Saturday, May 1, 2004
Treatment Resistance: Concepts and Management
in Mood and Anxiety Disorders Chair: Mark H. Rapaport, MD A. “Treatment Resistance in Mood and Anxiety Disorders: Evidence From Clinical Trials” – Ellen Frank, PhD B. “Clinical Pathways for Mood and Anxiety Disorders” – Waguih W. Ishak, MD C. “Psychotherapeutic Approaches for Patients With Treatment-Resistant Mood and Anxiety Disorders” – Edna B. Foa, PhD D. “Emerging Treatment Options in Treatment-Resistant Mood and Anxiety Disorders” – Mark H. Rapaport, MD This symposium, chaired by Dr. Mark Rapaport, MD, professor of psychiatry at the University of California at Los Angeles and chairman of the Department of Psychiatry and Mental Health at Cedars-Sinai Medical Center, presented a comprehensive review of evidenced-based information about treatment-resistant mood and anxiety disorders. Dr. Rapaport started the presentation by stating that “taking care of difficult-to-treat patients is critical.” To this end, the objectives of this symposium were to: · Review cutting-edge pharmacologic and somatic treatments for difficult-to-treat mood and anxiety disorders · Describe rates of treatment resistance for various mood and anxiety disorders · Review the outcome of cognitive behavioral therapy (CBT) for obsessive compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) · Recognize optimal treatments in refractory depression and anxiety disorders Treatment Resistance in Mood and Anxiety Disorders: Evidence From Clinical Trials Ellen Frank, PhD, Professor of Psychiatry and Psychology at the University of Pittsburgh School of Medicine Dr. Ellen Frank, PhD, started her presentation by reviewing the 3 stages of depression (acute, continuation, and maintenance) and stating that achieving treatment response is not enough, since depressive symptoms may still exist, and that the goal of treatment should be full remission during the acute phase. During the continuation and maintenance phases, the goals should be prevention of relapse and recurrence, respectively. Treatment resistant is a misleading term, implying that the fault of treatment failure lies with the patient, not the physician. A more appropriate term is difficult to treat, correctly implying that the responsibility lies with the physician and that more work needs to be done. Depression can be difficult to treat because of psychiatric comorbidities (panic disorder, social phobia, or PTSD), medical comorbidities, or sociodemographic contexts (pregnancy, poverty, responsibility for ill family members). Patients may also have subsyndromal comorbidies such as panic disorder (PD), eating disorders, social phobia, or PTSD. According to Dr. Frank, “patients may not meet the criteria for these syndromes, but have the ‘flavor’ of them.” Multiple studies show the negative impact of PD and other anxiety symptoms on the treatment outcome for major depression with both psychotherapy and pharmacotherapy. In women with comorbid PD, the time to remission was significantly delayed. PD’s negative effect on depression is due to a decrease in the tolerance of side effects, interference with treatment compliance, and additive effect on depression rating scales. To deal with drug adverse events (AEs), it is beneficial to start at doses below the recommended starting doses to allow patients the time to tolerate AEs. Interpersonal psychotherapy for depression with panic symptoms was observed to reduce scores on the Hamilton Depression Rating and Anxiety scales (HAMD and HAMA) and the Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q) at the end of 16 sessions and 3 months after treatment end. Subsyndromal social anxiety comorbidity makes depression difficult to treat since patients may find it difficult to come in for treatment visits, thus making it difficult for a physician-patient alliance to develop. Dr. Frank indicated that probing for subsyndromal comorbidies can be complicated by overreliance on structured diagnosis guidelines, rendering the physician less sensitive to clinical intuition. Thinking beyond DSM criteria as well as consulting the Spectrum Project Web site, www.spectrumproject.org, for structured clinical interviews and self-report questionnaires can assist the physician. Mothers who are depressed can be difficult to treat due to the stigma associated with depression, especially in custody cases. Mothers tend to place the needs of their families ahead of their own. There is also the difficulty of obtaining mental health services for mothers due to limited time and money. Why is it important to treat