Joshua D. Bess, MD

In psychiatric practice, many depressed patients lack an optimal course of treatment-ie, a “simple” antidepressant medication, with or without psychotherapy-that results in complete symptom remission. The simplest definition of treatment-resistant depression (TRD) is “failure to achieve a response to a medication to any degree short of remission.”

 Addressing the complicating factors that may be responsible for TRD early may improve treatment outcomes.

The role of subtyping and bipolarity in TRD was discussed in Part 1 of this 2-part article

Confounding Factors in TRD Part 1: The Role of Subtyping and Bipolarity

). Here we review a number of the most common confounding factors of TRD but limit our scope to comorbidities that can be directly addressed and treated by psychiatrists. Subtle maladaptive personality traits or inherent temperamental factors may play a role in sustaining depression in certain individuals. Axis I diagnoses, such as eating disorders, anxiety disorders, and sleep disorders, complicate the treatment of depression unless they are directly addressed. Dissociative disorders may also complicate the treatment of depression.

The role of anxiety and anxiety disorders in TRD

Clinicians have long recognized that treatment of depression may be unsuccessful if accompanying anxiety disorders are not recognized and addressed. Even comorbid subsyndromal anxiety symptoms can complicate the treatment of depression and lead to TRD. Anxiety and depression co-occur frequently, sometimes with one or the other as the primary and preceding diagnosis, but often with a mixture of depressive and anxiety symptoms that is difficult to disentangle historically or clinically.

In their examination of generalized anxiety disorder (GAD) and its association with major depression, Moffitt and colleagues

 followed a group of approximately 1000 New Zealanders from birth to age 32. In this cohort, either MDD or GAD presented as the initial illness. High comorbidity of the two illnesses was demonstrated: 72% of patients with GAD had lifetime MDD, and 48% of MDD patients had lifetime GAD. The extent of the association between depression and anxiety disorders in general is further illustrated by the National Comorbidity Survey, which found that an anxiety disorder was present in 58% of the patients with a lifetime history of depression.

Anxiety symptoms may make depression harder to treat. Studies have shown that comorbid anxiety in depression is associated with greater severity and longer time to recovery; poorer response to medication; multiple drug trials; more frequent relapses and recurrences; increased social and vocational disability; and perhaps most importantly, an increased rate of suicide, especially in the first year of treatment.

One dissenting study found no association between GAD and TRD; however, this study had a small sample size, and it was a retrospective analysis of failed drug studies.

 Furthermore, this negative study focused narrowly on GAD, while confirmatory studies look more broadly at anxiety disorders and include subsyndromal symptoms, such as psychic anxiety, worry, phobic symptoms, and somatic anxiety.

 Subsyndromal symptoms can be debilitating, even when they do not meet DSM criteria. A comprehensive evaluation for an accompanying DSM-IV-TR anxiety disorder in patients with depression should include screening for agoraphobia, GAD, obsessive-compulsive disorder, panic disorder, PTSD, social phobia, and specific phobia (formerly simple phobia). Although any of these might accompany a specific depression diagnosis, the most commonly reported are social phobia, specific phobia, and PTSD.

The increased risk of treatment resistance in depressed patients with anxiety symptoms has also been demonstrated in the geriatric population. A recent study of patients older than 70 years with major depression used a self-rating scale for anxiety and found that elevated scores on this scale were associated with poorer response to treatment, increased rate of recurrence in the first 2 years of illness, and increased rate of treatment drop-out.

 Anxiety was viewed in this population as creating a “brittle response” to standard antidepressant treatment. Interestingly, in this study, adjunctive lorazepam (added to paroxetine) did not improve outcomes. The authors suggest that further studies of adjunctive use of psychotherapies and atypical antipsychotic medications in the elderly are needed.

What are the implications of this strong association between anxiety and depression? The most dreaded outcome of depression is suicide, and the destabilizing effect of anxiety in patients who are struggling with suicidal impulses in the setting of major depression increases this risk. Fawcett

 exemplifies this with case reports of 3 patients who ultimately committed suicide and who serve as object lessons for those who care for patients with major depression in both inpatient and outpatient settings.

These cautionary tales illustrate the importance of monitoring for anxiety and agitation in depressed patients. Be particularly aware of escalating anxiety that can accompany the onset of treatment with antidepressants, including SSRIs and TCAs. Because patients with anxiety disorders tend to be very sensitive to the adverse effects of medications, consider beginning antidepressants at lower than usual dosages and slowly titrating the dosage in depressed patients with comorbid anxiety.

The increased suicide risk in the first year of treatment mandates that follow-up psychiatric treatment should be well-designed and reliable. The ongoing suicide risk assessment of patients with depression should give special valence to accompanying anxiety, and its presence may call for increased monitoring or hospitalization.

Pharmacological management of patients with mixed anxiety-depression might include benzodiazepines, but their risks of sedation and dependence must be considered. Although many of the SNRIs and SSRIs have received separate indications for various anxiety disorders, there may be differential responses to these medications. For instance, one study reported better outcomes with the SNRI venlafaxine than with the SSRI fluoxetine for patients with MDD and GAD.

