The initial approach to patients with refractory or chronic depression begins with a comprehensive assessment of Axis I psychiatric disorders, including information from the patient as well as collateral sources. Unrecognized syndromal or subsyndromal psychiatric conditions (e.g., bipolar disorder, atypical depression, anxiety disorders, psychosis, substance abuse) may be found in some patients with chronic or treatment resistant depression, and the presence of any of these associated conditions has obvious implications for considering particular pharmacotherapy and/or psychotherapy treatment options (). Similarly, information (from the patient and collateral sources) about current psychosocial functioning; optimal functioning in past years; and “basic” personality traits as a child, teenager, and young adult, especially during times when the patient has not been depressed, is needed in the assessment of Axis II disorders. Finally, past medication and psychotherapy treatment history is essential, including quantitative and qualitative information about treatment type, duration, adequacy, tolerability, compliance, and outcome ().
For patients with clear-cut Axis II comorbidity, it is helpful to provide a nonjudgmental and nonpejorative description of the clinical assessment to the patient, including education about the nature of personality disorders and their potential impact on the course and treatment of depression. The treatment plan should be guided by the case formulation and past treatment history and should include considerations of various medication alternatives (), medication combinations (), and psychotherapies (Table Feedback for treatment of patients with depression).
TABLE Feedback for treatment of patients with depression
The clinician should provide…
- • A nonpejorative, nonjudgmental description of the clinical assessment
- • Psychoeducation regarding the nature of personality disorders and potential impact on the course and treatment of depression
- • A treatment plan guided by case formulation and past treatment history
- • Consideration of various medication alternatives, medication combinations, and psychotherapies
The relationship between personality disorder clusters and Axis I disorders suggests particular medication strategies (). Depressed patients with Cluster C anxiety-related personality disorders might benefit more from the use of serotonergic antidepressant drugs that have been found to be effective in the treatment of various anxiety disorders. The SSRIs (i.e., fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, or escitalopram) and venlafaxine are effective treatments for generalized and social anxiety symptoms. Venlafaxine also has been shown to be effective in treatment-resistant depression () and more effective than SSRIs in patients with nonrefractory depression (). The antidepressants nefazodone and mirtazapine also have beneficial effects on symptoms of anxiety among patients with depression, and these might be appropriate alternatives to the SSRIs or venlafaxine. The antianxiety drug buspirone may have antidepressant effects at higher doses and could be used alone or in combination with one of these antidepressant medications. Obsessive-compulsive symptoms respond preferentially to the SSRIs or to the tricyclic antidepressant (TCA) clomipramine. Depressed patients with Cluster C personality disorders who fail to respond to adequate trials of the newer generation antidepressants (e.g., two or more SSRIs, venlafaxine, nefazodone, and mirtazapine) might benefit from the older generation TCA or monoamine oxidase inhibitor (MAOI) antidepressant drugs (). In particular, the MAOI phenelzine and the TCA clomipramine have demonstrated efficacy in the treatment of anxiety disorders and have especially good track records in the treatment of refractory depression (). Atypical forms of depression also respond preferentially to MAOIs ().