mothers? First, of the 20% of women experiencing an episode of depression, two-thirds are mothers. Second, parental mood disorder increases risk for mood disorders in children. Depressed mothers are the least available for treatment. Offering treatment in a location that the population already frequents is a way of making treatments more accessible and less time consuming. Dr. Frank reviewed the results of an interesting study in which psychotherapy was offered at a large, conveniently located, supermarket for 4 months. After 8 weeks, there was significant reduction of depression symptoms as recorded on various depression rating scales (HAMD [17-item], Beck Depression and Anxiety Inventory scales). This trend remained at 6-months’ follow-up. After the presentation, Dr. Frank was asked how one can decide whether psychotherapy or pharmacotherapy is advisable in a busy outpatient practice. She said there’s no clear data to advise on which treatment to start with; however, due to the time constraints in a outpatient practice, pharmacotherapy would be a good starting point. Dr. Frank summarized her presentation by stating that tailoring treatments to a patient’s specific needs and circumstances appears to lead to full and sustained remission in difficult-to-treat patients. Clinical Pathways for Mood and Anxiety Disorders Waguih William IsHak, MD, Director of Psychiatry Residency Training Program, Cedars-Sinai Medical Center, Los Angeles, California Dr. IsHak presented data on clinical pathways, generally recommended potential steps in the diagnosis and treatment of a condition or procedure for individual patients. These are management tools based on clinical information developed from evidence-based psychiatry, practice guidelines, or expert consensus statements. These clinical pathways are able to standardize care for 60% to 70% of patients with similar diagnosis, procedure, or symptom (Wigfield A, Boon E. Br J Nurs. 1996;5:732-735). “Measuring outcome is not just symptom improvement, it’s functional improvement as measured by disability scales such as the Sheehan Disability Scale and the Endicott Work and Productivity Scale,” according to Dr. IsHak. Using examples, Dr. IsHak described guidelines for biopsychosocial evaluation, diagnosis, and treatment. He emphasized that “the golden rule is the establishment of a good solid rapport with the patient.” A diagnostic work-up is also very important. “It’s not just getting the clinical interview done,” he said. Asking questions is the only way to get a full picture of the patient’s condition. In choosing medication, start with the drug of choice for at least 6 weeks at an adequate dose level. If according to the Quick Inventory of Depressive Symptomatology-Self Report scale (QIDS-SR) there’s little or no response, switching to another class of antidepressant for another 6 weeks at an adequate dose is warranted. After this second 6-week period, if there is little or no response, a biopsychosocial re-evaluation to reassess the diagnosis should be implemented. If the diagnosis remains unchanged, augmentation with medications or psychotherapy should be implemented for 12 more weeks. After this 12-week period, the QIDS-SR should be applied again. If there is still little or no response, the biopsychosocial re-evalution should be repeated. If the diagnosis remains unchanged, an MAOI should be used for 12 weeks at an adequate dose and the QIDS-SR reapplied. If there is still little or no response, the patient is considered “treatment refractory,” and other assessment and treatment alternatives (such as ECT) should be pursued. With the use of clinical pathways as described above, there is still more information needed on adequate dosing strategies, augmentation strategies, and the relationship between psychosocial stressors and response to biological interventions (eg, how does antidepressant drug use help if the patient is depressed because of a job loss?). To illustrate, Dr. IsHak queried the audience on what they considered an adequate dose of venlafaxine. There was no consensus from the audience as to what was considered an adequate dose. In summary, clinical pathways can be seen as a game plan for the patient from beginning to end. In Dr. IsHak’s words, “begin with the end in mind.” Psychotherapeutic Approaches for Patients With Treatment-Resistant Mood and Anxiety Disorders Edna B. Foa, PhD, Professor of Clinical Psychology in Psychiatry and Director of the Center for the Treatment and Study at the University of Pennsylvania. Dr. Foa described the efficacy of cognitive