 There may also be a role for other medications in patients with depression accompanied by anxiety, including low-dose atypical antipsychotics, anticonvulsants (divalproex, carbamazepine, gabepentin, lamotrigine, and topiramate have shown effects in smaller studies), and buspirone.

 Î²-Blockers are useful in blocking peripheral manifestations of anxiety, but caution is advised when treating depressed patients because of the possible depressogenic effect.

Dissociative phenomena and their relationship to TRD

In the evaluation and treatment of patients with depression, dissociation in one of its many forms is easily overlooked as a contributing factor for treatment resistance. In DSM-IV-TR, dissociative disorders are Axis I disorders in which there are significant disruptions in memory, consciousness, identity, or the perception of the environment. There are currently 5 dissociative diagnoses in DSM-IV-TR: dissociative identity disorder (formerly known as multiple personality), dissociative amnesia, dissociative fugue, depersonalization disorder, and dissociative disorder not otherwise specified (NOS).

A thorough psychiatric evaluation includes screening questions for dissociative phenomena, especially when a patient presents with a known history of trauma or abuse. However, patients may not be open about abuse histories and may also fail to spontaneously disclose dissociative experiences, especially if the focus of the evaluation is on mood symptoms. Psychiatrists who treat large numbers of patients with dissociative disorders find that in many, the condition has been undiagnosed for a number of years.

Depression and dissociative disorders both represent final common pathways for patients who have suffered abuse in childhood or have undergone traumatic incidents as adults. For this reason, when a patient has such a history, it may be important to consider using a structured interview for dissociative disorders, such as the Structured Clinical Interview for DSM-IV (SCID-D), or a screening tool, such as the Dissociative Experiences Scale.

Using these instruments, one inpatient study of 171 consecutively admitted patients to a state hospital in Massachusetts found that 15% of these patients met criteria for a dissociative disorder. In this study, the most common dissociative diagnoses were dissociative identity disorder, dissociative amnesia, and dissociative disorder NOS. Furthermore, and relevant for considerations of TRD, there was a high rate of comorbid depressive illness among the patients with the various dissociative disorders.

Dissociative phenomena can be mistaken for psychosis. Marcum and colleagues

 reported the case of a 29-year-old man who had failed to respond to a high-dose antidepressant and antipsychotic regimen for what was presumed to be a major depression with psychotic features. This patient had experienced childhood sexual abuse at the hands of an older brother. A sodium amytal interview gave strong evidence for dissociative identity disorder, and the patient subsequently responded to hypnotherapeutic sessions, with a marked decrease in depressive symptoms and normalization of biological markers for depression.

Disturbance of sleep is a common complaint among patients with MDD and other Axis I disorders. In the initial treatment approach for a patient who presents with insomnia and depressed mood, a sedative/hypnotic or low-dose trazodone at bedtime is often used to supplement the main full-dose antidepressant. Usually, sleep quality and quantity improve with depression. However, when mood symptoms fail to respond to adequate psychotropic management or psychotherapy, TRD should be suspected. Further workup for comorbid medical issues or review of the differential diagnoses is necessary.

Multiple factors related to sleep may contribute to poor response in depression treatment. Lack of exercise, insufficient time for sleep, shift work, and disruptive drugs and substances (eg, excessive or ill-timed use of alcohol and caffeine) can lead to poor sleep quality, daytime sleepiness, or fatigue.

Perhaps less identified in psychiatry offices are sleep-related breathing problems-most commonly obstructive sleep apnea (OSA). OSA is a sleep disorder characterized by repeated obstruction of the upper airways resulting in apnea (complete) or hypopnea (partial), with corresponding oxygen desaturations and arousals from sleep.

OSA is common in both clinical and general populations. The estimated prevalence of OSA in Veterans Health Administration patients is 2.91%.

 This compares well with the 2.1% prevalence observed in a general population, cross-sectional telephone survey in Western Europe.

 However, approximately 20% of patients with MDD also have a breathing-related sleep condition.15 The converse relationship yielded a similar concurrence rate. These data confirm that depressed patients are at higher risk for sleep apnea.

While OSA and depressed mood commonly occur together, it is unclear whether depression is a primary process or the manifestation of disordered sleep. Excessive daytime sleepiness, impaired concentration, low libido, memory difficulties, and neuropsychological testing deficits are among the consequences of OSA. These symptoms overlap with MDD. Treatment of both disorders are needed to minimize their effects on the patient.

The diagnosis of OSA requires referral to a sleep specialist who can perform a specialized physical examination and who has access to a sleep laboratory for polysomnography. For financial and logistical reasons, it is not feasible to send every depressed patient for full-night polysomnography. While limited studies (nonneurophysiological recording of sleep and oxygenation patterns) have been used, polysomnography provides more definitive exclusion or confirmation of OSA. One study evaluated an optimal screening process based on patient symptoms that would initiate a more formal sleep evaluation.

 When severe snoring, observed apnea during sleep, or excessive daytime sleepiness is endorsed, referrals for polysomnography will yield sleep apnea rates up to 60%.

