The Psychopharmacology of Anxiety

The range of medicinal compounds useful for anxiety disorders has expanded from antidepressants, benzodiazepines and buspirone to include anticonvulsants, some antipsychotics and herbal/alternative compounds. Frequently, combination therapy is needed (e.g., antidepressant and benzodiazepine) to achieve maximum efficacy and tolerability.

Epidemiologic studies (e.g., Kessler et al., 1994; Lecrubier, 1998) show that between 30% and 60% of patients with anxiety disorders have comorbid illnesses such as depression or a substance abuse disorder. The presence of comorbid psychiatric and medical conditions guides drug therapy selection. For example, antidepressants are preferred if comorbid depression exists, and benzodiazepines may be problematic in those with active substance abuse disorders. A World Health Organization study found that recognition of comorbidity in anxiety disorders was a key reason for preferentially prescribing antidepressants rather than benzodiazepines in most primary care practices worldwide (Lecrubier, 2001).

When symptoms of anxiety persist and cause functional impairment, a thorough diagnostic assessment is needed to determine if one or more of the following distinct DSM-IV-TR anxiety disorders are present: generalized anxiety disorder (GAD), social anxiety disorder (SAD, also known as generalized social phobia), obsessive-compulsive disorder (OCD), panic disorder (PD) or posttraumatic stress disorder (PTSD). An individualized, evidence-based approach that utilizes established dosing and appropriate duration of therapeutic trial (typically six to 12 weeks) for each anxiety disorder is needed for treatment success. Typically, medication is needed to decrease symptoms sufficiently for patients to participate in psychotherapeutic and behavioral interventions. Establishing rapport with the patient through counseling about the illness and medication management can improve treatment success (Gorman, 2001).

Antidepressants

SSRIs. Selective serotonin reuptake inhibitors are broad-spectrum anti-anxiety agents considered first-line therapy for all major anxiety disorders. (There are, however, differences in current approved U.S. Food and Drug Administration indications, dosing and pharmacokinetic/drug interaction profiles). According to several reviews (Ballenger, 2001; Brunello et al., 2000; Pigott and Seay, 1999), 50% to 75% of patients with anxiety disorders experience significant benefit after adequate dose and duration of therapy with an SSRI. Fluoxetine (Prozac) is perhaps the most activating SSRI, with once-daily dosing in the morning recommended for most patients. Fluvoxamine (Luvox) is better tolerated with bedtime dosing, and citalopram (Celexa), paroxetine (Paxil) and sertraline (Zoloft) should be initiated in the morning with a change to bedtime dosing if drowsiness occurs.

The SSRIs can cause dose-related nausea, restlessness, insomnia and sexual dysfunction, although they are generally better tolerated with less toxicity in overdose compared to tricyclic antidepressants and monoamine oxidase inhibitors. Several investigators (Fava et al., 2000; Lake et al., 2000; Mace and Taylor, 2000) described less common but potentially serious adverse effects, including hyponatremia, extrapyramidal side effects, weight gain and increased bleeding. As described by Black et al. (2000), SSRI withdrawal reactions, such as anxiety, diarrhea, fatigue, gait instability, headache, emesis, tremor, paresthesias and visual disturbances, can occur upon abrupt discontinuation of an SSRI after one month of therapy. Symptoms resolve within 72 hours of restarting SSRI therapy.

In considering SSRIs for specific anxiety disorders, SSRIs and clomipramine (Anafranil) are significantly more effective than other less serotonergic antidepressants in alleviating symptoms of OCD, according to several well-controlled trials (Pigott and Seay, 1999). Significant efficacy may take 10 to 12 weeks at maximally tolerated doses. The time to onset of effect is longer when treating OCD compared to SAD, GAD and even PD, in which symptoms lessen within one month of treatment at antidepressant doses. Key distinguishing features of OCD pharmacotherapy include a negligible placebo response and high relapse (>90%) upon drug discontinuation.

Compared to those with depression and other anxiety disorders, individuals with PD and PTSD are frequently more sensitive to the activating side effects of SSRIs (Ballenger et al., 1998; Brunello et al., 2001; Davidson, 2000). Lower initial doses are needed to improve tolerability. In 1998, an International Consensus Group on PD, led by Ballenger, recommended initiating SSRI therapy at lower doses (e.g., paroxetine at 10 mg, sertraline at 25 mg) with titration based on tolerability to usual antidepressant doses. In 2001, Goddard and colleagues reported that clonazepam (Klonopin) 0.5 mg tid added to sertraline therapy 100 mg/day for PD resulted in more rapid onset of anti-panic effect (one week versus three weeks) and good tolerability. The clonazepam was tapered off over three weeks and discontinued without incident. Clearly, combination therapy is preferred when rapid relief of symptoms is needed.