behavioral therapy (CBT) for anxiety disorders. There are 3 CBT programs for anxiety disorders: exposure therapy, anxiety management procedures, and cognitive therapy. Exposure therapy is a set of techniques that help patients learn that their fear is unrealistic or exaggerated. Anxiety management is a set of techniques to help patients manage their anxiety through relaxation training, controlled breathing, positive self-talk, social skills training, and thought stopping. Cognitive therapy is a set of techniques that helps patients change their negative, unrealistic thoughts. It is estimated that 80% of patients with anxiety disorders and PTSD, 75% of anxiety disorders patient with obsessive-compulsive disorder (OCD), 75% of anxiety disorder patients with panic, 60% of anxiety disorders patient with social anxiety , and 55% of anxiety disorder patients with generalized anxiety disorder (GAD) benefit from CBT. Despite these response rates, a substantial number do not respond to CBT. Prolonged exposure therapy has proven helpful in patients with PTSD. According to her studies, PTSD patients undergoing prolonged exposure reported less PTSD after treatment. Imaginal exposure coupled with cognitive therapy led to a greater reduction in PTSD severity than imaginal exposure or supportive counseling alone. For OCD, cognitive behavioral therapy involves exposure in vivo (prolonged confrontation with anxiety-evoking stimuli), imaginal exposure (prolonged imaginal confrontation with feared disasters), and ritual prevention (voluntary abstinence from compulsions). A combination of exposure in vivo and ritual prevention led to a marked decrease in the severity of anxiety. To enhance the benefit of CBT: · Treatment programs that include exposure are more successful · Adding exposure improves outcomes of cognitive therapy alone for PTSD · Adding ritual prevention to exposure improves outcomes for OCD · For PTSD, extending treatments improves outcomes for slow responders · For PTSD, adding CBT improves outcomes for partial responders to medication Regarding comorbidity with depression: · Depression does not impede treatment benefit for PTSD · Severe, bur not moderate, depression impeded treatment success of OCD · Depression impedes treatment benefit for social anxiety disorder and GAD · Risk for suicide always needs to be evaluated The effect of substance abuse on the success of treatment for anxiety is unknown since most studies have excluded patients with substance abuse; however, CBT that addressed both PTSD and substance abuse is promising. As a recurring theme in this symposium, superior rapport between patient and physician led to increased treatment benefit. Panic disorder patients who rated their therapists as caring, involved, and modeling self-confidence benefited more from treatment. In PTSD, nonresponders perceived treatment to be less credible and were less motivated than responders. Studies on combat/terror survivors and sexual assault have shown considerably decreased severity in PTSD after treatment with prolonged exposure therapy. Nonexperts can learn how to administer prolonged exposure in as little as 5 days and effect results similar to experts. The clinical implications are: · Select treatment that has shown best outcome · Include all the active components of that program · Emphasize importance of attending treatments regularly and completing homework exercises · Establish a rapport by being warm and accepting while adhering to treatment protocols · Increase expectations of success by sharing information about treatment effectiveness · Maximize treatment credibility by providing patient with clear rationale for how/why treatment works To receive training, one can consult the following organizations: · Association for Advancement of Behavior Therapy · Anxiety Disorder Association of America · International Society for Traumatic Stress Studies · OCD Foundation · Specialty Centers for Cognitive-Behavior Therapy Emerging Treatment Options in Treatment-Resistant Mood and Anxiety Disorders Mark H. Rapaport, MD. Chairman of the Department of Psychiatry and Mental Health at Cedars-Sinai Medical Center in Los Angeles, California. To complement the presentations of Drs Frank, Foa, and IsHak, a review of accepted and experimental pharmacologic treatment approaches were reviewed to aid clinicians in treating patients with severe, treatment-resistant mood and anxiety disorders. Incomplete recovery is a risk factor for treatment resistance. In Dr. Rapaport’s words, “identify people and treat aggressively.” Up to one