Chapter 13 Chronic generalised anxiety
CLASSIFICATION, EPIDEMIOLOGY AND AETIOLOGY
Generalised anxiety disorder (GAD) is diagnosed in people with excessive worry and anxiety, which the person finds difficult to control. Somatic complaints and sleeping problems often accompany the anxiety. According to DSM-IV diagnostic criteria, in addition to uncontrollable worrying, there must also be at least three of six somatic symptoms (restless, fatigue, concentration problems, irritability, tension or sleep disturbance), occurring for a period of at least 6 months.1 For a diagnosis of GAD to be reached, significant distress or impaired functioning from the condition must be present. As in MDD, a number of exclusion criteria must also be ruled out (for example, symptoms must not be confined to features of another mental disorder or due to substance use or general medical conditions). Occasional worry and situational anxiety is a normal human experience; true chronic generalised anxiety is a disorder whereby the worrying becomes self-perpetuating and uncontrollable, has a number of distressing somatic features and causes marked impairment of work or social functioning. It should be noted that the diagnosis of GAD is fairly restrictive in terms of the requirement of a long duration and multiple somatic symptoms. As the condition commonly waxes and wanes, the DSM-IV diagnosis may be excessively restrictive in clinical practice.2 A utilitarian diagnosis may involve a period of anxiety or worry that is bothersome to the patient and has occurred for longer than 2 weeks. It is also worth considering that in some people GAD may reflect ‘trait anxiety’—that is, a person whose personality archetype is that of a chronic worrier.
Anxiety disorders are second only to MDD as the most commonly diagnosed psychiatric conditions in primary care,3 with GAD being present in 22% of primary care patients who complain of anxiety problems.4 Consistent with the DSM-IV manual’s description of the 1-year prevalence of GAD as approximately 3%,1 a sample of 10,641 Australians interviewed in 1997 had a 1-month prevalence of 2.8% and a 12-month prevalence of 3.6%.5 Lifetime prevalence of GAD is approximated at around 5–6%.4 Anxiety symptoms are endemic in depression,6 and true comorbidity of depressive and anxious conditions commonly occurs.7,8 Studies have revealed that approximately 60–80% of patients with GAD will suffer from a mood disorder within their lifetimes.9,10 Pure GAD (without other comorbid psychiatric disorders) exists at around 25%.4 The socioeconomic burden of GAD is immense, with sufferers more likely than any other patient group to make frequent medical appointments and use medical resources. In a study of 36,435 GAD patients aged 18 to 64 identified from a claims database, the average total healthcare costs per patient was US$7451.10 Patients with comorbid depression were found to have on average 10% higher costs. As in the case of major depressive disorder, only approximately 40% of sufferers seek treatment and 60% will achieve full or partial remission for over 5 years.11
The pathophysiology of GAD is still uncertain. It appears that GAD has a strong underlying genetic component, which may be triggered into expression by environmental factors.12 Current evidence indicates that the neurobiological influence involves abnormalities of serotonergic, noradrenergic and GABAergic transmission, which is reflected in the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenalin reuptake inhibitors (SNRIs) and benzodiazepines, which modulate the previously mentioned pathways, respectively.13 Although still not understood, the main neurocircuitry involved in the panic, fear and anxiety response in humans appears to involve the prefrontal cortex, the hippocampus and the amygdala.14 Psychological causes may also exist, for instance a specific cognitive bias to increased attention and misinterpretation of ambiguous stimuli, which are perceived as threatening.11
RISK FACTORS
Several risk factors and protective factors exist for GAD (see Figure 13.1). The primary risk factor for developing GAD appears to be genetic.12 Significant familial aggregation also exists, with a strong correlation between the sufferer and a first-order relative with the disorder.15 An anxiogenic familial environment appears also to contribute to the development of the pathology, although the data suggest that genetics are the dominant factor.12 Women are twice more likely to experience GAD than men, and a diagnosis of GAD is uncommon in children and adolescents with the incidence of GAD greatly increasing later in life (onset is usually after 25 years of age).15 As discussed above, comorbidity with depression is common, so it is salient to do a screening for GAD when depressive symptomatology is present. Comorbidity with other psychiatric disorders is more common than not, with an estimated 90% of GAD patients having one or more disorders such as social phobia, panic disorder, obsessive-compulsive disorder and bipolar depression.16 In fact, the diagnosis of GAD may be seen as a risk factor for the development of these other psychiatric disorders and also of alcohol and substance abuse disorders.17