Depression and eating disorders are known to be highly comorbid. In a critical review of the literature on the comorbidity of depressive disorders and eating disorders, Godart and colleagues

 determined that comorbidity rates for bulimia nervosa and depressive disorders range from 24% to 90%; for anorexia nervosa, comorbidity rates range from 31% to 89%. In fact, patients with bulimia not only had higher lifetime prevalence rates of depression than controls, but they also had higher rates than patients with bipolar disorder or schizophrenia.

 found that bulimic symptoms were predictive of future depressive symptoms. Persons with eating disorders had significantly higher scores on the Beck Depression Inventory than controls and those who have chronic pain.

 The severity of disordered eating symptoms and that of depressive symptoms is highly correlated. In addition, as the eating disorder symptoms improve and resolve, so do the mood symptoms.

 In a prospective study, Angst and colleagues

 followed patients over 20 years to characterize differences between episodic depression and long-term depression. Binge eating was more common in the group with long-term depression.

However, in anorexia nervosa, the direct effects of starvation may confuse the diagnosis of depression. Persons with anorexia often have depression-like symptoms, including fatigue, poor sleep, lack of interest in sexual activity, and flat mood.

 With chronic disordered eating, feelings of helplessness and hopelessness also often become prominent. In a study of 70 patients, Coughlin and colleagues

 showed that psychological complications related to disordered eating worsened the longer the starvation or binge-purge behavior lasted. Primary efforts toward nutritional restoration and development of healthy eating patterns should play a critical role in these patients. In 4 placebo-controlled trials, there was no evidence that antidepressants had a positive effect on weight gain, the eating disorder, or associated psychopathology.

TRD is difficult to affirm in patients with low body weight. Correction of the eating disorder, especially in malnourished patients, may allow better attribution of depressive symptoms to an underlying mood disorder. In addition, establishing the timeline of a depressive disorder in relation to an eating disorder through detailed history and collateral reports may help justify continued antidepressant use in the midst of an eating disorder. In normal-weight patients with disordered eating, antidepressants are likely to be more effective.

Factors that contribute to TRD are not limited to those described in this article. Substance and alcohol abuse or dependence often elude an initial evaluation and undermine even the most aggressive antidepressant strategies. In addition, interactions with prescribed medications-not just drugs of abuse-can alter pharmacodynamics and/or pharmacokinetics, which necessitates closer monitoring and possible dosage adjustments.

On the medical side, several conditions besides sleep apnea are associated with depression.

 Vigilant efforts to detect and treat anemia, hypothyroidism, heart disease, or even occult cancer remove barriers to depression treatment and improve a patient’s overall health. In addition, the issue of the relationship of chronic pain to depression is a complex one deserving of attention.

Editor’s Note: Our Category 1 CME articles are on hiatus for the summer. In the meantime, we invite you to test yourself: read the article, take the posttest on the next page, and then check the answer key on the last page of this article for the correct answers.

 Findings from the National Comorbidity Survey indicate that ____ of patients with a lifetime history of depression have a comorbid anxiety disorder.



Which of the following is associated with comorbid anxiety in depression?



Higher degree of neurocognitive problems


 It is clear that depression is a manifestation of disordered sleep as a result of obstructive sleep apnea.



 The Mini-Mental State Examination can be used to determine the co-occurrence of depression and dissociative disorder.



 Which of the following statements is true concerning the relationship of depression to dissociative disorders?



 Neither one can be associated with history of childhood trauma.


 Failure to diagnose dissociative disorder may lead to unsuccessful treatment of depression.


 In a Massachusetts inpatient study, fewer than 5% of the patients had some form of dissociative disorder.


 Depression and dissociative disorders have low comorbidity.

 Which of the following is used as first-line therapy for a patient who presents with co-occurring depression and insomnia?



 An SSRI or SNRI supplemented by a sedative/hypnotic or low-dose trazodone at bedtime.


 Several glasses of wine in the evening, along with cognitive-behavioral therapy


What percentage of patients with MDD also have a breathing-related sleep condition?



Clinicians who treat elderly patients with depression and associated anxiety should be alert for all but one of the following:



 Increased rates of recurrence of illness


Comorbidity rates for anorexia nervosa and depressive disorders range from



Treating the malnourishment related to an eating disorder first may allow better assessment and treatment of depressive symptoms.



Answer key to the Mine Your Mind posttest:

1, D;   2, C;   3, B;   4, B;   5, B;   6, A;   7, B;   8, D;   9, C;   10, A.

Barbee JG. Treatment-resistant depression: advances in assessment. 

Casher MI, Gih D, Bess JD, Agarwala P. Confounding factors in TRD (Part 1): the role of subtyping and bipolarity. 

Moffitt TE, Harrington H, Caspi A, et al. Depression and generalized anxiety disorder: cumulative and sequential comorbidity in a birth cohort followed prospectively to age 32 years. 

Rapaport MH. Prevalence, recognition, and treatment of comorbid depression and anxiety.

 Kornstein SG, Schneider RK. Clinical features of treatment-resistant depression.

 Pollack MH. Comorbid anxiety and depression. 

 Petersen T, Gordon JA, Kant A, et al. Treatment resistant depression and axis I co-morbidity. 

