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When Depression Does Not Respond to Medications

December 22, 2011 —

When Depression Does Not Respond to Medications
Treatment Resistant Depression: Understanding the Illness

Scott T. Aaronson, MD

Depression is not a single illness with a single etiology but a symptom of a wide variety of conditions that require different approaches. The majority of patients we meet on the Retreat have had a difficult to treat mood disorder. Often their illness has failed to respond to outpatient treatment. The first order of business is to understand each person’s illness. To do this we collect information and clarify the diagnosis.

Gathering History

When I interview someone with a difficult to treat depression, I want to understand several features of their illness:
1. Is this a new condition or have they had other episodes of depression?
2. How long have they been depressed in the current episodes, meaning when were they last functioning well?
3. How many separate episodes of depression have they had in their lifetime, in the past five years, in the past year? A separate episode would be when there are at least two months without significant depression between episodes.
4. Are they ever fully well or do they go between a chronic mild or moderate depression and a marked or severe depression?
5. What symptoms define their depression? Are there sleep disturbances, appetite problems, cognitive difficulties, anxiety symptoms? Are they able to function in some spheres but not in others? Are any symptoms not consistent with a primary diagnosis of depression?
6. Have they ever felt suicidal? Have they ever tried to hurt themselves? If they thought about or attempted suicide was it to end the pain or see how others would respond? Did they feel they deserved to die? Were they sorry they were not successful?
7. Did life events provoke a depressive episode or did it seem to have a life of its own? Did life events once cause depression but now it seems to happen on its own cycle?
8. Does anything reliably relieve depression? This could be anything from medication, to interpersonal contact, to intense exercise or even substance abuse.
9. Is there any seasonal component to the illness? If there is a seasonal component when each year will it start and when will it stop? Will a fall or winter vacation to a sunny place change the course of the illness? Does your sleep or eating pattern change in the fall or winter?
10. Is there any family history of psychiatric illness? Is anyone’s illness like the patient’s? If so, did they respond to a particular treatment?
11. Is there any medical illness associated with the depression?
12. Have they ever responded to any treatment for their illness? How long did it take to respond? How long did the response last?
13. How reliable with taking medication have they been?
14. Has substance abuse ever been a problem and if so, what were/are the substances of choice?
15. Is there any pattern of interpersonal behavior and functioning that is suggestive of a personality disorder?

All these questions are aiming to clarify the diagnosis and to offer any insight as to what the best treatment strategies may be. Hints about seasonality or good results with exercise may suggest a different approach than someone with excessive rumination or low energy.

Through this gathering of information we may find that the primary diagnosis may be something other than depression or that a co-morbid disorder may be leading to an inadequate treatment response.

Diagnostic Considerations

When a patient has had multiple courses of treatment with antidepressants resulting in only a brief response, no response or even a worsening of symptoms other diagnostic considerations must be considered. While some of these patients may have a treatment resistant depression, many have been incorrectly or incompletely diagnosed and treated. Other diagnostic possibilities include psychotic or delusional depression and bipolar depression. As well, the co-existence of substance abuse or anxiety disorders, especially post-traumatic stress disorder can make depression more complicated to effectively treat. Sometimes a medical illness can present with depression.

Subtle symptoms of psychosis or bipolarity which can elude diagnosis, sometimes for years, but make treatment more complicated. Psychotic symptoms which are defined as any loss of touch with reality and can be seen in two general forms—hallucinations, where one can hear, or less often see things that others cannot, and delusions where one has a fixed belief that is at odds with reality. Delusions in particular can be subtle and passed off as just part of the depression when they present as guilty ruminations about deserving to die or fears of poverty that are out of touch with reality. While consistent with the depression (also called mood congruent), when someone’s thoughts are at odds with reality, they are unlikely to respond to antidepressants alone and will usually require the use of antipsychotics or electroconvulsive therapy.

Depression can be part of a cyclical mood disorder called bipolar disorder. When patients have some history of clear elevation in mood, increased physical activity, rapid or pressured speech along with episodes of poor judgment, bipolar disorder is usually reliably diagnosed. However, should someone’s mood cycle not include purely manic episodes, a bipolar diagnosis is often missed. Among the most common missed presentations is a patient who cycles between a slowed down or retarded depression and an agitated depression. The agitated depression, especially when it includes racing thoughts, poor sleep without significant daytime tiredness and an increase in physical activity (even if purposeless) may represent a mixed state. A mixed state is the combination of the activation of mania with the poor mood of depression. Commonly, when patients cycle between a retarded and an agitated depression there is often a history of becoming agitated when put on antidepressants. As well, patients with some form of bipolar disorder do not usually respond to antidepressants alone and can do worse on these medications. A few traits we look for to see if bipolar disorder could be present include: a family history of bipolar disorder, onset of illness before age 25, a pattern of three or more depressive episodes in a year, a seasonal pattern of worsening symptoms, rapid onset or relief of symptoms (hours rather than weeks to get worse or better), and temperamental patterns in one’s life. Temperamental patterns suggest a storminess in one’s life and often a degree of chaos that is seen more often in bipolar disorder than in depression. It may show itself through a pattern of many job switches, several marriages, or legal problems.

When patients with depression also have a concurrent problem with substance abuse, it is usually impossible to treat the depression until the substance of abuse is stopped. My expression is “when the car is at the bottom of the lake, you don’t send a scuba diving team down to fix the car, you pull the car out of the lake.” It is sometimes interesting to look at the preferred substance of abuse. Few patients with pure depression tend to abuse stimulants like cocaine, methamphetamine, methylphenidate or dextroamphetamine. Patients with depression find that the post use depression is so crippling that they tend to gravitate toward other drugs. I find that many of the people who abuse stimulating drugs have one or another form of bipolar disorder.

Depressive illness often presents with a co-morbid anxiety disorder. Anxiety disorders include post traumatic stress disorder (PTSD), generalized anxiety disorder, panic disorder, or obsessive compulsive disorder. A treatment plan needs to be developed to address all aspects of the illness. Many of the antidepressant medications we use also have efficacy in treating anxiety symptoms. In particular, PTSD often requires a comprehensive treatment approach that targets the specific presentation for each patient.

Many medical illnesses can present as depression or can have depression as a symptom of their illness. These conditions can include hypothyroidism, cancer, heart disease, diabetes, fibromyalgia, dementia, Parkinson’s Disease, and autoimmune diseases. Here too, to get as complete a response as possible, a treatment plan will need to address all facets of the illness.

Too often, what looks like a treatment resistant depression can be an inadequately treated depression. With the pressure of managed care driving more mental illness to be treated by primary care clinicians and/or non-physician mental health professionals, many patients have never been tried on medication, or had an adequate trial of medication. An adequate trial of antidepressant medication is for a minimum of four to six weeks at an adequate dosage (which is often more than the minimum dosage approved by the FDA). Clinicians may stop medication before an adequate trial period is passed or before an adequate dosage is achieved. As well, many patients do not take their medications reliably enough for an adequate trial. It is important to keep in mind that intolerance of a medication does not equal nonresponse, and the presence of residual symptoms after antidepressant treatment also does not mean nonresponse.

Depression has many different causes, many possible genetic contributions and many different presentations. The more we can understand each individual’s presentation, the better we can offer care tailored to meet their needs.