CONVENTIONAL TREATMENT
Medical treatment of anxiety disorders primarily focuses on pharmaceutical and psychological interventions. Pharmacotherapies include synthetic anxiolytics (for example, benzodiazepines, pre-gabalin, β-blockers and buspirone), and antidepressants (for example, tricyclics, monoamine oxidase inhibitors and SSRIs/SNRIs).18 Current evidence supports the use of both antidepressants and benzodiazepines, with some studies indicating that paroxetine and venlafaxine are the preferable choices. Several issues are present with respect to treatment of anxiety disorders with benzodiazepines. Common side effects include sedation, motor disturbance and cognitive interference (due to GABA-α1,2 agonism), while long-term treatment (> 2 weeks) may cause dependence and withdrawal issues.18,19 Abrupt cessation of benzodiazepines may cause rebound symptoms such as insomnia, agitation and digestive disturbance, and the patient’s anxiety may return to an even higher level than before treatment.19 Psychological interventions include a variety of cognitive, behavioural and interpersonal techniques.11 Combination approaches using psychological and pharmacotherapy treatments are commonly recommended; also, evidentiary support does not currently endorse this approach over using each as a monotherapy.20 The combination does, however, seem to make sense, as pharmacotherapies such as benzodiazepines (or natural alternatives such as Piper methysticum) may elicit an immediate benefit while psychology techniques have been shown to lessen the chance of relapse over the long term.11,20
KEY TREATMENT PROTOCOLS
treatment to ameliorate anxiety. Psychological intervention also at this time may be beneficial by working on interpersonal and behavioural skills, and the elimination of anxiogenic self-talk. It is also worth noting that a depressive phase often occurs after an episode of GAD,21 so patient education and prevention strategies are vital. The final main protocol in treating GAD is to educate the patient about self-help interventions they can use to better manage their stress. The use of bibliotherapy, massage, aromatherapy and exercise, and the adoption of calming euthymic activities or hobbies, may also be beneficial (these are reviewed below). While individually each of the aforementioned interventions may possess limited evidence, or have a small clinical effect, the use of many of these self-help techniques in the context of an overall lifestyle pattern may provide a sustained healing effect.
Although the goal is to use evidence-based treatments, it is encouraging to know that any therapeutic interface will commonly promote an anxiolytic effect. Evidence reveals that sufferers of GAD commonly experience other presentations of anxiety such as panic attacks and social phobias.23 Because of this, thorough case taking needs to be employed to assess for any comorbidities. Panic attacks are a severe manifestation of anxiety, and their co-occurrence with GAD or MDD indicates a more severe condition, resulting in a potentially poorer prognosis and more demanding treatment protocol. In the case of comorbid social phobia, behavioural and interpersonal issues need to be explored via an appropriate psychological intervention. As detailed below, several theories and models exist.
GABA pathways and the limbic system
The key biological pathway involved in the presentation and modulation of anxiety disorders involves gamma aminobutyric acid (GABA).11 GABAergic neurones and receptors are involved in the main mode of inhibitory transmission in the central nervous system, and these innervations densely occupy parts of the anxiety/fear-modulating corticolimbic system such as the hippocampus and amgydala.25 GABA-α receptors are the principal target of benzodiazepines, exerting affects such as anxiolysis, sedation and anticonvulsant effects.13 Stimulation of GABAergic pathways also modulates the release of several key neurochemicals (for example, noradrenaline, serotonin and dopamine), although the exact effects are still disputed. Herbal medicines may exert GABA-modulating activity; however, no definitive GABA-α1,2 modulation has been demonstrated to date in humans by any herbal medicines. Valerenic acid from Valeriana officinalis has, however, demonstrated GABA-A receptor (β3 subunit) agonism; this mechanism has been identified as an important pharmacodynamic action responsible for the plant’s anxiolytic and hypnotic action.26
The phytotherapy that has received the greatest attention regarding GABAergic activity is Piper methysticum (kava). Current evidence indicates that kavalactones (the resinoid lipid-soluble constituents found primarily in the root and stem) modulate GABA activity via alteration of lipid membrane structures, and sodium channel alteration, rather than by significant GABA-α1,2 agonism.27–29 Importantly, this activity in animal models was found to occur in the anxiety/fear modulating hippocampus and amygdala. Other neuromodulatory activity effecting anxiolysis are considered to involve