 Fawcett J. The detection and consequences of anxiety in clinical depression. 

 Kessler RC, Nelson CB, McGonagle KA, et al. Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey. 

 Andreescu C, Lenze EJ, Dew MA, et al. Effect of comorbid anxiety on treatment response and relapse risk in late-life depression: controlled study. 

 Silverstone PH, Salinas E. Efficacy of venlafaxine extended release in patients with major depressive disorder and comorbid generalized anxiety disorder. 

 Bernstein EM, Putnam FW. Development, reliability, and validity of a dissociation scale. 

Saxe GN, van der Kolk BA, Berkowitz R, et al. Dissociative disorders in psychiatric inpatients. 

 Marcum JM, Wright K, Bissell WG. Chance discovery of multiple personality disorder in a depressed patient by amobarbital interview. 

The International Classification of Sleep Disorders. Diagnostic and Coding Manual.

 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

 Ohayon MM. The effects of breathing-related sleep disorders on mood disturbances in the general population. 

 Godart NT, Perdereau F, Rein Z, et al. Comorbidity studies of eating disorders and mood disorders: critical review of the literature. 

 Presnell K, Stice E, Seidel A, Madeley MC. Depression and eating pathology: prospective reciprocal relations in adolescents. 

Coughlin JW, Edwards R, Buenaver L, et al. Pain, catastrophizing, and depressive symptomatology in eating disorders. 

 Angst J, Gamma A, RÃ¶ssler W, et al. Long-term depression versus episodic major depression: results from the prospective Zurich study of a community sample. 

 Woodside BD, Staab R. Management of psychiatric comorbidity in anorexia nervosa and bulimia nervosa. 

 Claudino AM, Hay P, Lima MS, et al. Antidepressants for anorexia nervosa. 

 Schellander R, Donnerer J. Antidepressants: clinically relevant drug interactions to be considered. 

 Benton T, Staab J, Evans DL. Medical co-morbidity in depressive disorders. 

Articles

The role of subtyping and bipolarity in TRD was discussed in Part 1 of this 2-part article. Here we review a number of the most common confounding factors of TRD but limit our scope to comorbidities that can be directly addressed and treated by psychiatrists.

Confounding Factors in Treatment-Resistant Depression (Part 2): Comorbidities and Treatment Resistance

In psychiatric practice, treatment-resistant depression (TRD) is not unusual. In his 2008 review of the various definitions for TRD, including that of adequate clinical trials of at least 1 antidepressant, and perhaps 2, Barbee

concluded with the view that the simplest definition of TRD is “failure to achieve a response to a medication to any degree short of remission.” We can gain much by stepping back from a patient with TRD and doing a careful assessment for complicating factors that can prevent remission of depressive symptoms.

Confounding Factors in TRD Part 2: Comorbidities and Treatment Resistance

"), we discuss a number of the most common confounding factors of TRD. Here we look at subtyping and bipolarity and their role in TRD. Personality factors also affect treatment response in patients with depression. Unrecognized (or ignored) comorbid Axis II pathology, such as borderline personality disorder (BPD), can closely mimic various Axis I depression diagnoses, to the point where the clinician questions whether persistent or lingering dysphoric states are truly “depression.” In Part 2, we will discuss comorbidities in depression and their role in treatment resistance.

Outcomes are worse for patients with a history of childhood adversity or for patients who are in stressful or untenable psychosocial situations (eg, an abusive relationship, an ongoing custody battle). Depressive illnesses are both common and difficult to eradicate in such patients without attention to the “whole picture.” Poor treatment responsiveness is also associated with lack of social supports. Likewise, when the incentives, conscious or unconscious, for the “sick role” and psychiatric disability are greater than the rewards of euthymia, clinicians can easily find themselves thwarted in their treatment attempts.

Treatment resistance can occur when subtyping of depression is inaccurate or disregarded. This can be seen with melancholic features, which are presented as a specifier for major depression in DSM-IV-TR. The criteria for the melancholic features specifier are, in some measure, exaggerations of the neurovegetative symptoms of depression (


Melancholic features specifier for major depressive episode

“Melancholia” has been suggested as a separate diagnostic category for DSM-5; the criteria would include

• Disturbed mood of apprehension, worry, or despondency

• Psychomotor disturbance of agitation, retardation (including stupor or catatonia or both)

• At least 2 vegetative signs: poor sleep, poor appetite, disturbed libido, problems with cognition

• At least 1 of the following: abnormal dexamethasone suppression test or high nighttime cortisol levels; or decreased REM latency or other sleep abnormalities

Independent of the classification issues with respect to melancholic features, findings suggest differential responses to treatment when major depression is accompanied by melancholic signs and symptoms. These differences include a more favorable response profile with medications, especially with TCAs and other dual-action antidepressant classes, than with psychotherapies, as well as an increased response to ECT.

Catatonic subtyping involves considerations similar to those for melancholic features. Signs of catatonia are easily missed and are often mistaken for the less ominous “psychomotor slowing” seen so commonly with many depressions. The basic catatonic features are motoric immobility or overactivation (catatonic excitement), negativism, mutism, posturing, and echophenomena. Many psychiatric residents and even some experienced practitioners are not well versed in examining patients for catatonia, even though the condition is relatively common on psychiatric inpatient units, where many patients with refractory depressions are admitted.