Subtle signs of bipolar disorder (e.g., mood instability and impulsive behaviors) in patients with Cluster B personality disorders provide a clinical rationale for trying different mood-stabilizing medications, such as lithium, anticonvulsant drugs, or atypical antipsychotic drugs, either alone or in combination with antidepressant drugs (), especially in patients with borderline personality disorder (). Despite potential concerns about toxicity among patients prone to impulsive overdoses, lithium has been found to reduce the risk of suicide attempts and suicide deaths in bipolar disorder () and to reduce anger and suicidal thoughts in borderline personality (). Lithium also is the best studied and most effective augmentation therapy for refractory depression. Anticonvulsant drugs (e.g., valproic acid, lamotrigine, carbamazepine, and oxcarbazepine) are now used relatively more often than lithium in clinical practice for the treatment of bipolar disorder. There is developing evidence that they also may be effective in the treatment of borderline personality () and to have significant antidepressant effects in unipolar and bipolar depression, including refractory depression (). However, anticonvulsants may be less effective than lithium in reducing suicide attempts and suicide deaths in patients with bipolar disorder (), although these drugs have not been directly compared in the treatment of patients with borderline personality. Atypical antipsychotic drugs (e.g., risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are now being used with increased frequency, often in combination with antidepressants, for the treatment of patients with bipolar disorder (), refractory depression (), and borderline personality (). A recent study found that olanzapine alone and in combination with fluoxetine was more effective than fluoxetine alone for treating depression and impulsive aggression in patients with borderline personality, although fluoxetine alone also led to a substantial reduction in depression and impulsive aggression (). Bipolar depression, which is often chronic and refractory to treatment, may respond somewhat better to MAOIs (), the novel antidepressant bupropion (), the anticonvulsant lamotrigine (), or the combination of olanzapine and fluoxetine (). Because of pharmacological differences among drugs within the group of anticonvulsants and within the group of atypical antipsychotics, depressed patients with Cluster C personality disorders who fail to respond to an initial trial of a mood-stabilizing medication might benefit from switching to an alternative drug from the same class. However, after failing to respond to adequate trials of at least two drugs from the same group, consideration should be given to switching to an alternative class of medication.
Patients with Cluster A personality disorders show subtle psychotic symptoms (e.g., paranoia or odd thoughts and behaviors) that may support the use of antipsychotic drugs (). The antidepressant effects of atypical antipsychotics, especially when combined with antidepressants, provide further clinical justification for their use in refractory depression as well as in psychotic depression (). Because of pharmacological differences among atypical antipsychotic drugs, depressed patients with Cluster A personality disorders who fail to respond to an initial adequate trial of one medication might benefit from switching to an alternative antipsychotic. The older tetra-cyclic antidepressant amoxapine has antipsychotic and antidepressant effects and has been found to be effective alone in the treatment of psychotic depression (). Electroconvulsive therapy (ECT) is considered a viable alternative to medications for the treatment of psychotic depression and should not be overlooked in depressed patients with comorbid personality disorders, especially in the presence of severe levels of depression or treatment resistance (). Some guidelines for the use of medications in treatment-refractory depression are listed in Table
Suggested guidelines for psychopharmacological intervention in patients with treatment-refractory depression:
- • The initial choice of antidepressant medication should be based on depression subtype, associated symptom features, comorbidity desired and/or expected side-effect profile, and prior medication history.
- • Each medication should be used at the maximum tolerated approved dose for at least 6-12 weeks. In select cases, doses higher than the manufacturer’s recommended maximum can be used with appropriate clinical monitoring.
- • The goal of treatment should be full remission of depressive symptoms and significant recovery of psychosocial functioning.
- • For patients showing a significant partial improvement with a single antidepressant drug, augmentation with a second agent or combination with a second antidepressant is preferred over switching to an alternative antidepressant.
- • Recommendations for antidepressant augmentation include lithium, atypical antipsychotic drugs, buspirone, thyroid hormone, lamotrigine, and stimulant drugs. Recommendations for antidepressant combinations include mirtazapine plus selective serotonin reuptake inhibitors (SSRIs) or venlafaxine, bupropion plus SSRIs or venlafaxine, and tricyclic antidepressants plus SSRIs or venlafaxine.
- • For patients showing minimal or no improvement with a single antidepressant drug, switching to an alternative antidepressant is preferred over augmentation with a second agent.
- • For patients failing an initial trial of an SSRI antidepressant, switching to an alternative SSRI is appropriate. Patients failing trials of two SSRI antidepressants should be switched to an alternative antidepressant from a different class.
- • Lithium, anticonvulsant drugs, and atypical antipsychotic drugs can be used together with antidepressants to treat associated symptoms (e.g., anger, mood instability, impulsiveness, subtle psychosis) and may also augment the mood effects of antidepressants.
- • For patients with chronic and refractory depression, an effective medication or combination of medications should be maintained indefinitely with periodic clinical assessments for safety and tolerability. Medications should be slowly tapered and discontinued only after a long period of full remission and recovery.