Placebo response is endemic in sufferers of anxiety, with approximately 25% receiving marked benefit from a placebo (dummy) intervention!22
a down-regulation of β-adrenergic activity and MAO-B inhibition.30 Interestingly, inhibition of the re-uptake of noradrenaline in the prefrontal cortex has been demonstrated in animal models.30 This facilitates kava’s unique effect of enhancing mental acuity while relaxing the body and calming the mind. This effect is of a distinct advantage compared to alcohol and benzodiazepines, which cause deleterious cognitive effects. Another advantage of using kava in anxiety disorders is that kavalactones have also demonstrated relaxation of muscular contractibility via modulation of sodium and calcium channels.31 Somatic tension is a common occurrence in anxiety disorders.11
Strong evidence supports the use of kava in treating anxiety disorders. A Cochrane review of 12 randomised, double-blind, controlled trials of rigorous methodology using kava mono-preparations (60 mg–280 mg of kavalactones) in anxious conditions revealed positive results in favour of the phytomedicine.32 A meta-analysis of seven homogenous trials using the Hamilton anxiety scale33 (HAMA) demonstrated that kava reduced anxiety significantly compared to placebo. This effect was supported by another meta-analysis based on six placebo-controlled, randomised trials using a standardised kava extract WS1490 in anxiety (assessed via HAMA).34 Medicinal use of kava is currently restricted in the European Union, and Canada over hepatoxicity.35 The World Health Organization (WHO) has recommended research into ‘aqueous’ extracts of the plant to establish its safety and efficacy in treating anxiety disorders.35 This is in preference to previous acetonic or ethanolic extracts, which may be implicated in hepatoxic reactions. A recent clinical trial sought to assess the effects of an aqueous extract of kava (see the box below).
Other herbal medicines that may affect anxiolysis via limbic system interaction with evidence from human studies include Passiflora incarnata, Scutellaria lateriflora, Melissa officinalis and Ginkgo biloba Passiflora incarnata has traditional usage in the treatment of anxiety and neurosis.37 A Cochrane review of passionflower in the treatment of anxiety included two randomised controlled trials (RCTs) that met inclusion criteria with a total of 198 participants.38 One, a study comparing P. incarnata extract (90 mg/day) to the benzodiazepine mexazolam (1.5 mg/day), revealed no statistical differences in outcome. A trend towards advantage of phytomedicine over the
THE KAVA ANXIETY DEPRESSION SPECTRUM STUDY (KADSS)36
benzodiazepines was noted with respect to decreased sedation and job performance. The other trial included in the review, a pilot RCT using P. incarnata extract on 36 patients with GAD, demonstrated equivalent efficacy of the HM with oxazepam (30 mg/day) in reducing anxiety.39 The herb was determined to cause fewer side effects.40 A recent study using P. incarnata (500 mg) in a controlled study involving 60 patients with preoperative anxiety (90 minutes before surgery) revealed significantly lower anxiety (assessed via a numerical rating scale) in the active group than in the control group.41 No significant differences occurred between other psychological variables, for example recovery and psychomotor function.
The fragrant herbal medicine Melissa officinalis has traditional usage as a mild sedative and an antispasmodic.37,42 A double-blind, placebo-controlled, randomised, balanced crossover experiment involving 18 participants using two separate single doses of a standardised M. officinalis extract (300 mg, 600 mg) and placebo showed that acute dosing of the herbal medicine demonstrated a significant increase in self-rated calmness on a Defined Intensity Stressor Simulation (DISS) test.43 A subsequent crossover RCT using a standardised M. officinalis and Valeriana officinalis product in 24 healthy volunteers demonstrated that a 600 mg dose of the combination lowered anxiety levels compared to control on the DISS.44
Scutellaria lateriflora is a traditional anxiolytic herbal medicine that has been used to treat a variety of nervous system disorders in Native American and eclectic medicine.37 In an animal maze test model, the herb displayed anxiolytic effects, with the compounds baicalin and baicalein purported to be involved in this activity via GABA-α binding.45 A double-blind, placebo-controlled crossover study of 19 healthy adults demonstrated that S. lateriflora dose-dependently reduced symptoms of anxiety and tension after acute administration compared to control.40 It should be noted that the methodology of this trial was weak and further research is required to confirm the herb’s efficacy.