Patients with psychotic features and/or melancholic features are more likely to have accompanying catatonic features as well, which is consistent with the notion that all of those specifiers point to a more severe biological process than that seen in uncomplicated major depression. When catatonic features are recognized by elicited history or on examination, special treatment considerations come into play. These include the need for high-dose benzodiazepines; consideration of ECT; and special care with use of antipsychotic medications (especially high-potency conventional antipsychotics) because of their tendency to worsen catatonic symptoms.

Failure to detect “hidden” psychosis accompanying depression or inattention to special considerations with known psychotic depression can lead to ineffective treatment with antidepressants alone. Even with optimal treatment, the presence of psychosis in patients with major depression is often associated with a more severe course and includes more repeated hospitalizations, decreased responsiveness to treatment, and higher relapse rates.

Accurate subtyping of depression thus dictates that clinicians become adept at ferreting out psychotic symptoms in patients who do not have obvious delusions or hallucinations. This often requires a high index of suspicion and intensive interview techniques. Patients may not spontaneously mention, for instance, that they are seeing malevolent “shadowy figures” out of the corners of their eyes. Likewise, without probing questions in the interview, subtle evidence of a delusional thought process (eg, is the patient really financially broke or is he or she suffering from a delusion of poverty?) can easily be overlooked.

In a recent chart review, symptoms of psychosis in depression were missed 27% of the time in an aggregate of patients on the inpatient psychiatric units of 4 academic medical centers.

 Estimates of the incidence of psychosis in depression range from 14% to 20%, which represents a considerable number of patients who would be categorized as having TRD if the psychosis is not recognized and they subsequently fail to respond to antidepressant treatment. Current evidence supports the conclusion that psychotic depression responds best to ECT or, when that treatment is not available or feasible, to a combination of an antidepressant and antipsychotic medication.

The atypical features of increase in appetite or weight and hypersomnia are sometimes referred to as “reverse vegetative signs,” but the full atypical syndrome also includes mood reactivity, a “leaden” feeling in the extremities, and exquisite sensitivity to social rejection. Earlier studies showed superiority of MAOIs to TCAs for atypical depression, but with the ascendancy of SSRIs and SNRIs, MAOIs have generally fallen out of favor.

 MAOIs are further disadvantaged by their associated diet and medication restrictions and less favorable adverse-effect profile. Nonetheless, recognition of atypical features of depression in a given patient should lead to consideration of use of an MAOI. Lack of recognition of atypical features may lead to an impression of TRD.

Patients who have bipolar disorder may show poor, erratic, or even “paradoxical” responses to therapy with antidepressants alone.

 When subtle evidence of bipolarity is overlooked and patients subsequently have numerous unsuccessful trials of non–mood-stabilizing antidepressant agents, these patients are thought to have treatment-resistant unipolar depression. When a patient who presents with a depressive state reports a history of classic manic symptoms, such as spending sprees, elation, flight of ideas, and grandiosity, very few experienced clinicians would overlook a bipolar diagnosis.

Beginning with the work of Akiskal and Pinto,

 there has been heightened recognition that genotypic bipolarity may not fully manifest itself phenotypically. There are patients with bipolar spectrum illness who do not present obvious historical accounts of mania or hypomania. It is often only after a period of years of illness that a patient is recognized as having bipolar II disorder rather than unipolar depression. The Mood Disorder Questionnaire (MDQ), designed for use in primary care clinics, is useful in screening for bipolarity in patients with depression.

 The MDQ can be combined with a comprehensive clinical interview for detection of hidden bipolar variants. Once a bipolar component is strongly suspected, the pharmacological strategy should shift from use of pure antidepressant agents (eg, monotherapy with SSRIs, SNRIs, or TCAs) toward a predominance of mood-stabilizing agents or ECT.

Most psychiatrists with extensive experience in treating depressed patients develop an intuitive sense that there are patients with “personality issues” who do not respond to treatment as readily as psychologically healthy peers with similar degrees of depression. One way that this is conceptualized is resistance directed toward or involving medication.

 Numerous studies have examined the comorbidity of Axis II disorders and depression, but fewer studies have looked at the impact of personality disorders on overall treatment responsiveness. Other studies have bypassed DSM categories altogether and have focused instead on more basic personality traits, attitudes, and/or temperament variables that create the “culture” in which depression can both germinate and sustain itself despite seemingly adequate treatments.

The relationship between personality factors and depression is complex and difficult to study for a number of reasons. Depression itself confounds the accurate assessment of personality. Patients in the throes of a depressive episode may appear to have-indeed, often meet criteria for-a personality disorder. Many patients who do meet criteria for an Axis II diagnosis during a mood episode no longer meet those criteria once their depression has been adequately treated. In short, depression can induce a psychological state that resembles a personality disorder.

Personality disorders are currently conceptualized not as static configurations of traits but rather as fluid constellations that can fluctuate with internal and external stressors.

