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.

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.

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.

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.

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.