An active psychoeducational and skills-oriented approach to psychotherapy is generally most useful for refractory and chronic depression in patients with comorbid personality disorders (). This approach should emphasize practical interpersonal, cognitive, and behavioral interventions that are individually tailored to help the patient achieve well-defined goals (see Table Suggested guidelines for psychotherapeutic intervention in patients with treatment-refractory depression). A specific and detailed problem list of psychosocial difficulties is needed for setting short- and long-term treatment goals. The therapist and patient must work together to establish an agreement about the problems, goals, and potential strategies to try in therapy, with a willingness to try alternative approaches when an initial strategy is ineffective. It should be emphasized that although problems generally have solutions, better ways of coping with problems may be available when solutions are not immediately possible. The use of an eclectic mix of psychosocial methods is designed to address comprehensively the myriad complicated problems encountered in these patients (). Moreover, this approach uses various treatment strategies that have been specifically developed and/or used for these types of patients ().
TABLE Suggested guidelines for psychotherapeutic intervention in patients with treatment-refractory depression
- • The therapy relationships should be collaborative and centered around the goal of teaching new skills to improve coping with a chronic illness. Pair core therapeutic skills (e.g., empathy and understanding) with the ability to provide appropriately specific, targeted interventions (e.g., relaxation training, activity scheduling, problem solving, or cognitive restructuring).
- • Make judicious use of examples from other medical models in which rehabilitative interventions are used to enhance the outcome of a chronic disorder (e.g., poststroke rehabilitation, pain management, or orthopedic rehabilitation).
- • Express cautious optimism that problems can be addressed with varying degrees of success. It is important, however, to understand the patient’s pessimism and to elicit feedback about what has not worked well in the past.
- • Establish stepwise, short-term goals that specifically address the patient’s problems or symptoms. Use graded tasks or intermediate assignments to approach more daunting or potentially overwhelming problems.
- • Meet frequently and, if necessary, shorten sessions to enhance learning and retention. Keep sessions active and avoid the “silent treatment.” Obtain feedback at the beginning and the end of treatment sessions so that the patient’s reactions to therapy can be monitored and properly addressed. Be vigilant concerning subtle affective and behavioral reactions within sessions as an in vivo source of feedback.
- • Use homework assignments and in-session rehearsal to facilitate development of new coping skills. It is important to avoid implicit criticisms about difficulties in therapy, such as homework noncompliance. The therapist must address his or her own dysfunctional cognitions blaming the patient for “not wanting to get better.”
- • Involve spouse or significant others to provide psychoeducation and to enhance alliance with family members.
- • Establish intermediate and long-term goals as symptomatic improvement and short-term goals are accomplished.
- • Do not terminate treatment until the patient has achieved a remission and sustained it for at least 4-6 months.
CBT (cognitive-behavioral therapy) is the best studied form of psychotherapy for chronic and refractory depression (). Modifications of CBT also have been developed to address the treatment of anxiety disorders and personality disorders (). Homework assignments are used to monitor and record the particular problems, situations, negative or distorted thoughts, and behavioral responses that occur outside therapy, contribute to depression, and can be addressed within therapy sessions. Refractory and chronically depressed patients are often predisposed to assume a more pessimistic, hopeless, and passive role in their lives, which reinforces the depressed state. In cognitive-behavioral therapy, patients learn to approach problems one step at a time by breaking them down into more discrete and potentially solvable tasks. The important goal is task completion, however, and not necessarily a successful outcome. Patients are also encouraged to pursue various activities that can lead to feelings of pleasure and success and that can counter symptoms such as lack of motivation, isolation, and withdrawal. By way of example, a depressed person who has long been rigid, perfectionistic, overly preoccupied with details, indecisive, and excessively devoted to work may have a comorbid obsessive-compulsive personality disorder. Therapeutic techniques in CBT may be appropriate for addressing depressive symptoms as well as underlying obsessive-compulsive traits in such a patient.