 In this dynamic system, the development of a major depression would represent a “negative” internal factor that could disrupt personality homeostasis to the point where a personality disorder emerges. Further complicating the relationship between depression and personality is the observation that evidence of personality pathology in late adolescence or early adulthood may actually represent the early signs of a mood disorder. Finally, for many patients, the relationship between mood symptoms and personality variables may be mediated through complex, cascade-like mechanisms. For instance, patients with BPD may lead a chaotic and self-defeating lifestyle that results in alienation from social support, which, in turn, leads to loneliness and isolation-and ultimately to depression.

The intricate relationship between personality and depression defies easy understanding. Nevertheless, in the following section, we break down the issue into a number of general categories and highlight the implications for the evaluation and treatment of TRD.

Personality style characteristics, traits, and temperament

Researchers and psychologists tend to favor dimensional classifications of personality over the categorical approach put forth in DSM texts through DSM-IV-TR. (The upcoming DSM-5 personality section is heavily influenced by the dimensional approach to diagnosis.) An advantage of dimensional approaches is that they include psychological variables that are reliably rated. Some of these factors are inheritable and therefore can be linked with biological markers, specific neurotransmitters, or neuroimaging variations.

 One popular way to conceptualize personality dimensionally is the 5-factor model that includes the polar dimensions of neuroticism-stability, introversion-extraversion, openness-closedness to experience (in other systems, this is called thrill seeking vs harm avoidance), agreeableness-antagonism, and conscientiousness-negligence.

A similar dimensional system is Cloninger’s temperament/character model,

 which includes 4 temperament dimensions (harm avoidance, novelty seeking, reward dependence, and persistence) and 3 character dimensions (self-directedness, cooperativeness, and self-transcendence). All are thought to represent significant genetically based contributions to overall personality.

In one study, the Tridimensional Personality Questionnaire was given to patients with major depression to see whether 3 of Cloninger’s dimensions (novelty seeking, harm avoidance, and reward dependence) remained stable with changes in mood. Reward dependence and novelty seeking were stable in the face of affective changes, while harm avoidance tended to be heightened with depressive illness and reduced with treatment.

Findings from a study using still another dimensional personality model suggest that the distinct personality style traits of perfectionism and anxious worrying contributed to depression in a group of 54 patients. The researchers speculated that these traits also had a role in treatment resistance.

Drawing from among the various dimensional systems, poor outcome in treatment of depression has also been associated with high levels of neuroticism, high scores on harm avoidance, and a tendency toward introversion.

 In patients with TRD, those with high degrees of neuroticism respond better to TCAs than to MAOIs. Introversion includes social inhibition, which reflects a tendency to avoid mixing with others. Social inhibition is overrepresented in patients who have hard-to-treat depressions.

There is also consistent evidence that the trait of harm avoidance is associated with serotonergic functioning, which suggests that medications that target the serotonin system are useful for patients with TRD who have high harm-avoidance scores.

 Although further associations of different traits with various neurotransmitter systems have been postulated, studies to reliably demonstrate these relationships have been inconsistent.

Despite its limitations, the categorical approach to personality disorder diagnosis is firmly ensconced in the practice of American psychiatry and is likely to remain so, even with the anticipated changes in DSM-5. So, does a comorbid personality disorder-as defined by current DSM (pre–DSM-5) criteria-predict a poor treatment outcome in patients with depression?

 concluded that the evidence for worse outcomes in patients with depression and comorbid personality pathology was inconclusive. However, a meta-analysis of 32 studies of depression treatment outcomes in which the presence of personality disorders was also formally assessed found robust evidence for less response to treatment in patients with a concurrent personality disorder.

 Furthermore, recent data from the Collaborative Longitudinal Personality Disorders Study of nearly 2000 patients confirm that many DSM personality disorders, and BPD in particular, are associated with persistence of depressive symptoms.

Perhaps the strongest evidence for increased treatment resistance in the BPD population is the finding that ECT-arguably the most potent treatment modality for depression-was much less effective in patients with MDD who had comorbid BPD. These patients had a remission rate of only 22% with ECT, compared with 56% for patients with other personality disorders and 70% for patients with no diagnosed personality disorder.

Speculations about the reason for disparities in responsiveness to ECT and medications in patients with BPD involve a number of issues in the relationship of mood and affect to BPD. First of all, the diagnosis of BPD includes a number of items with mood content. These items overlap considerably with items on depression rating scales: suicidal ideation and behaviors, affective instability with periods of intense dysphoria, and long-term feelings of emptiness. Clinicians can easily get caught up in unsuccessful efforts to eliminate these character-based vulnerabilities through aggressive somatic treatments.

Alternatively, even with a clear diagnosis of both MDD and BPD, the biological features of depression that occur in patients with BPD may be different from those in patients without associated BPD. Whatever the mechanisms of reduced efficacy of depression treatment in BPD, recognizing this comorbidity is enormously important.

Nonpharmacological treatments are first-line and remain the mainstay of continuing treatment even when medications are added. The best evidence-based approach to date is dialectical behavioral therapy (DBT), either added to a partially effective pharmacological regimen or substituted for a regimen that has had no benefit whatsoever.

