The Psychopharmacology of Anxiety

Benzodiazepines are effective first-line treatments for PD, SAD and GAD in select patients when rapid onset is essential and substance abuse is not an issue. Daily benzodiazepine therapy provides symptom relief with good tolerability in one to two weeks for 60% to 70% of patients, according to reviews by Ballenger (2001), Gorman (2001) and Brunello et al. (2000). Compared to antidepressants, benzodiazepines are more effective for physical symptoms of anxiety, particularly in the first three weeks of treatment. Disadvantages of benzodiazepines include the risk of memory problems, decreased coordination and withdrawal symptoms upon abrupt discontinuation, including nervousness, insomnia, restlessness, nausea, lethargy and (rarely) seizures. Paradoxical reactions to benzodiazepines are possible and include emotional lability, agitation and occasionally rage reactions (Gutierrez et al., 2001).

Benzodiazepine selection is based on each drug's pharmacokinetic properties. For example, when qd or bid dosing is preferred, clonazepam (t½: 20 hours to 50 hours) is a good option. If drug accumulation is a concern, lorazepam (Ativan) is preferred due to its intermediate half-life (10 hours to 20 hours). Alprazolam (Xanax) is the most-studied benzodiazepine for PD, and it should be considered if clonazepam is ineffective. Disadvantages of alprazolam include a requirement for multiple daily dosing and a difficult and potentially serious withdrawal (Ballenger et al., 1998; Gorman, 2001).

Inter-individual variability in response exists, meaning if alprazolam is effective, equipotent doses of clonazepam may or may not be effective (Rosenbaum, 1990). Clonazepam may be less likely to produce a reinforcing euphoria, compared to diazepam (Valium) or alprazolam. Risk of benzodiazepine abuse must be assessed on a case-by-case basis. Personality disorders, history of alcohol or substance abuse, and genetic predisposition contribute to a likelihood of abuse. However, benefits of benzodiazepine therapy far outweigh risks for many patients with anxiety disorder who are unable to find relief with antidepressants (Ballenger, 2001; Gorman, 2001; Shader and Greenblatt, 1993).

Buspirone is a 5-HT_1A receptor partial agonist with well-documented efficacy for GAD (Ballenger, 2001). Buspirone is ideal for GAD patients who cannot tolerate antidepressant therapy and do not want the sedation, cognitive impairment or adverse interaction with alcohol associated with benzodiazepine therapy. Buspirone has not been shown to be effective for other anxiety disorders (Apter and Allen, 1999) except as an adjunct to SSRIs for some patients with OCD, SAD and PTSD who are partial responders or who tend to suffer sexual side effects. Disadvantages of buspirone compared to benzodiazepines include delayed onset of effect (two to four weeks) and poor patient satisfaction. Buspirone should be initiated at 5 mg tid or 7.5 mg bid and titrated as tolerated to a usual effective dose of between 20 mg/day and 40 mg/day. Common adverse effects that typically subside with treatment include jitteriness, dizziness, nausea and headache.

Researchers have investigated GABAergic anticonvulsants like valproate (Depakene) and gabapentin (Neurontin) for anxiety disorders (Keck et al., 1993; Pande et al., 2000, 1999). Three small, uncontrolled studies describe valproate as an effective anti-panic treatment at doses between 500 mg/day and 2250 mg/day (Primeau et al., 1990). Onset of therapeutic effect occurred between two and four weeks of treatment; adverse effects were nausea, dizziness, drowsiness, tremor and diarrhea. Valproate, carbamazepine (Tegretol) and lamotrigine (Lamictal) were studied in small, uncontrolled trials and described as effective for hyperarousal, aggression, impulsivity and explosiveness associated with PTSD (Brunello et al., 2001).

Gabapentin 600 mg/day to 3600 mg/day was compared to placebo in separate trials studying PD and SAD. Only the most severe PD patients responded, while the patients with SAD improved significantly more than with placebo. Reported adverse effects included somnolence, dizziness and nausea. Until anticonvulsants are found comparable to standard antidepressant or benzodiazepine therapy for anxiety disorders, they should be considered for treatment-refractory patients or if a comorbid condition warrants anticonvulsant therapy.

