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Treatment-Resistant Mood Disorders
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Book description

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.

Reviews

‘The excellence of this book is the section on special patient populations. They are all extremely well covered … This book will be valuable for researchers, academics who are interested in the scholarly reviews and algorithms of treatments, clinicians with special interest in affective disorders, and any clinician who would like a valuable resource book in their library.’

Source: International Journal of Geriatric Psychiatry

'The book is strong on the psychological aspects and it is pleasing to note that dysthymia - a difficult concept in relation to these disorders - is sensibly handled, as this has often caused confusion in the US/UK literature.'

Source: British Journal of Psychiatry

'It is a good description of current thinking and a useful book to have for reference text.'

Source: Journal of Psychosomatic Research

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Contents


Page 1 of 2


  • 1 - The characterization and definition of treatment-resistant mood disorders
    pp 3-29
  • View abstract

    Summary

    This chapter reviews the methodological considerations and current limitations involved in the characterization and definition of treatment-resistant mood disorders, concentrating mainly on treatment-resistant depression (TRD) and highlighting the advances that have been made towards consensus on this subject. It discusses the research and clinical implications, influencing the definition of treatment-resistant mood disorders. Diagnostic validity and the recognition of depression subtypes and comorbid conditions are crucial elements in the evaluation and management of TRD. The efficacy of pharmacotherapy in mood disorders varies according to the treatment phase. Treatment is divided into acute, continuation and maintenance phases. Research on treatment resistance in bipolar and dysthymic disorders is also essential since both conditions have been poorly investigated in regard to definition of resistance. Significant improvement in the understanding of TRD depends on the accurate recognition of a number of diagnostic and treatment variables, which are independent of the characteristics of patients.
  • 2 - Overview of treatment-resistant depression and its management
    pp 30-46
  • View abstract

    Summary

    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.
  • 3 - Psychoneuroendocrine aspects of treatment-resistant mood disorders
    pp 49-79
  • View abstract

    Summary

    Clinical applications of psychoneuroendocrinology are largely in their infancy, but certain strategies have already entered clinical practice and others appear promising. This chapter deals with the more well-established hormonal therapies for treatment-resistant depression. Thyroid augmentation in treatment-resistant depression and in rapid cycling bipolar affective disorder has received the greatest empirical support, followed by estrogen replacement therapy or estrogen augmentation in postmenopausal women. Strategies directly targeting the hypothalamic-pituitary-adrenal (HPA) axis (for example, antiglucocorticoids, dexamethasone, DHEA) are being actively investigated but, to date, have not received sufficient empirical support to enter into routine clinical practice. The prediction that drugs that directly lower HPA axis activity should have antidepressant effects has been widely studied in patients with Cushing's syndrome but only recently in psychiatric patients with major depression. For individual treatment-resistant patients who have exhausted other options, however, empirical trials with informed consent and with attention to possible side-effects, seem reasonable.
  • 4 - Estrogen and depressive illness in women
    pp 80-95
  • View abstract

    Summary

    One of the most consistent findings in the epidemiology of mental disorders is the higher prevalence of depressive illness in women than in men. This chapter reviews neurological effects of estrogen that have been elucidated since the 1980s so as to provide a scientific basis for possible biological mechanisms of action of this sex steroid on affective states. Estrogen induces RNA and protein synthesis via genomic mechanisms, which, in turn, cause changes in levels of specific gene products, such as neurotransmitter synthesizing enzymes. The chapter discusses the clinical studies of estrogenic effects on mood in non-clinical and in clinical populations with regard to the therapeutic use of estrogen in depressive disorders in women. Although there have been few systematic investigations of the use of estrogen in treatment-resistant depression, several controlled studies and case reports serve to provide some evidence of its effects.
  • 5 - Sleep abnormalities in treatment-resistant mood disorders
    pp 96-110
  • View abstract

    Summary

    This chapter reviews the existing literature on the relationship between sleep and mood disorders, in particular, treatment-resistant disorders. It also reviews the subjective and objective changes in sleep that occur in depressive and manic episodes, and describes how these sleep findings may be predictive of treatment-resistant states. Normal sleep consists of alternating rapid eye movement (REM) and non-REM epochs. Deliberate sleep deprivation produces an antidepressant effect in major depressive episodes (MDE) patients. While acute sleep deprivation can be beneficial for symptoms of depression, like any effective therapy, there are side effects. For some depressed individuals, sleep deprivation simply induces fatigue. The application of sleep deprivation to treat treatment-resistant depressions and sleep induction to treat treatment-resistant manic states holds promise. The relative contribution of primary sleep disorders to treatment-resistant mood states is virtually unknown and warrants investigation.
  • 6 - Structural and functional brain imaging in treatment-resistant depression
    pp 111-141
  • View abstract

