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tDCS for treatment-resistant depression

Introduction Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation (NIBS) technique, whereby a subthreshold, continuous electrical current (typically 1–2 mA) is applied to the brain via two or more electrodes, placed over the scalp ( ). The conventional tDCS device consists of a portable, battery-operated machine, connected through conductive cables to two electrodes (an anode and a cathode), that are cushioned in saline-humidified sponge pads (…

Transcranial magnetic stimulation for treatment-resistant depression

Introduction Although diverse treatments are currently available for depression, one class of treatments that holds significant promise, especially for treatment-resistant depression (TRD) in the near future, is neuromodulation. This growing category of treatment techniques includes interventions, either electrical, chemical, or mechanical in nature, that directly modify the function of the nervous system ( ). The oldest form of neuromodulation, electroconvulsive therapy (ECT), is still the most…

Opioid agents for treatment-resistant depression

Introduction Almost 70% of depressed individuals do not adequately respond to common antidepressants and need multiple therapeutic trials in order to achieve a full remission. Furthermore, according to the STAR*D study, patients who need more trials had the greatest risk of failure ( ). This subgroup of subjects experiencing TRD is more likely to suffer from recurrent episodes and shows a higher risk to manifest substance…

Inflammation and treatment resistance: Mechanisms and treatment implications

Introduction Increasing data indicate that the immune system in general and inflammation in particular may play a role in the pathophysiology of psychiatric disorders including depression and anxiety ( ). These data include evidence of low-grade inflammation in subgroups of patients with a variety of psychiatric diseases as well as effects of inflammatory mediators on neurotransmitter systems and neurocircuits that regulate behavior ( ). Interestingly, there…

Psychedelic agents for treatment-resistant depression

Acknowledgments Effort for authors was provided by The Center for Psychedelic and Consciousness Research which is funded by the Steven and Alexandra Cohen Foundation, Tim Ferriss, Matt Mullenweg, Craig Nerenberg, and Blake Mycoskie, and by NIH grant T32DA07209. Introduction Classic psychedelics are serotonergic agonists that can produce profound changes in perception, mood, and cognition. The past two decades have been marked by a renewal of interest…

Ketamine/esketamine for treatment-resistant depression

Introduction In recent years, ketamine, its individual enantiomers, and related compounds have been a major focus of research and clinical development for the treatment of depression. With the United States Food and Drug Administration (USFDA) approval of esketamine for the indication of treatment-resistant depression in 2019, use of the treatment has rapidly increased in clinical settings. As such, it is important for clinicians and researchers to…

Combining antidepressants to address treatment-resistant depression

Financial disclosures As discussed in Chapter 1 , it is helpful to define treatment-resistant depression (TRD). Although one defines treatment resistance, it is clear that this is a very significant clinical problem. We now know from multiple randomized controlled clinical trials and years of clinical experience that only a minority of patients are able to attain remission after treatment with an adequate dose of an antidepressant…

Adjunctive strategies for treatment-resistant depression

Overview The problem of nonresponse to antidepressant medications is essentially as old as this area of therapeutics: Even during the 1960s and 1970s, it was known that the likelihood of response to a tricyclic antidepressant (TCA) was far from certain, and perhaps 40% to 50% of depressed patients would not obtain significant symptom relief despite an adequate course of treatment ( ). Among the other treatments…

Switching antidepressants in patients with treatment-resistant depression

Introduction Despite the availability of many therapeutic strategies, the optimal treatment of depression remains a major challenge. The overall effectiveness of antidepressants remains limited, and in almost 30%–50%, the response to treatment will be insufficient or absent ( ; ). The concept of treatment-resistant depression (TRD) is often used to characterize these complex situations where more than one antidepressant trial is needed to achieve response or…

