (with no specific diagnostic criteria). In both studies, there were no significant differences and dropout rates were similar.

Safety Issues A case study has been reported in which self-administration led to severe nausea, vomiting, drowsiness, prolonged QTc and episodes of nonsustained ventricular tachycardia.[40]

Conclusion There are too few data on whether passion flower is effective to reach a conclusion. There is a need for comparisons with placebo and with antidepressant medication.

St John's Wort (Hypericum Perforatum)

Description St John's wort is a flowering plant used as a traditional remedy. In many countries, extracts of St John's wort are widely used for depression, but also for anxiety and sleep disorders.

Therapeutic Mechanism There is evidence of serotonergic, dopaminergic and GABAminergic activity.[41]

Review of Efficacy Many trials have been carried out on St John's wort for depression, but much less is known regarding its effects on anxiety disorders. Two randomized trials have been reported. One study compared St John's wort with placebo over 12 weeks in 60 people with obsessive–compulsive disorder.[42] No significant differences were found. The second trial compared St John's wort to placebo over 12 weeks in 40 people with social phobia.[41] Again, no significant effects were found.

Safety Issues The use of St John's wort causes fewer side effects compared with the use of antidepressants.[43] However, it may have clinically important interactions with a range of prescribed medications, including anticancer agents, anti-HIV agents, anti-inflammatory agents, antimicrobial agents, cardiovascular drugs, CNS agents, hypoglycemic agents, immunomodulating agents, oral contraceptives, proton pump inhibitors, respiratory system agents and statins.[44]

Conclusion The available evidence does not support a role for St John's wort in the treatment of anxiety disorders.

Valerian (Valeriana Officinalis)

Description Valerian is a plant commonly used for insomnia and also anxiety. The root can be used dried, as an extract or in a tincture.

Therapeutic Mechanism More than 150 constituents have been identified, including valepotriates, volatile oils and sesquiterpenes; however, none appear to be solely responsible for its effects (2004). Valerian interacts with GABA and one component has been found to bind to benzodiazepine receptors.

Review of Efficacy A Cochrane review of RCTs or quasi-RCTs of valerian for anxiety disorders only found one trial to review.[45] This was a small, 4-week trial in 36 adults diagnosed with generalized anxiety disorder who were randomized to valerian, diazepam or placebo. There was no significant difference in symptom reduction between valerian and placebo. There was also no significant difference between valerian and diazepam when symptoms were measured by clinicians, but diazepam had significantly lower symptom scores than valerian when symptoms were self-rated.

Safety Issues Valerian is on the US FDA's Generally Recognized as Safe list. Side effects such as nausea, headache, dizziness and upset stomach have been reported in fewer than 10% of participants in randomized trials.[46]

Conclusion Valerian for anxiety disorders has not been adequately investigated.

Withania Somnifera (Ashwagandha)

DescriptionWithania somnifera is a plant that has been used for centuries in India to treat a variety of ailments, including stress and anxiety.[47] The roots are the main part of the plant used for therapeutic purposes.

Therapeutic Mechanism The therapeutic mechanism is thought to involve its agonistic effects on GABA neurotransmission.

Review of Efficacy A review found one double-blind, placebo-controlled study of Withania somnifera in 39 patients with ICD-10 anxiety disorders.[47] The trial found a significant superiority of Withania over placebo after 6 weeks, and it caused no more adverse effects than placebo.

Safety Issues Extensive toxicological studies in animals indicate that it is nontoxic in a wide range of reasonable doses.[47] Anecdotal reports suggest that Withania somnifera may potentiate the effects of barbiturates. Large doses have been shown to cause gastrointestinal upset and may possess abortifacient properties, so it should not be taken during pregnancy.[48]

Conclusion Withania somnifera has been inadequately investigated for anxiety disorders. One controlled study shows promising anxiolytic effects, but it requires replication.

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