    Summary

    This chapter shows that structural and functional brain imaging methods have offered into the neural substrates of affective processes as well as the current and possible future utility of these methods in the evaluation and management of patients with treatment-resistant mood disorders. Neuroanatomic models of the substrates of affective processes were originally derived from non-human animal studies in addition to postmortem and in vivo studies of humans with brain trauma, neurologic, and psychiatric disorders. The chapter reviews brain imaging studies in mood disorders, which in many cases demonstrate disruptions in anterior paralimbic structures and anterior basal ganglia-thalamocortical circuits. Many of these studies involved treatment-resistant patients or patients in tertiary care institutions and thus may be particularly indicative of the neurobiology of treatment-resistant mood disorders. Thus, a useful initial approach to the treatment-resistant mood disorder patient is to reassess whether the disorder is primary or secondary.
  • 7 - Immunologic factors in treatment-resistant depression
    pp 142-156
  • View abstract

    Summary

    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.
  • 8 - Selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors in treatment-resistant depression
    pp 159-179
  • View abstract

    Summary

    This chapter discusses evidence concerning the efficacy of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) in treatment-resistant depression. It examines the variety of options available for managing non-responders to these medications. The difference between non-response and intolerance due to side effects has clinically significant implications. A patient who does not respond to an adequate trial of an antidepressant should usually next be treated with an antidepressant from a different class. There is no lack of treatment options for the depressed patient unresponsive to medication. The problem lies in the very profusion of options: how to choose between them, when and how to combine them, and what order in which to employ them. One way to simplify and categorize the options is wait, change, augment, or combine. Antidepressants are often helpful in syndromes other than depression.
  • 9 - Conventional and second generation monoamine oxidase inhibitors in treatment-resistant depression
    pp 180-193
  • View abstract

    Summary

    This chapter examines the efficacy of conventional and second generation monoamine oxidase inhibitors (MAOIs) in treatment-resistant depression. The three classical monoamine oxidase inhibitors used at present are phenelzine, tranylcypromine, and isocarboxazid. The new reversible and selective monoamine oxidase A inhibitors (RIMAs) such as moclobemide, brofaromine and toloxatone have fewer adverse effects and, because MAO-B is still available for tyramine degradation, there is no need for any no diet restrictions. Lithium carbonate is an effective potentiator of tricyclic antidepressants (TCAs). At present, there are no comparative studies evaluating the safety and efficacy of lithium potentiation of RIMAs. RIMAs offer a relatively safer option which can benefit the treatment-resistant patient. The first-line treatment for treatment-resistant depression should be a specific serotonin reuptake inhibitor (SSRI) such as fluoxetine, paroxetine, sertraline, and fluvoxamine, or a serotonin and norepinephrine reuptake inhibitor (SNRI) such as venlafaxine.
  • 10 - Drug combination strategies
    pp 194-222
  • View abstract

    Summary

    This chapter presents a discussion of the terminology of refractory depression, and three management strategies, namely optimization of the current drug, substitution of the current drug with a different drug, and combination of two or more drugs. It reviews and evaluates various combination approaches through a consideration of the following factors: mechanism of action, evidence of efficacy, specificity and predictors of response, safety, and clinical use. The chapter distinguishes three combination strategies on the basis of treatment objective: augmentation, acceleration, and stabilization. Augmentation refers to the simultaneous use of multiple agents to increase efficacy over what might be obtained with any one of the agents used. Some of the combination agents discussed in the chapter includes lithium, triiodothyronine (T3), buspirone, stimulants, neuroleptics, and 5-HT1A antagonists. Buspirone is an azapirone derivative which acts as an agonist at the 5-HT1A receptor.
  • 11 - Electroconvulsive therapy in medication-resistant depression
    pp 223-238
  • View abstract