Haloperidol (Haldol) and risperidone (Risperdal), two antipsychotics with significant dopaminergic blockade, may be useful adjuncts for patients with tics and OCD who fail SSRI therapy, (McDougle et al., 1994; Stein et al., 1997). Patients without tics did not benefit in these reports; however, one open trial (Pfanner et al., 2000) reported significant benefit when risperidone was added to SSRIs in 20 patients with OCD refractory to SSRI therapy. Case reports have noted that olanzapine (Zyprexa) and clozapine (Clozaril) may worsen obsessive-compulsive symptoms (Mottard and de la Sablonniere, 1999), although an open trial described olanzapine as a useful adjunct to SSRI therapy in refractory patients (Weiss et al., 1999). Clearly, antipsychotics should be reserved for patients with psychosis or treatment-refractory OCD, with careful monitoring to detect worsening of OCD symptoms.

The use of alternative therapies for chronic central nervous system illnesses such as headaches, depression and anxiety is increasing every year (Eisenberg et al., 1998). One survey reported that 54% of psychiatric outpatients tried alternative therapy to relieve both psychiatric and physical symptoms (Knaudt et al., 1999). Common attitudes that herbal remedies are "natural," have fewer side effects and are readily available contribute to their appeal to patients. Two herbal products commonly used to self-medicate symptoms of anxiety are valerian and kava kava. Clinicians should be aware of realistic expectations of these remedies in addition to possible adverse effects (Table).

Kava Kava (Piper methysticum). A meta-analysis documented greater efficacy of kava versus placebo for anxiety symptoms across several studies (Pittler and Ernst, 2000). One of the most extensive randomized, placebo-controlled studies evaluated the effects of kava in 100 patients diagnosed with agoraphobia, specific phobia, GAD and adjustment disorder with anxiety (Volz and Kieser, 1997). Patients treated with 70 mg kavalactones (the agent responsible for kava's psychotropic properties) three times daily showed significant improvement after eight weeks of treatment, with continued benefit at 24 weeks.

The recommended anxiolytic dose of kava is 50 mg to 70 mg purified kavalactones or 100 mg to 250 mg dried kava root extract, three times daily. Adverse effects of kava include morning fatigue and mild gastrointestinal disturbances (Pepping, 1999). Toxic doses (>300 g) may, however, cause progressive ataxia, muscle weakness, ascending paralysis and scaling of skin on the extremities (Singh and Blumenthal, 1997). Reports of hepatotoxicity are currently under investigation by the FDA. Kava can potentiate the effects of CNS depressants, including ethanol, barbiturates and benzodiazepines; therefore, concomitant use should be avoided. Finally, kava should be avoided during pregnancy due to the potential for loss of uterine tone (Brinker, 1998). While kava may be an effective and well-tolerated anxiolytic compound for many patients, there is no evidence to suggest it is more effective than antidepressants or benzodiazepines.

Valerian (Valeriana officinalis). Although used more often for its hypnotic properties, valerian is taken to relieve mild symptoms of anxiety (Hobbs, 1989). While there are no controlled studies describing efficacy for any diagnosed anxiety disorder, one paper (Kohnen and Oswald, 1988) reviewed valerian's effects in 48 subjects placed under an experimental social stress situation. These volunteers were randomized to receive valerian 100 mg, propranolol (Inderal) 20 mg, both agents or placebo administered 90 minutes before the situation. Valerian alone had no effect on physiological activation or concentration, but it did decrease somatic arousal.

Adverse effects associated with valerian include sedation and withdrawal symptoms similar to benzodiazepine withdrawal following abrupt discontinuation (Garges et al., 1998). Adverse effects and toxicity have not been adequately studied; however, four cases of hepatotoxicity associated with valerian use have been reported (Plushner, 2000). Additional studies are required to determine if valerian has any significant and sustained anxiolytic properties.

Pharmacotherapy for anxiety disorders is shifting away from benzodiazepines toward serotonergic antidepressants. Newer antidepressants, particularly SSRIs and venlafaxine, are increasingly utilized as first-line agents. Research shows that they are effective, generally well-tolerated and have low risk of abuse compared to benzodiazepines. Compared to buspirone, serotonergic antidepressants offer a broader spectrum of efficacy. They treat symptoms of PD, OCD, PTSD and comorbid major depression in addition to GAD.

Benzodiazepines are still widely prescribed. They have established efficacy for PD, GAD and SAD. Benzodiazepines offer a more rapid onset of benefit without the risk of sexual dysfunction associated with SSRIs and venlafaxine. Anticonvulsants and some antipsychotics are useful adjuncts for appropriate patients. Based on lack of controlled trials and risk of toxicity, kava-kava and valerian cannot replace established medicinal compounds.