 DBT, a form of cognitive therapy with a manualized approach, has shown its greatest effectiveness in decreasing suicidal and parasuicidal behaviors, with consistently positive outcomes in randomized controlled studies.

In recent years, evidence has also accumulated for effectiveness of other forms of psychotherapy for BPD, including psychodynamically informed psychotherapies and the group-based program STEPPS (Systems Training for Emotional Predictability and Problem Solving).

A solid clinical interview that focuses on the patient’s history of interpersonal and occupational functioning, repertoire of defenses, and interaction with the interviewer is usually sufficient. Some clinicians, especially those in a research or tertiary care setting, also use structured interviews designed to detect personality disorders. Supplemental interviews with family or close friends can be helpful, since the symptoms of a personality disorder are generally ego-syntonic and the patient may not perceive them as problematic.

The current system of payment for mental health care in the US can lead, or even incentivize, clinicians to focus on and code for Axis I disorders and their more readily reimbursed psychopharmacological treatment approaches. Busy clinicians might skip the systematic exploration of the patient’s history and current functioning necessary to make a personality disorder diagnosis. Nevertheless, good clinical care mandates that subtyping of depression is taken into account and that the possibility of a confounding personality disorder be considered in all patients with TRD.

Confounding Factors in Treatment-Resistant Depression: Part 1

Editor’s Note: Our Category 1 CME articles are on hiatus for the summer. In the meantime, we invite you to test yourself: read the article, take the posttest below, and then check the answer key on the last page of this article for the correct answers. 

1. Which of the following criteria for melancholia would be included were it to be a separate diagnostic category in DSM-5?

B. Psychomotor disturbance of agitation, retardation (including stupor, catatonia, or both)

C. Persistent symptoms of disorganized behavior

2. The recommended treatment when depression is accompanied by melancholic symptoms is psychotherapy.

3. Which of the following is NOT a treatment option for depression with catatonic features

A. High-potency conventional antipsychotics

4. Estimates of the incidence of psychosis in depression range from

5. Which of the following symptoms is most suggestive of the diagnosis of depression with atypical features?

B. Lack of reactivity to usually pleasurable stimuli

6. Which of the following tools can be used in primary care settings to screen for bipolarity in patients with depression?

7. One way to conceptualize personality dimensionally is the 5-factor model that includes which of the following?

8. Poor outcome in treatment of depression has been associated with high levels of neuroticism, high scores on harm avoidance, and a tendency toward introversion.

9. The remission rate was only _____ following ECT in patients with MDD and comorbid borderline personality disorder compared with a rate of ______ in patients with no diagnosed personality disorder.

The current system of payment for mental health care in the US can lead, or even incentivize, clinicians to focus on and code for Axis I disorders and their more readily reimbursed psychopharmacological treatment approaches.

Confounding Factors in TRD (Part 1): The Role of Subtyping and Bipolarity

The following case vignettes draw attention to the symptoms and signs of illness.

Anil is manic with mood-driven behaviors that are so out of control that he meets criteria for an involuntary hospitalization. Janice presents with psychosis-a delusion of impersonation, or Capgras syndrome. For both patients, a factor that will heavily influence treatment decisions, length of stay, medication adherence, need for extra support in the community-indeed the ultimate course of illness-is the patients’ level of insight.

Anil, a 20-year-old from India, now a college student in the United States, was involuntarily admitted to the psychiatric inpatient unit in a florid manic state, with rapid speech, flight of ideas, and sleeplessness. Before admission, he had been clocked driving at 100 mph. The intercepting police, noting his abnormal mental status, brought Anil to the emergency department. Mood stabilizer and antipsychotic medication settled him over a week, but he still persisted in believing the police “must have been drunk themselves,” since they assessed him as needing psychiatric help. “I’m not bipolar. Everybody has mood swings!” he insisted. He added, “I will take the medications while I am here, but I am not sure I really need them after I leave.”

Anil clearly does not accept the bipolar disorder diagnosis. Is this part of his illness and a sign that he is not yet stable? Should we trust him in a partial hospital or outpatient program or should he remain on a locked inpatient unit? In view of his lack of insight, does he need a change of medication? What should his family be told about his prognosis, especially if he persists in his denial of illness? Understanding insight is paramount for answering these questions.

Janice, a 27-year-old with schizophrenia, stopped taking her prescribed antipsychotic consistently. Within 2 months, her psychotic symptoms returned with full force, and she required hospitalization. She told the admitting psychiatrist that the woman who brought her to the emergency department was not her real mother, but rather “an actress playing her mother.” This misperception had likely played a role in threats she had made toward her mother on the day of admission. Questioned by the psychiatrist as to the plausibility of someone resembling her mother so precisely, she responded, “I don’t know how they did it, but somehow they were able to find someone!” A week after restarting her medication, Janice allowed that her imagination had been “playing tricks on her” and happily embraced her real mother.

Is Janice ready to go home after her week in the hospital? Does she really understand her illness well enough to be allowed to manage her own medications again? Does the risk of violence change the assessment? Should a long-acting injection be prescribed, given her history of nonadherence?

