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Controversy exists over antidepressant use in bipolar II depression.
To compare the safety and effectiveness of antidepressant v. mood stabiliser monotherapy for bipolar type II major depressive episodes.
Randomised, double-blind, parallel-group, 12-week comparison of venlafaxine (n = 65) v. lithium (n = 64) monotherapy in adult out-patients (trial registration number NCT00602537).
Primary outcome – venlafaxine produced a greater response rate (67.7%) v. lithium (34.4%, P<0.001). Secondary outcomes – venlafaxine produced a greater remission rate (58.5% v. 28.1%, P<0.001); greater decline in depression symptom scores over time (β=–5.32, s.e. = 1.16, χ2 = 21.19, P<0.001); greater reduction in global severity scores over time (β=–1.05, s.e. = 0.22, χ2 = 22.33, P<0.001); and greater improvement in global change scores (β=–1.31, s.e. = 0.32, χ2 = 16.95, P<0.001) relative to lithium. No statistically significant or clinically meaningful differences in hypomanic symptoms were observed between treatments.
These findings suggest that short-term venlafaxine monotherapy may provide effective antidepressant treatment for bipolar II depression without a statistically significant increase in hypomanic symptoms relative to lithium.
Depression can adversely affect employment status.
To examine whether there is a relative advantage of cognitive therapy or
antidepressant medication in improving employment status following
treatment, using data from a previously reported trial.
Random assignment to cognitive therapy (n = 48) or the
selective serotonin reuptake inhibitor paroxetine (n =
93) for 4 months; treatment responders were followed for up to 24 months.
Differential effects of treatment on employment status were examined.
At the end of 28 months, cognitive therapy led to higher rates of
full-time employment (88.9%) than did antidepressant medication among
treatment responders (70.8%), χ21 = 5.78, P = 0.02, odds ratio (OR) = 5.66,
95% CI 1.16–27.69. In the shorter-term, the main effect of treatment on
employment status was not significant following acute treatment
(χ21 = 1.74, P = 0.19, OR = 1.77, 95% CI
0.75–4.17); however, we observed a site×treatment interaction
(χ21 = 6.87, P = 0.009) whereby cognitive
therapy led to a higher rate of full-time employment at one site but not
at the other.
Cognitive therapy may produce greater improvements in employment
v. medication, particularly over the longer term.
Controversy exists over antidepressant use in rapid-cycling bipolar disorder.
Exploratory analysis of safety and efficacy of fluoxetine v. lithium monotherapy in individuals with rapid- v. non-rapid-cycling bipolar II disorder.
Randomised, double-blind, placebo-controlled comparison of fluoxetine v. lithium monotherapy in patients initially stabilised on fluoxetine monotherapy (trial registration NCT0O044616).
The proportion of participants with depressive relapse was similar between the rapid- and non-rapid-cycling groups (P=0.20). The odds of relapse were similar between groups (P=0.36). The hazard of relapse was similar between groups (hazard ratio 0.87, 95% CI 0.40-1.91). Change in mania rating scores was similar between groups (P=0.86). There was no difference between groups in the rate of syndromal (P-0.27) or subsyndromal (P=0.82) hypomania.
Depressive relapse and treatment-emergent mood conversion episode rates were similar for lithium and fluoxetine monotherapy and placebo during long-term, relapse-prevention therapy of rapid- and non-rapid-cycling bipolar II disorder.
There is conflicting evidence about comorbid personality pathology in depression treatments.
To test the effects of antidepressant drugs and cognitive therapy in people with depression distinguished by the presence or absence of personality disorder.
Random assignment of 180 out-patients with depression to 16 weeks of antidepressant medication or cognitive therapy. Random assignment of medication responders to continued medication or placebo, and comparison with cognitive therapy responders over a 12-month period.
Personality disorder status led to differential response at 16 weeks; 66% v. 44% (antidepressants v. cognitive therapy respectively) for people with personality disorder, and 49% v. 70% (antidepressants v. cognitive therapy respectively) for people without personality disorder. For people with personality disorder, sustained response rates over the 12-month follow-up were nearly identical (38%) in the prior cognitive therapy and continuation-medication treatment arms. People with personality disorder withdrawn from medication evidenced the lowest sustained response rate (6%). Despite the poor response of people with personality disorder to cognitive therapy, nearly all those who did respond sustained their response.
Comorbid personality disorder was associated with differential initial response rates and sustained response rates for two well-validated treatments for depression.