    Summary

    Electroconvulsive therapy (ECT) is an effective treatment for major depressive disorders. Medication resistance and persistent depression is encouraged by modern research practice. Before a depressed patient is labeled 'medication-resistant', the presence of delusions must be carefully assessed. A delusional mood disorder warrants intensive therapy, either with the combination of a neuroleptic and a tricyclic antidepressant drugs (TCA), both in high doses, or a course of ECT. The recognition of a major depressive mood disorder in an adolescent is difficult, and few studies find medications effective. It is now fashionable to develop clinical practice guidelines for the treatment of systemic disorders. A greater acceptance of ECT as an effective and safe treatment and its reasonable consideration before less effective treatments are tried will do much to relieve the burdens of therapy resistance of the severe mentally ill, for themselves, for their families, and for society.
  • 12 - Thyroid augmentation
    pp 239-251
  • View abstract

    Summary

    Thyroid hormones have been considered as viable treatments for patients with mood disorders, particularly those with treatment-resistant illness. Hypothalamic thyrotropin releasing hormone (TRH) has a regulatory effect on the thyroid axis by stimulating thyrotropin (TSH) which, in turn, regulates thyroid hormone synthesis and release. Triiodothyronine (T3) is the most widely and extensively studied thyroid hormone for the treatment of depression. It has been employed as monotherapy, to accelerate antidepressant effect and to augment therapeutic effects in antidepressant non-responders. The majority of the earlier studies employed T3 as it was felt that with its short half-life it would be less likely to cause symptoms of toxicity. It was assumed that thyroxine (T4) would be comparable to T3 in augmentation of antidepressant response as both would enhance thyroid hormone levels. Two of the most commonly employed antidepressant augmentation strategies are the addition of lithium and T3.
  • 13 - Cognitive therapy and psychosocial interventions in chronic and treatmentresistant mood disorders
    pp 252-270
  • View abstract

    Summary

    This chapter highlights the influence of psychosocial factors on the course and outcome of chronic and treatment-resistant mood disorders, and reviews the potentially important therapeutic role of psychosocial interventions. Many individuals with a chronic or treatment-resistant mood disorder who show a full or partial symptomatic response to pharmacotherapy still exhibit considerable impairment in their social, family and work role functioning. The chapter describes and identifies the evidence for the effectiveness of psychosocial approaches with this patient population, with an emphasis on cognitive therapy (CT) in chronic affective disorders. If a specific psychotherapy is to be introduced, it is preferable to choose one of the time-limited, 'manualized' therapies, such as CT or interpersonal therapy (IPT), that are of proven efficacy in acute mood disorders. Although CT has been described as a 'manualized' approach, most cognitive therapists employ considerable flexibility in developing a customized case conceptualization and treatment plan for each patient.
  • 14 - Chronic and refractory mood disorders in childhood and adolescence
    pp 273-287
  • View abstract

    Summary

    All childhood and adolescent depression can be characterized as 'refractory' if the measurement used is scientific evidence of efficacious treatments. There have been a small number of systematic studies reported examining the efficacy of psychotherapy interventions for child and adolescent depression. Treatment resistance is a difficult concept to operationalize in young populations, and may apply to a substantial proportion of children and adolescents who are seen clinically. It is clearly established that pediatric major depression is a valid diagnostic entity which as clinical continuity with adult affective disorders. Potential for overdose is a significant concern in the treatment of mood disordered children and adolescents. Selective serotonin reuptake inhibitors (SSRIs) have a very low potential of lethality, while the lethality of tricyclic antidepressants (TCAs) is very high. SSRIs have potential drug-drug interactions with thioridazine, TCAs, and terfenadine.
  • 15 - Treatment-resistant depression in the elderly
    pp 288-320
  • View abstract

    Summary

    The effective treatment of depression in the elderly is complicated by a number of factors. The true prevalence of treatment-resistant depression in elders has been estimated to range from 18 to 40%. Biologic changes that occur as a consequence of normal aging may contribute significantly to treatment difficulties and intolerance or ineffectiveness, especially if not fully appreciated. These changes are briefly reviewed in this chapter. The relationship of cognitive functioning to depression is complex. The management of resistant depression in elderly patients remains a clinical challenge. Age-related social, biologic, and medical complications create challenges that differ from the treatment of younger individuals. Confronted with an apparently treatment-resistant elderly patient, management should proceed in a logical stepwise manner. In patients with complex medication histories, it is often helpful to prepare a chronological summary of the treatment as far as records or memories permit.
  • 16 - Management of treatment-resistant depression during pregnancy and the postpartum period
    pp 321-349
  • View abstract