What is already known about insight in psychiatric inpatients?


There is ample literature on insight in psychiatric patients, with much of it concentrating on severely ill inpatients. Insight scales have been used to explore the relationship of insight with various clinical conditions, situations, and outcomes in hospitalized patients.

What new information does this article provide?


Despite the considerable research literature on insight, little information has permeated to the clinical practice of psychiatry. This article reviews the relevant studies involving insight and offers an overview and critique of the various rating scales for insight.

What are the implications for psychiatric practice?


Psychiatric assessments often give only cursory attention to the patient’s level of insight. This article provides practical tips for adding more detail to the assessment of insight in evaluations and progress notes. Improvement in insight assessments can help the clinician with important transitional stages in the patient’s treatment, including decisions around readiness for discharge and the level of monitoring required in the outpatient setting.

In written evaluations of psychiatric patients, many residents and attending psychiatrists include little nuance or detail on the insight component of the mental status examination. A review of initial psychiatric evaluations and progress notes shows that insight, often in a combined item listed as “Insight/Judgment,” is frequently described as “poor,” “fair,” “limited,” “improving,” etc. The use of these nonspecific adjectives can be attributed to time limitations and/or a desire for brevity. But these cursory terms also reflect the limited attention given to the assessment of insight in psychiatric training. After all, other, “sexier” elements of the mental status examination-thought content, thought process, mood, affect-are generally described more fully and with more specificity. Yet, a refined assessment of insight is equally important to the comprehensive patient evaluation, both on initial admission and on subsequent days. Simple adjectives do not capture the separate components of insight. The reader might reasonably ask, “poor insight into what?”

Deficits in insight have implications for numerous clinical inpatient hospitalization issues, including the decision to hospitalize a patient voluntarily or involuntarily in the first place. Other insight-related issues include adherence to treatment after discharge, guardianship/capacity assessments, readiness for discharge decisions, the choice of oral medications versus long-acting depot medication, recommendations for placement in a structured setting after discharge, and the referral of patients to appropriate psychotherapy on hospital discharge.

The etiology of lack of insight has been variously conceptualized as

• Stemming from neuropsychological (brain) deficits

• Part of the primary psychiatric illness itself (eg, poor insight as a symptom of mania)

• A form of defensive denial protecting the patient against the distress of awareness of illness

Regardless of the theoretical model-and it is likely that all apply in different circumstances-the assessment of insight should be detailed and well documented in the clinical record.

A sizable group of clinical researchers, within both psychology and psychiatry, have studied and clarified the concept of insight and its application to clinical states. There is abundant literature on the design and validation of rating scales of insight, and there are studies that correlate deficits in insight with psychiatric diagnoses and with various states of illness.

A moment’s insight is sometimes worth a life’s experience.
-Oliver Wendell Holmes Jr

Impaired insight is intrinsic to many, if not most, severe psychiatric conditions. Poor insight is a prevalent feature of schizophrenia, and lack of awareness of schizophrenic symptoms is correlated with poor medication adherence and higher rates of recidivism.

 Poor insight is also common in bipolar disorder, and although insight is more state-dependent in bipolar disorder than in schizophrenia, it correlates with poor treatment outcomes.

Poor insight in mania is not necessarily related to the presence or absence of psychotic symptoms.

 Multiple studies have shown correlations between poor medication adherence and lack of insight across diagnostic groupings.

 Assessment of insight has a pivotal role in the decision to give a psychotic patient a long-acting depot medication.

Finally, recent research has expanded into the neuropsychological underpinnings of insight. For instance, the literature suggests that insight deficits in schizophrenia show a greater correlation to the degree of cognitive impairment than to acute psychopathology.

In a general context, meanings assigned to insight generally combine some metaphorical use of terms related to seeing and perception, or words that imply comprehension and self-knowledge. For instance, synonyms for the word “insight” include vision, understanding, awareness, intuition, perception, acumen, comprehension, discernment, and perceptiveness. To illustrate this further, one needs only to note that “insight-oriented psychotherapy” and “insight therapy” are often used interchangeably with other terms for psychodynamic therapies, eg, psychoanalytic psychotherapy, psychodynamically oriented psychotherapy, and even “uncovering therapy.” The insight gained in these therapies can be considered a product of working through of psychological conflict and a concomitant awareness of the self that was previously preconscious or unconscious (the dictionary’s “glimpse or view beneath the surface”).

In contrast to the more comprehensive psychoanalytic concepts, insight has a more circumscribed meaning in the psychiatric mental status examination, especially with severely ill inpatients. In this context, insight refers to awareness of one’s current psychiatric condition or illness, the ramifications of said illness, attribution of the cause of illness, and appreciation of the need for treatment.

Insight can be assessed in the course of a typical evaluation or follow-up interview with augmentation by questions borrowed from any of the validated insight rating scales.

Author | Joshua D. Bess, MD

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Confounding Factors in Treatment-Resistant Depression (Part 2): Comorbidities and Treatment Resistance

Confounding Factors in TRD (Part 1): The Role of Subtyping and Bipolarity

Determination and Documentation of Insight in Psychiatric Inpatients