While Ginkgo biloba is primarily studied for neuromodulatory activity for the treatment of cognitive conditions, studies have documented mood modulation in cognitively impaired subjects.46 A 2006 RCT involving 82 subjects with GAD using G. biloba EGb 761 extract (480 mg or 240 mg per day) or placebo for 4 weeks revealed a significant dose-dependent reduction of HAMA over placebo in the 480 mg/day and the 240 mg/day G. biloba groups.47
Eschscholtzia californica, Zizyphus jujuba and Valeriana spp. are other plant medicines with encouraging activity; however, to date no human clinical studies have been conducted using these as monotherapies to treat anxiety disorders. Studies are required to validate these traditional uses. Eschscholtzia californica promisingly exerts binding affinity to GABA receptors, with flumazenil (a benzodiazepine receptor antagonist) suppressing these sedative and anxiolytic effects.48 Animal models have revealed that the jujubosides in Zizyphus jujuba inhibit glutamate-mediated pathways (excitory pathway) in the hippocampus.49 Other studies using suanzoaren (a traditional Chinese medicine formula containing Z. jujuba as the principal herbal medicine) in animal models have demonstrated modulation of central monoamines and limbic system interaction.50,51
Magnesium has an important role in neurological activity, and deficiency of the nutrient may cause neuropathologies.52 Magnesium ions regulate calcium ion flow in neuronal calcium channels, helping to regulate neuronal nitric oxide production.53 The deficit of neuronal magnesium ions may be induced by stress hormones, excessive dietary calcium and dietary deficiencies of magnesium.53 Studies using animal models have demonstrated that magnesium deficiency can cause depression and anxiety-like behaviour. After magnesium administration to deficient animals, anxiolytic activity was demonstrated in mice during elevated plus maze and forced swim tests.54 Magnesium appears to exert its anxiolytic effect by the involvement of the NMDA/glutamate pathway, and this activity may involve the glycine(B) sites.55 Interaction between magnesium and benzodiazepine/GABA-α receptors may also be involved in producing anxiolytic-like activity.56 A preliminary controlled study for the relief of mild premenstrual symptoms using combinations of magnesium, vitamin B6, magnesium and vitamin B6, and placebo for one menstrual cycle in 44 women showed no overall difference between individual treatments.57 Further specific subanalyses, however, showed a significant effect of 200 mg/day Mg + 50 mg/day vitamin B6 on reducing anxiety-related premenstrual symptoms (nervous tension, mood swings, irritability or anxiety). Although encouraging, the design of the study and the modest results preclude a firm conclusion of efficacy.
Endocrinological factors
Although not entirely understood yet, the endocrine system has a distinct role in stress and anxiety, with HPA-axis hyperactivation being regarded as a prime component in chronic anxiogenesis.58 CAM interventions that modulate the HPA axis may have a role in treating stress and anxiety (see Section 5 on the endocrine system). Among CAM interventions that may provide HPA-axis modulation are herbal ‘adaptogens’ and ‘tonics’, including Withania somnifera and Rhodiola roseaWithania somnifera is classified in Ayurvedic medicine as a ‘rasayana’, a medicine used to enhance physical and mental performance and ward off disease.59 The plant has been adopted recently into Western herbal materia medica for its use in nervous system and endocrine disorders.42 An animal study observed adaptogenic effects of W. somnifera in a stress-inducing procedure, via the attenuation of stress-related parameters (cortisol levels, mental depression and sexual dysfunction).60 The purported active constituents, the glycowithanolides, were administered orally in an animal model once daily for 5 days, and were discovered to induce an anxiolytic effect comparable to that produced by lorazepam relevant tests (elevated plus maze, social interaction and feeding latency in an unfamiliar environment tests).61
Rhodiola rosea may also have a place in treating generalised anxiety, especially if presenting with fatigue and cardiovascular problems. A small pilot trial used a standardised R. rosea (Rhodax®) formulation in 10 participants with diagnosed generalised anxiety disorder. Participants received 340 mg of Rhodax® in two divided doses for a period of 10 weeks.62 Results demonstrated a significant drop on the Hamilton Anxiety Scale. Although baseline levels on the Hamilton Depression Rating Scale were low, a statistically significant response also occurred on this outcome measure. While this study yielded a positive outcome, the uncontrolled design and small sample temper confidence in the results. A caveat that should be observed by clinicians using R. rosea root for anxious presentations is that the herb has (dose-dependently) been found to cause anxiety, irritability and insomnia in some people.