    Summary

    The management of pregnant and postpartum women with major depression may be complicated, especially when pharmacological therapies are involved. The most common situations that the clinician encounters in the management of reproductive age women with treatment-resistant depression include: inadvertent conception during treatment; prepregnancy consultation; exacerbation of psychiatric symptoms during pregnancy and/or the postpartum period; and/or prophylactic treatment planning for women at high risk for a postpartum mental illness. This chapter emphasizes the components of an individualized comprehensive risk-benefit assessment, and proposes general algorithms for systematically approaching these situations. It presents a brief overview of the most salient information on the antidepressants, mood stabilizers, benzodiazepines, and electroconvulsive therapy (ECT). Pharmacological augmentation strategies have not been well documented in pregnancy. Considering the variety of augmentation strategies available and lack of information for use in pregnancy, any recommendations are speculative and empirically derived.
  • 17 - Preliminary algorithms for treatment-resistant bipolar depression
    pp 350-404
  • View abstract

    Summary

    This chapter presents a series of treatment algorithms which may be used as a general guide in sequencing treatment so that patients who fail to respond to first-line conventional treatment may still achieve a substantial amelioration of depressive syndromes or recurrences. Depression in most treatment-resistant bipolar patients can usually be adequately treated. The authors have been able to model the loss of efficacy via tolerance to the anticonvulsants carbamazepine, lamotrigine, diazepam, and valproate in the model of amygdala-kindled seizures. The incidence of clinical tolerance development to lamotrigine in the affective disorders and dose regimens most likely to prevent this occurrence require further observation and study. With the availability of a large number of putative treatment agents within each class of drug for bipolar illness (mood stabilizers, antidepressants, and antimanics) appropriate sequencing and management of complex drug combinations may be fraught with difficulty, but at the same time potentially life-saving.
  • 18 - Medical disorders and treatment-resistant depression
    pp 405-429
  • View abstract

    Summary

    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.
  • 19 - Psychiatric comorbidity in treatment-resistant depression
    pp 430-478
  • View abstract

    Summary

    Extensive co-occurrence of major depressive disorder (MDD) with other psychiatric disorders, particularly anxiety, personality, and alcohol and substance use disorders has been well documented within clinical and community samples. This chapter clarifies salient features of psychiatric comorbidity in MDD as well as limitations of current knowledge in this area, and offers practical strategies for the management of treatment-resistant depression (TRD) when complicated by co-occurrent psychiatric illness. As many as one-quarter of adults presenting with MDD are thought to have a 'double depression' in which dysthymia is conceptualized as a comorbid disorder upon which MDD is superimposed. In the approach to patients with TRD and psychiatric comorbidity it is likely that several important treatment goals exist simultaneously. Psychiatric comorbidity presents abundant challenges to clinical practice but also serves as a guide to developing rational treatments and innovative strategies in the approach to treatment-resistant depression in the complicated patient.
  • 20 - Suicide in treatment-refractory depression
    pp 479-488
  • View abstract

    Summary

    Depression in certain types of individuals carry an increased risk of suicide. In the context of untreated high risk factors and increasing despair, it is no mystery that treatment-resistant depression (trd)/treatment-refractory depression (TRD) accentuates the risk of suicide inherent in a high risk individual. It seems important to consider both chronic and acute risk factors in the assessment of suicide risk, especially when deciding on intervention strategies and tactics. Studies of nearly 100 inpatient suicide records and approximately 30 outpatient suicide cases suggest four typical clinical patterns. Illustrative case vignettes are presented to emphasize these observed patterns. These patterns are not by any means exhaustive, but may be a useful beginning for the clinician treating various forms of treatment-resistant or refractory depression to be able to recognize. Expertise in the treatment of resistant depression is a skill that every practicing clinician should develop.
  • 21 - The economic impact of treatment non-response in major depressive disorders
    pp 491-503
  • View abstract

    Summary

    This chapter focuses on the economic impact of treatment non-response in major depressive disorders (MDD). Patient responses to initial therapy for MDD fall into four basic outcome categories. The frequency and health-care costs are associated with all four treatment outcome categories. The cost of treatment non-response is best measured relative to the costs experienced by patients who succeed on their initial course of therapy. The costs of non-response are measured relative to the costs patterns achieved by patients with an adequate course of therapy in terms of dose and duration. Multivariate ordinary least-squares (OLS) regression analyses were used to investigate the impact of the patient's drug use profile on health-care costs. The antidepressant drug therapy outcomes achieved by newly treated California Medicaid (Medi-Cal) patients are presented in the chapter. An adequate course of therapy on the initial antidepressant therapy prescribed was achieved by 17.1% of all treated patients.

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