Treatment-Resistant Mood Disorders

Objective: The objective of the study was to explore the presentation of symptoms in patients suffering from treatment-resistant mood disorder (TRMD), and associated clinical features, including age, gender, and comorbid conditions, that lead towards the development of treatment-resistant mood disorder. Furthermore, the study analyses the available psychotherapeutic treatment modalities and evidence-based non-medical treatment approaches for TRMD. Method: The current study utilized a systematic review approach where 37 articles were studied and three articles were theoretically sampled to authenticate and signify the findings. PRISMA guidelines were followed and the review was conducted by searching social sciences databases and electronic libraries including Google Scholar, Sage Journal, and Science Direct (1990-2020). Results: The results suggested that psychotherapeutic interventions including cognitive behavior therapy, mindful-based cognitive therapy; and interpersonal and social rhythm therapeutic interventions are efficacious modalities for treatment when in augmentation with psychopharmacological treatment. Bipolar diathesis and comorbid conditions of anxiety and personality disorders are possible causal factors in developing the condition of treatment resistance in mood disorders. The prevalence rate of TRMD is more common in females and in late adulthood. The analysis also suggests that there are numerous risk factors contributing to making a mood disorder treatment-resistant over a period of time; the most observed conditions were physical and psychological comorbidity, inaccurate diagnosis, lack of proper medical treatment, illness severity, and late age diagnosis. In evidence-based non-medical treatment approaches aerobics demonstrated promising results in improving the condition of complex mood disorders. Conclusion: It was concluded that psychotherapeutic interventions in augmentation with pharmacological modalities enhance the efficacy of treatment.


INTRODUCTION
The world has been plagued with many diseases over time and has posed great threats and challenges for the health sector.Inevitably, this has been a continuous delineated involving significant aspects regarding the development of illness, related facets (age, gender, comorbid conditions) and possible treatment options which helps in critically evaluating treatment plans.
Treatment-resistant depression (TRD) refers to two adequate trials of antidepressant's (AD's) from different classes with different presumed mechanisms of action 1 .Treatment-resistant mania (TRM) is the maximal tolerated lithium in combination with valproate or carbamazepine for a period of three times the average cycle length, or six months, whichever is longer, in the absence of antidepressants or other cyclepromoting agents. 2 The course of treatment-resistant mood disorder (TRMD) is a continuum ranging from partial response to complete treatment resistance rather than an all-or-nothing phenomenon.Eighty percent of patients who required multiple AD trials relapsed within the first year following remission (Readmission & Premature Death): STAR*D studies. 3Considerable features that should be kept in mind include pseudo resistance including misdiagnosis and inadequate treatment such as compliance, dosage, duration, and AD's trials. 4Other factors might involve age, having early onset before eighteen years and in some cases late onset after sixty years. 5ender is another factor as women demonstrate less responsiveness to AD's trials. 68][9] Evidence-based practices include pharmacotherapy, augmentation including cognitive behavior therapy and interpersonal therapy.There is increasing awareness that the majority of depressed patients either fail to respond to an appropriate antidepressant drug trial or present a partial response, with substantial residual symptomatology and, as a consequence, an increased risk of relapse. 10Several pharmacological strategies have been developed for depressed patients who fail to respond to standard drug treatment, 5,[10][11][12][13] but limited research has been done on non-pharmacological approaches for TRD.The basic clinical questions are when and for whom psychotherapy should become a treatment option.In TRD, there is a need for augmenting practice guidelines with patient-specific recommendations that take into account individual variables such as history and previous treatment response.
When a psychotherapeutic intervention is planned in the setting of current drug treatment, the choice of switching or augmenting strategies should be guided by clinical judgment.When switching is endorsed, it is generally wise to postpone it to a later phase of psychotherapy, also because discontinuation symptoms, that do not necessarily abate in a couple of weeks, may have an unfavorable impact on the initial phase of psychotherapy. 14The study in hand focused on identifying the functional consequences of treatment resistance among mood disorders, its manifestation and trajectory, and important clinical features to understand the available evidence-based treatments in a better way.

The Review Question:
• What is the presentation of treatment-resistance in mood disorders?Direct (1990-2020).The keywords that were searched included treatment-resistant mood disorders (TRMD), development of TRMD, clinical features of TRMD, age onset of TRMD, gender differences in TRMD, and comorbid conditions of TRMD, evidence-based psychotherapeutic intervention for TRMD, evidencebased non-medical treatment approaches for TRMD.In addition, the citation of reviewed articles was further explored.
The searched results were studied including titles, abstracts, and the full copy, and screened to ensure the parameters of inclusion and exclusion criteria as follows: • All the studies must include a psychotherapeutic intervention.• All the studies included defined TRMD based on the criteria of resistance to medication.After the screening process, a quality assessment was carried out to eliminate potential biases including culture bias, time lag bias, and outcome reporting bias.A total of forty articles were included in the current systematic review.