Monoamine oxidase inhibitors for treatment-resistant depression

Introduction Oral irreversible inhibitors of the intracellular enzyme, monoamine oxidase, have been in clinical use for over 60 years. As a group, they constitute the oldest class of antidepressants. The monoamine oxidase inhibitors (MAOIs) were developed decades ago out of the search for novel antituberculous drugs. One such drug, iproniazid, was serendipitously discovered to have mood-elevating properties in patients with tuberculosis ( ). These observations, first…

Tricyclic antidepressants for treatment-resistant depression

Introduction As a group, the tricyclic antidepressants (TCAs) comprise the second-oldest class of antidepressants, beginning with the serendipitous discovery in the late 1950s that imipramine, investigated initially for its sedative properties, was effective for patients with severely depressed mood, marked psychomotor retardation, lethargy, hopelessness, and a diurnal fluctuation in symptom severity ( ; ). A large number of TCAs were subsequently introduced, including the tertiary-amine agents…

Tools to aid precision treatments to prevent or manage treatment-resistant depression (TRD): Pharmacogenomics, machine learning, and artificial intelligence

Disclosures LCB is a stockholder and former employee of Myriad Genetics, former employee and current consultant to Tempus Labs, Principal Consultant for Great Scott! Consulting, founding member of Pharmacogenetics Research Network (PGRN), and member of the Clinical Pharmacogenetics Implementation Consortium (CPIC). CAB is the founder and shareholder of Sequence2Script Inc. and a member of the CPIC and Pharmacogene Variation Consortium (PharmVar). HAE is a former employee…

Treatment algorithms for treatment-resistant depression

Introduction An algorithm is a stepwise solution used for problem solving. In medicine, the clinical algorithm, most commonly represented as a flow chart, is used in clinical decision-making processes to address diagnosis and treatment ( ). Since the 1990s, many clinical algorithms have emerged as a consequence of evidence-based medicine (EBM), which is defined as the integration of “individual clinical expertise with the best available external…

Modeling treatment-resistant depression in the preclinical setting

Introduction This is an exciting time in the field of psychiatry. The advent of rapid-acting antidepressants (ADs) like ketamine has sparked a paradigm shift in how we think about the biological basis of treatment-resistant depression (TRD) and has inspired creative solutions in preclinical model development. The purpose of this chapter is to review current and emerging preclinical research trends capable of characterizing the mechanisms mediating and…

The neurobiology of treatment-resistant depression

Introduction Multiple treatment modalities are effective for major depressive disorder (MDD), including medications, certain psychotherapies, and brain stimulation approaches such as electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS). However, treatment resistance, that is lack of full symptom remission after one or more rounds of antidepressant treatments of adequate dose and duration, is the rule, not the exception with MDD ( ). For example, the…

The economic burden of treatment-resistant depression: Cost-of-illness perspective

Introduction Depression affects more than 264 million people worldwide ( ), making it one of the most prevalent of all medical conditions ( ). The sheer prevalence of depression is troubling, in and of itself. It is a chronic, relapsing illness that causes considerable burden from persisting residual deficits in energy level, motivation, cognitive capacity, and other emotional functions necessary for optimum functioning. It thus comes…

Clinical and epidemiological predictors of treatment-resistant depression

Introduction Treatment-resistant depression (TRD) is common among individuals with major depressive disorder (MDD), with over one-third of patients being unable to reach an adequate level of symptomatic improvement after trying an antidepressant (AD) treatment ( ). However, it is unclear which factors may lead to poor response to treatment, categorically defined as “treatment resistance.” It is also unclear whether the lack of response to a medication…

Defining treatment-resistant depression, difficult-to-treat depression, and staging treatment intensity

Introduction Depression has enormous impact on individuals, their families, and society. Fortunately, there are many effective treatments options ( ). However, unfortunately, a significant proportion of patients do not achieve sustained remission, despite serial treatments ( ). “Treatment-resistant depression (TRD)” is a well-established term and concept to define such patients. While the definition of TRD is arbitrary and there is a lack of complete consensus, it…