This chapter provides specific consideration to the problem of a pseudo-treatment-resistant depression (TRD), where a medical condition is misdiagnosed as major depression and so does not respond to antidepressant treatment. Amongst medical causes of depression the most frequent appear to be endocrine, in particular thyroid. The chapter presents the evidence supporting a more direct link between many neurological disorders and major depression. The background prevalence rate of major depression is already high in two groups of patients at risk for HIV infection, namely homosexual men and intravenous drug users. Psychiatrists and other mental health professionals can make an indispensable contribution by raising awareness amongst their colleagues of the importance and frequent neglect of major depression in many common medical disorders ranging from stroke to coronary artery disease. In these situations better recognition and treatment of major depression can only but make a valuable contribution to enhancing patient care.
There is considerable evidence that major depressive episode (MDE) in general, and treatment-resistant depression (TRD) in particular, may be accompanied by an immune-inflammatory response, as demonstrated by: an acute phase response (APR); an increased production of cytokines such as IL-6; and, activation of lymphocytes (T cells). Many studies have demonstrated an excessive hypothalamic-pituitary axis (HPA) activity in TRD. The APR seen in MDE is often accompanied by reduced levels of total serum protein (TSP) and changes in electrophoretically separated serum protein fractions. Acute phase proteins (APPs) migrate electrophoretically between albumin and γ-globulin fractions. The presence of APPs suggests that 5HT system disregulation may be related to the APR and to autoimmune pathogenesis in some MDE patients. The induction of anti-5HT and antiganglioside antibodies has been found to occur with viral infections and in response to stress and the production of cytokines.
While antidepressants have helped millions worldwide, a substantial proportion of patients fail to respond or remit. There is little published information available to clinicians for diagnosis and management of treatment-resistant depression, so they have had to make difficult decisions about treatment options with very limited data. The editors and their internationally distinguished team of contributors have set out to address this problem, giving a critical assessment of all aspects of treatment-resistant depression: causes, epidemiology, comorbidity, evaluation and treatment. This timely book will be invaluable to clinicians, neuroscientists, researchers and graduate students.
This chapter defines the concept of treatment-resistant depression (TRD), which is distinguished from 'pseudo-TRD' resulting from either misdiagnosis, unrecognized concurrent medical and psychiatric illnesses, inadequate antidepressant treatment or unrecognized pharmacokinetic factors interfering with adequate treatment. In formulating a treatment approach to TRD, some type of illness measurement or 'staging' is useful as a measure of the level of severity of the disease. A clear majority of antidepressant treatments were inadequate and failed to meet minimal therapeutic requirements. The two major factors to be reviewed in determining trial adequacy are medication dosing and trial duration. The chapter reviews several approaches for optimizing treatment and minimizing resistance in depressed patients, as well as some suggested approaches for directly treating TRD. Finally, a careful consideration and pursuit of all treatment options at each stage of TRD with ongoing diagnostic reevaluation permits the clinician to handle the difficult syndrome of TRD more effectively.
As many as 60–70% of depressed patients fail to achieve complete remission. In its broadest sense, treatment-resistant depression (TRD) characterizes the vast majority of depressed patients in therapy, and substantially contributes to the overwhelming morbidity and mortality associated with depressive illness. TRD is now recognized as a major public health problem which accounts for a disproportionate amount of physician treatment time, and as much as $50 billion in annualized healthcare expenditures (Greenberg et al., 1993).
The paucity of systematic data on TRD has led to inconsistent definitions and treatment approaches. While ad hoc definitions of TRD have been used to identify patients for specific treatment studies, the clinical applicability of these definitions is limited (Souery et al., 1999). Almost three decades after its initial description, TRD continues to be ‘an important clinical problem that is surprisingly understudied. The decision regarding what to do for patients who fail to respond to an adequate trial of an antidepressant must be made by a clinician without the benefit of controlled studies that compare subsequent treatment strategies.’ (Nierenberg, 1991).
The lack of response to initial antidepressant treatment has important clinical implications and results in considerable suffering and an increased risk of suicide. The recent demonstration of a ‘therapeutic decrement,’ whereby patients who have not responded to one antidepressant drug will have 20% less likelihood of responding to the next drug treatment (Amsterdam & Maislin, 1994) has critical treatment implications. It suggests that the current clinical practice of prescribing low doses of antidepressants for brief periods may, in itself, contribute to the development of TRD.