RESULTS
The data search by keywords yielded seventy articles and forty articles met the inclusion criteria; three of which were theoretically sampled to match the findings.These studies were categorized into review papers, systematic reviews and metaanalyses, descriptive and exploratory researches,

A h e a d o f F i n a l P u b l i c a t i o n
and experimental design researches including socio-demographic variables, clinical features, and definition of treatment resistance in mood disorders and outcome of psychosocial interventions; Google Scholar (25%), Science Direct (35%), Taylor and Francis (5%), Springer Link (7.5%), Sage Journal (7.5%), Willey Online Library (10%), National Library of Medicine (5%), and Cambridge University Press (5%).

DISCUSSION
Comprehensive analysis of the literature revealed the course of illness in treatment-resistant depression (TRD) is expectedly worse: severity is higher, relapse is more frequent, and patients experience greater functional impairment compared to those with uncomplicated MDD. 3,15,16One of the most significant findings of the study was that treatment-resistant disorders can be treated more efficaciously when in augmentation with psychotherapeutic interventions.Utilizing new drug trials have been found to be rather ineffective.The efficacy of psychotherapy for treatment resistance in depression using a metaanalysis along with meta-regression was studied, the results demonstrated that augmenting psychotherapy with usual routine treatments of drug therapy and neurostimulatory treatments for the condition of TRD is well justified and leads to better and productive results as compared to pharmacological treatment alone. 17indings of experimental research illustrated that the most powerful tool for psychotherapeutic intervention lies within cognitive behavior therapy.Treatment resistance in mood disorders may include nonconclusive or wrong diagnosis that is an expression of the inability to manage bipolar disorder, a manifestation of psychotic or melancholic depression, misdiagnosed non-melancholic conditions, secondary depression, and organic determinants.Studies have demonstrated that clinical features were consistent across existing literature, particularly late age and female gender were the predominant demographics affecting the trajectory of TRMD.
Findings of many studies have illustrated that bipolar disorder and co-morbid conditions including anxiety disorders and personality disorders specifically have a significant relationship with the category of mood disorder.Furthermore, studies have stated this as a term of "bipolar diathesis" referring to bipolar disorders as the beginning or the result of a TRD or mood disorder.One culture-specific study reflected that obesity is also linked with TRMD based on the Flow Chart.1.
Flow Chart.2.Early onset, comorbid conditions of anxiety disorder and substance use disorder, and higher rates of suicidal attempts are common correlates in TRMD.In women, anxiety condition has higher comorbidity.

Kenny & Williams 2007 Clinical Audit 2004
The efficacy of MBCT was studied in depressed patients in a longitudinal study suggesting improvement in depression with an effect size of 1.04.Furthermore, the participants experienced remission with some returning to experiencing normal or near to normal levels of mood.

Chart review of outpatient clients
June 2000 -May 2001 The 80% of patients diagnosed with bipolar disorder manifested evident symptoms of bipolarity and were referred to as depressive patients.A frequent treatment option was a switch towards mood stabilizers.Findings posit that unipolar depression converts into TRMD due to bipolar diathesis as no response was shown on the drug trial of antidepressants.Using CBT in combination showed longitudinal results in patients with refractory depression.Improvement in quality of life was also reported over an average of forty-six months; forty months after the end of therapy.

Parker et
prevalence of the demographics in a clinical sample.They explored the bidirectional relationship of body mass index and its treatment outcome with treatmentresistant depression among adolescents.The results of the study established that being in the overweight category did not affect the overall response toward treatment and otherwise i.e. the efficacious treatment for depression did not affect the weight or body mass index (BMI). 18oreover, an experimental study finding illustrated that along with psychotherapeutic interventions, aerobics is also an effective exercise to counter TRD.They carried out research to study the effects of physical exercise on complex mood disorders in a twelve-week program among youth and adults.The results found that when aerobics is practiced in a supportive group setting, mood symptoms improve over time given that social support is also being received which was perceived as an important factor in the program's success. 19However, it was further proposed that the research is required to identify specifically the mechanisms underlying the therapeutic benefits associated with therapy programs utilizing physical exercises.

CONCLUSION
The findings of the review illustrate those psychotherapeutic interventions, such as cognitive behavior therapy, mindful-based cognitive therapy and interpersonal and social rhythm therapeutic interventions are effective treatment modalities when used in augmentation with psychopharmacological treatment.Furthermore, it was found that when substantial attention is given to psychoeducation and enhancement of coping strategies in clients, treatment resistance can be countered.Bipolar diathesis and comorbid anxiety and personality disorders are possible clinical features associated with treatment resistance in mood disorders.
Treatment resistance in mood disorders may include a lack of appropriate diagnosis which will result in an inability to manage bipolar disorder, depression with psychosis or melancholic depression.Misdiagnosis of non-melancholic conditions, secondary depression, and organic determinants can also be a related causal factor.Development of mood disorders is more common in late age and female gender.Obesity is found to have no link with treatment resistance in mood disorders.Aerobics have been found to be a possible non-medical treatment approach in improving the condition of complex mood disorders when used in combination with psychotherapy and social support.

Table - I
: Description of studies included.