____________________________________________________________________________ Anxiety Disorders
dissociation, complete loss of appetite, and epileptic seizures. Most experienced prolonged post-withdrawal symptoms. Many initially tried withdrawing by abruptly stopping benzodiazepine usage at home; most stated this resulted in perceived epileptic seizures. All favored gradual, long-term tapering over abrupt withdrawal [237]. Normally used to reverse benzodiazepine overdose and post- surgery sedation, flumazenil has shown effects that diminish benzodiazepine withdrawal severity and duration and improve abstinence rates. Dosage and infusion rates vastly differ between these two indications [238]. Flumazenil requires IV or subcutaneous infusion, because its brief half-life and extensive gastric metabolism prohibit oral use [239]. In a study of flumazenil IV infusion, 29 patients stopped benzodiazepines and began flumazenil 1.6 mg/day and oral clonazepam 2–6 mg/day. Antidepressants were started three weeks before the trial or were maintained. Clonazepam was tapered during outpatient follow-up. No patient dropped out, withdrawal severity showed significant linear reduction through the seven-day infusion, and 53% remained free of clonazepam and other benzodiazepines at six-month follow- up [240]. In patients with protracted withdrawal at 47 weeks, IV flumazenil significantly reduced aggression and hostility compared with placebo [241]. In research focused on subcutaneous infusion of flumazenil, patients were switched to oxazepam, began a 48-hour taper, and started flumazenil 16 mg over 96 hours. Subcutaneous infusion significantly reduced psychologic distress and benzodiazepine withdrawal symptoms during treatment. Patients with the highest initial withdrawal severity showed greatest improve- ment. Patients reported high treatment comfort, willingness to receive the treatment again, and likelihood to recommend it to a friend [239]. Flumazenil attenuates chronic benzodiazepine withdrawal symptoms by up-regulating benzodiazepine receptor bind- ing sites to reverse uncoupling between benzodiazepine and GABA binding sites on the GABA-A complex. This reversal of GABA-A functional alteration helps explain its effect on benzodiazepine withdrawal and reports of positive effects on mood, memory, cognition, and motor performance [229].
With apparent patient nonresponse to treatment, clinicians should explore other factors before deciding the next therapy approach. The two broad causes of treatment resistance are pseudo-resistance and true treatment resistance [28]. Treatment Pseudo-Resistance Pseudo-resistant patients have not actually received sufficient treatment, because of ineffective treatment matching for the anxiety diagnosis, insufficient medication dose or psycho- therapy delivery, or patient non-adherence. Treatment pseudo- resistance may be the result of ineffective drug therapies, such a bupropion, beta-blockers (except in performance anxiety), buspirone and trazodone (except in GAD), and TCAs in SAD. Insufficient dosages and waiting an inadequate period for onset are also factors. The time for treatment onset is often longer for anxiety than depression. Patients may not fully respond until 8 to 12 weeks, and response may further increase in the second 6 months. Waiting an adequate time for response may be difficult for patients and healthcare providers, who may feel a need to change prescriptions or the regimen if a patient is distressed over his or her continued anxiety symptoms [28]. Poor patient adherence may also present as apparent treatment resistance. Only half of patients refill their first prescription, and many patients discontinue their drug in the first six months of treatment [136; 185]. Nonadherence may result from medication intolerance or side effects. Even if patients with troubling side effects do not stop the drug, the inher- ent distress avoidance and anticipatory anxiety with anxiety disorders can delay achieving adequate dose or taking medica- tion long enough for response. Therapeutic skills can help to gain patient trust and overcome their anxiety of medication; adherence improves with medication counseling [136; 185]. Medication beliefs or attitudes that contribute to poor adher- ence include [28]: • Unrealistic expectations • Negative beliefs of perceived harmful effects • Stigma • Not “buying in” to treatment rationale or difficulty believing that treatment will work • Psychologic conflicts over dependence and fear of becoming “addicted” to the medication • Preference for psychotherapy over medication (as patients are less likely to adhere to a treatment modality they prefer less) Following adherence and remission or large improvement, some patients will become non-adherent, and relapse follows. This may be addressed by explaining that the disorder requires ongoing treatment, like diabetes or any other chronic disease.
CLINICAL ISSUES Poor Treatment Response or Nonresponse
An estimated 30% to 60% of patients with anxiety disorders do not achieve meaningful symptom reduction or remission with initial therapy [242]. Decades of psychopharmacologic research have yielded safer, more tolerable side-effect profiles, but without improved efficacy in anxiety disorders. With poor or non-response, clinicians and patients then must decide how treatment should proceed, but research that best informs this clinical dilemma is only beginning to emerge. Given the limita- tions of SSRIs and benzodiazepines, investigators are pursuing novel treatment approaches and molecular targets [136].
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