Therapy with SSRIs significantly decreases the frequency of or extinguishes panic attacks, lessens anticipatory anxiety, and can even improve phobic symptoms (Ballenger et al., 1998; Leinonen et al., 2000). Hyperarousal and psychological numbing or avoidant symptoms of PTSD are more responsive to SSRI therapy than re-experiencing the trauma (Brady et al., 2000; Davidson, 2000). It may take eight to 12 weeks for full therapeutic response for PD and PTSD. Maintenance therapy for six months to one year has demonstrated efficacy in preventing symptom relapse in PTSD and PD, respectively. However, longitudinal studies conducted over a lifetime are needed.

Generalized anxiety disorder and SAD are the most recent disorders to demonstrate clear therapeutic benefit from SSRI therapy (Ballenger, 2001; Brunello et al., 2000). Compared to benzodiazepines, antidepressants are more effective for psychic symptoms, like worries. Usual antidepressant doses are effective after about one month of treatment. Duration of therapy requires further study.

Venlafaxine. In 2000, Gelenberg et al. and Rickels et al. published studies establishing venlafaxine extended release (Effexor XR) as an effective, well-tolerated medication for GAD. It is likely effective for SAD and PD as well, according to positive clinical trials (Kelsey, 1995; Papp et al., 1998). Its efficacy for PTSD and OCD, however, requires further study. As do SSRIs, venlafaxine can cause nausea, sexual dysfunction and hyponatremia. In addition, dizziness, flushing and sweating are possible side effects -- as is increased blood pressure, particularly at doses >300 mg/day (Thase, 1998). When initiating venlafaxine, gradual titration based on tolerability is best (for example, venlafaxine XR 37.5 mg qam, increased by 37.5 mg to 75 mg weekly to a usual effective dose of between 150 mg/day and 225 mg/day).

Mirtazapine. Several reviews of small, uncontrolled trials and case studies report efficacy for mirtazapine (Remeron) in treating PTSD, PD and GAD, either alone or in combination with SSRI therapy (Brunello et al., 2001; Falkai, 1999; Good and Petersen, 2001). Mirtazapine increases noradrenergic outflow pre-synaptically via -2 antagonism, in addition to modulating serotonin function via post-synaptic 5-HT₂ and 5-HT₃ antagonism. Compared to SSRIs, it is not associated with nausea or sexual dysfunction, but it can cause significant sedation and weight gain. There are rare (0.1% to 1%) reports of bone marrow suppression; thus, careful monitoring in immunocompromised patients is required (Hutchison, 2001). Mirtazapine's place in therapy requires further study.

Nefazodone. Several reviews of open trials and case reports (Ballenger, 2001; Brunello et al., 2001) describe nefazodone (Serzone) in antidepressant doses as a useful option in treating GAD, PTSD and PD (Papp et al., 2000). Nefazodone modulates serotonin through pre-synaptic reuptake inhibition and post-synaptic 5-HT₂ antagonism. Compared to SSRIs, nefazodone causes less nausea, sexual dysfunction and restlessness, and it causes more sedation, dry mouth and constipation. Case reports describe successful remission of SSRI-associated akathisia after switching to nefazodone (Chelben et al., 2001). A controlled trial reported significantly less delayed ejaculation and anorgasmia associated with nefazodone as compared to paroxetine and sertraline (Waldinger et al., 2001). Recent reports of nefazodone hepatotoxicty (Eloubeidi et al., 2000) necessitate careful monitoring, patient counseling and avoidance in patients with liver disease.

TCAs. Among the TCAs, imipramine (Tofranil) has the most well-established efficacy for significantly decreasing symptoms of PD, GAD and SAD, according to clinical trials (Charney et al., 1986; Rickels et al., 1993) and several reviews (Ballenger, 2001; Brunello et al., 2000; Gorman, 2001). Other TCAs are likely effective for these three disorders as well, although several researchers, including Goodman et al. (1990), discovered that TCAs other than clomipramine were ineffective for OCD.

The TCAs have third-line status in the treatment of anxiety disorders due to toxicity in overdose and adverse effects that include orthostasis, dry mouth, constipation, sedation and risk of heart block that necessitates baseline and follow-up electrocardiogram monitoring. Low initial dosing is recommended, particularly in patients with PD, to improve tolerability, although effective doses are within the antidepressant dosing range (Ballenger et al., 1998).

MAOIs. The monoamine oxidase inhibitor phenelzine (Nardil) has well-established efficacy for treating PD and SAD (Ballenger et al., 1998; Brunello et al., 2000). It may be effective for some patients with PTSD as well, although efficacy studies are conflicting. Tranylcypromine (Parnate) is less well-studied. Adverse effects such as dizziness, insomnia and weight gain, in addition to drug interactions and dietary restrictions, limit MAOI usefulness.

Benzodiazepines

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

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.

Anticonvulsants

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.

Antipsychotics

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.

Herbals

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.

Summary

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.

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