The Psychopharmacology of Anxiety
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).
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
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.