Approach to a Patient with ‘Treatment Refractory’ Depression in The Medical Setting: Part 1

May 15, 2008

bellevue.jpgCommentary by Brian Bronson, MD, Chief of Psychosomatic Medicine, VA New York Harbor, New York Campus 

Summary: Symptoms of depression in the medical setting may not respond to usual pharmacologic antidepressant treatment for a number of reasons. These may include an incorrect psychiatric diagnosis; failure to consider underlying medical causes of the symptoms; or insufficient antidepressant medication trial due to poor patient adherence, insufficient dose or length of trial. There is no consensus as to the definition of ‘treatment refractory’ depression. However, when the above steps have not resulted in improved outcome, the clinician may either change to an alterative antidepressant, or add a second medication as adjuvant treatment if the patient had a partial response to the first medication. Failure to modify critically important environmental or psychosocial stressors may also impair a full treatment response. Part I of this discussion focuses on making the correct diagnosis. Part II will summarize pharmacologic management concepts for treatment non responders.

Part I:

Review of symptoms and clarification of primary diagnosis is an important first step to treatment non-responders in medical settings. Depressive disorders in primary care medical settings are frequently missed, yet they are not uncommonly misdiagnosed or treated. While antidepressants have good empiric evidence in reducing symptoms of both Major Depressive Episodes and Adjustment Disorders with Depressed Mood, patients with a variety of other primary psychiatric diagnoses and primary medical diagnoses may appear depressed or complain of depressive symptoms such as insomnia or a low mood as epiphenomena. Insomnia in particular is a very non-specific symptom and frequent hallmark of emotional distress in general, and in clinical settings is over-attributed to primary depressive disorders, as is loss of appetite in medically ill populations.

Psychiatric diagnoses that are sometimes misdiagnosed as clinical depression include Bipolar Mood Disorder during depressive or mixed manic-depressive phases, anxiety disorders such as Generalized Anxiety Disorder, Panic Disorder or Post-Traumatic Stress Disorder, Schizophrenia or Schizoaffective Disorder, Depressive or Bipolar type, addictive disorders most commonly alcohol use disorders, and neurodegenerative disorders most commonly early dementia. In inpatient medical settings, delirium is the most common diagnosis mislabeled as depression. In all of these conditions, presenting complaints such as a depressed mood, insomnia, poor concentration, fatigue or subjective concentration or memory problems are common.

Bipolar disorder generally requires monotherapy or polytherapy that includes an anticonvulsant, lithium or atypical antipsychotic, even if the primary subjective complaint of the patient is a depressed mood. Antidepressants frequently make symptoms of bipolar disorder worse with greater anxiety, agitation, irritability and insomnia.

Bipolar mood disorder is frequently mislabeled as depressive disorder, because patients generally present to clinicians during episodes of depression, or because they complain primarily of the depressive symptoms of mixed manic-depressive phases. The ‘classic’ euphoric state of mania is relatively uncommon compared to more irritable, agitated or dysphoric bipolar states. Diagnostic suggestions to differentiate pure depressive or ‘unipolar mood disorders’ from bipolar disorder follows: 1)Observe psychomotor activity level. Patients in manic, hypo-manic or mixed manic-depressive states are all more psychomotorically agitated than usual, compared to the relative slowing of speech and movements seen in depression. 2)Differentiate insomnia with daytime sleepiness and fatigue, seen in depression, from a decreased need for sleep with increased energy, seen in manic, hypomanic or mixed states. 3)Observe speech: Manic, hypomanic and mixed states present with rapid, verbose and sometimes loud speech that may be difficult to interrupt, contrasting with the normal or slowed, and softened and relatively less productive speech in a depressive episode.

Given the prevalence of bipolar mood disorder, its under-recognition and its often poor response to antidepressant treatment alone, it is important to screen all patients who present with depressive symptoms for symptoms of bipolar disorder as well as a prior diagnosis or family history of bipolar disorder disorder, prior to initiating antidepressant treatment.