half of treatment-resistant depression cases are due to improper dosing or noncompliance. Under normal circumstances, 33% to 40% of major depressive disorder (MDD) patients achieve remission during initial treatment. Up to 20% of MDD patients fail to achieve remission after 3 aggressive treatment trails. To this end, depression-targeted psychotherapies may work even if pharmacotherapies have failed. In a recent study published in the Proceedings of the National Academy of Sciences by Dr. Charles Nemeroff, patients on combined therapy with nefazodone and group CBT responded better than patients receivingeither therapy alone. Principles of Medication Management · 40% to 50% of the time, initial antidepressant medication does not produce response · Within-class switches or out-of-class switches succeed 50% of time · Whether to switch or augment depends on prior history, desired simplicity, patient status, and cost To augment current antidepressant therapy, there are various drugs that can be used (ie, lithium, second antidepressants, stimulants, buspirone, antoconvulsants, pindolol). It is important to note that before augmentation, the patient must be on an adequate dose of the first medication. There have been many studies of lithium augmentation of SSRIs, but most are short-term studies of 2-4 weeks’ duration. Response time is about 2 weeks with lithium augmentation. Thyroid augmentation has been studied with tricyclic antidepressants (TCAs). Augmenting a TCA with an SSRI can achieve a more rapid onset of action and increased remission rates. It has been observed that many patients do well with the addition of the stimulant, modafinil, to SSRI therapy. Dr. Rapaport noted that atypical antidepressants are now refered to by the FDA as “broad-spectrum antidepressants”. These broad-spectrum antidepressants may provide synergistic clinical effects due to their inhibitions at multiple neuroreceptors. In a study of patients not responding to fluoxetine treatment, patients were randomized to treatment with fluoxetine and placebo, olanzapine and placebo, or fluoxetine and olanzapine. Patients on the combination of fluoxetine and olanzapine demonstrated rapid improvement and statistically significant better response compare to either alone. In a large trial of 700 patients, patients on a combination regimen of the SSRI, citalopram and risperidone achieved a more robust antidepressant response in MADRS scores and achieved a higher percentage (59.3%) of remissions compared with citalopram monotherapy (9.8%). However, as Dr. Rapaport stated, “quality of life is more important and considered effective treatment as opposed to an improvement in a Hamilton score.” To this end, risperidone therapy improved cognitive assessment in attention/working memory, executive function and attention, and processing speed. For anxiety disorders, augmentation has benefits as well. Olanzapine augmentation of an SSRI for PTSD led to statistically significant improvement over SSRI monotherapy (Stein MB, et al. Am J Psychiatry. 2002;159:1777-1779.). Risperidone augmentation of an SSRI led to improvement in various aspects of PTSD. For OCD, risperidone augmentation of an SSRI led to a reduction in the Yale-Brown Obsessive-Compulsive Scale (McDouglas CJ, et al. Arch Gen Psychiatry. 2000;57:794-801). Dr. Rapaport was queried on appropriate choices for augmentation therapy, to which he responded that the individual patient characteristics and challenges presented determine this. For example, patients with anxiety and irritability are augmented with lithium, while those with anxiety without irritability are augmented with mirtazapine. Dr. Rapaport delved into the area of genes and the environmental interaction. Genes do not code for illness, but for vulnerability. This vulnerability is expressed only if challenged by stresses above a certain threshold. In a study by Smeraldi E, et al. (Mol Psychiatry. 1998;3:508-511), augmenting fluvoxamine treatment with pindolol improved antidepressant response in patients with the genotype for depression vulnerability compared to fluvoxamine monotreatment. A new emerging area described by Dr. Rapaport is vagal nerve stimulation (VNS) therapy. By stimulating the afferent limb of the vagus nerve you can reduce blood pressure and mood disorders. In a 24-month study of VNS therapy, continual improvement in response and remission was seen during the 24 months of therapy (Marangell LB, et al. Biol Psychiatry. 2002;51:280-287). In another study, patients on VNS therapy demonstrated superior response compared with placebo. |