Anxiety disorders, psychotic disorders and substance use disorders may also be mistaken for primary depressive disorders. Anxiety disorder symptoms such as excessive fear, autonomic nervous system hyperactivity and insomnia may improve partially with most classes of antidepressants, excluding buproprion, though some patients require treatment with a benzodiazepine as the primary or adjunctive medication for a full response. Primary psychotic disorders such as schizophrenia require an antipsychotic medication as the primary treatment. Frequent use of substances, especially cocaine and alcohol, is associated with significant mood and anxiety symptoms as patients alternate between states of intoxication and cessation. Symptoms of depression are less likely to remit in the presence of ongoing illicit drug or alcohol use and may in fact remit on their own with cessation of that substance. Patients who meet criteria for an addiction and a primary depressive episode, ie still meet criteria for a depressive disorder during periods of complete sobriety, require a combined treatment approach for the substance abuse and depressive disorder simultaneously.

In light of the above discussion, it is critically important that primary care providers are very familiar with the specific nine DSMIV diagnostic criteria of a Major Depressive Episode and can differentiate depression from these other common psychiatric conditions. Prior to starting antidepressant treatment, providers should review with the patient each of the nine DSM Major Depression symptoms, as well as the presence and extent of alcohol or illicit drug use, the presence of any of the above bipolar symptoms, and their prior psychiatric diagnosis and treatment history. Use of patient self-rated screening tools for depression such as the nine item Patient Health Questionnaire (PHQ-9) may provide useful diagnostic and baseline information to supplement the clinical interview.

Underlying medical disorders may also present with primary depressive or co-occurring physical and depressive symptoms leading to an incorrect diagnosis of a major depressive disorder or adjustment disorder. Empirical data supporting the treatment efficacy of antidepressant medications has derived largely from studies on medically healthy patients. Patients with medical co-morbidities are generally excluded from antidepressant studies, leaving the impact of antidepressants in medically ill populations less established. Anecdotal evidence suggests that depressive symptoms that are the direct physiologic result of an underlying medical condition or in patients with co-morbid addictive disorders do not respond well to antidepressant medications. The range, of medical disorders which may manifest with depressive symptoms is quite large.

Common examples of depressive symptoms as epiphenomenon of primary medical disorders follow: dysphoria and insomnia associated with hypoxia or subjective difficulty breathing in chronic obstructive pulmonary disease or congestive heart failure; failure to thrive including weight loss and a decline in self-care seen in both malignancies and dementia; fatigue, low mood and poor concentration as symptoms of poorly controlled diabetes mellitus among other less common endocrinologic disorders; depressed mood, irritability and insomnia in acute and chronic pain. Other less common examples include anxiety or depression in hypo or hyperthyroidism, or mood, behavioral and cognitive complaints in a primary CNS mass or vitamin b12 deficiency. In all of the above examples, depressive symptoms will generally improve with stabilization of the underlying medical condition and not with antidepressants. Continued depressive symptoms despite optimized medical treatment may warrant an antidepressant trial.

For further reading, please see:

Menza, Matthew
STAR*D: The Results Begin to Roll in
Am J Psychiatry 2006 163: 1123

A. John Rush
STAR*D: What Have We Learned?
Am J Psychiatry, Feb 2007; 164: 201 – 204. 

Image coutesy of Ehrman Medical Library, Bellevue Hospital, A view of the hospital from the East River, in 1879

2 Responses to Approach to a Patient with ‘Treatment Refractory’ Depression in The Medical Setting: Part 1

  1. Alex Sicre on May 16, 2008 at 11:21 am

    If you are looking for a medication adherence tool to help with your clinical trials, please contact me:

    Intelecare is a healthcare technology company focused on enhancing medication adherence. We have created a proprietary medical reminder platform that sends user created reminders via email, text and voice messaging. One of our products, IntelePhase, has been developed to increase medical adherence for clinical trials.

    If you are interested, please visit our website,, to learn more and contact me at your convenience.

    Thank you.


  2. Tracey Marks, MD on April 29, 2009 at 8:59 pm

    Thanks for the comprehensive review. I find that another problem with recognizing bipolar disorder is that often the patients who do experience the more euphoric, productive hypomanic symptoms will not present to a doctor because of the perceived benefit of being manic and their reluctance to have that state go away. Then when they have a depressive episode, they may not remember the hypomanic state because they saw it as desired or normal.