Many depressed patients with personality disorders have difficulties with emotional dysregulation, and they may have significant problems with irritability, anger, and controlling impulsive behaviors (). Various cognitive and behavioral strategies, such as identification of cognitions associated with angry outbursts, distraction, guided imagery, relaxation techniques, and skills training, have been used in anger management. For example, a comprehensive cognitive-behavioral treatment model known as dialectical behavior therapy (DBT) has been developed for patients with borderline personality disorder (). In DBT, patients learn greater awareness and acceptance of their emotions, thinking, and patterns of behavior, and they develop alternative self-control skills that can be used to manage intolerable emotional states and reduce maladaptive behaviors. Patients learn to identify the chain of thoughts and feelings that precede maladaptive behaviors, and they learn to implement alternative ways of coping. For example, a chronically depressed person who has a longstanding pattern of unstable interpersonal relationships, poor self-image, mood instability, and impulsive behaviors consistent with a comorbid borderline personality disorder would be a good candidate for dialectical behavior therapy.
IPT is an effective treatment for depression, although it is not as well studied as CBT (cognitive-behavioral therapy). Interpersonal difficulties are an obvious problem in patients with personality disorders, and these problems are accentuated in the face of chronic or refractory depression. Some effort has been made to tailor IPT to these patients (). Much of the focus in IPT is on difficulties in the patient’s current interpersonal relationships, including problems associated with grief, interpersonal role disputes, role transitions, and interpersonal deficits, although past interpersonal problems also are explored and are used to understand maladaptive patterns and to identify areas for change. Patients are encouraged to examine how depression has affected their lives and how they can work to become well again. Techniques commonly used in IPT include facilitating affect (e.g., expressing repressed anger), encouraging activity and socialization, exploring different options for achieving life goals, examining communication problems, clarifying the patient’s understanding of his or her interpersonal style, and using the therapy relationship to examine and work through interpersonal problems. For example, a chronically depressed person who is socially inept and inhibited avoids occupational activities that involve significant interpersonal contact and is inhibited in new interpersonal situations because of feelings of inadequacy may have an underlying avoidant personality disorder, and the use of IPT might be appropriate for targeting his or her depression and interpersonal difficulties. Marital discord also is associated with a poor antidepressant treatment outcome, and some patients may benefit from couple’s therapy ().
Social skills training (SST) is a particular behavioral approach that targets inadequate or dysfunctional interpersonal behaviors (). Because important reinforcers for most adults occur in interpersonal activities, insufficient positive reinforcement of nondepressed behavior may contribute to the development or persistence of depression. Poor interpersonal function can be attributed to many factors, including inadequate or maladaptive social skills, a failure to recognize or accurately interpret social cues, a lack of assertiveness, and a belief that their skills will be ineffective in social situations. Chronically depressed patients, especially those with comorbid personality disorders, may be socially ineffective or may engage in interpersonally aversive behaviors that worsen their psychosocial problems (). SST consists of evaluating the patient’s social performance, practical social skills training, role playing and practice exercises to reinforce these skills, learning perceptual skills to use in interpersonal situations, and teaching patients to monitor their performance and to provide themselves with positive reinforcement. Thus, patients learn practical skills that will improve their relationships, increase their socialization, and enhance their self-esteem by their interpersonal success. SST has been shown to have a significant antidepressant effect and improve the psychosocial environment of depressed patients (). An SST treatment model has also been developed for use in the treatment of patients with personality disorders (). For example, a depressed person who has a pervasive pattern of social and interpersonal deficits because of odd beliefs, peculiar speech, and eccentric behaviors may have a comorbid schizotypal personality disorder. The use of SST may be helpful in the overall management of such a patient.
Cognitive-behavioral analysis system of psychotherapy (CBASP) is a psychotherapy model that was specifically developed for the treatment of chronic depression (). CBASP is a highly structured therapy that combines important elements of CBT, IPT, and SST. The emphasis in CBASP is on teaching patients to associate their behavioral responses and faulty interpretations of events with interpersonal outcomes. Careful attention is paid to potential pitfalls in the therapeutic alliance that can derail therapy. An important goal of CBASP is for patients to learn to take a perspective that facilitates achieving their desired outcome in interpersonal situations and to take actions that lead more directly to their desired outcomes, with consequent improvements in social support systems. Cognitive-behavioral analysis system of psychotherapy has been shown to be as effective as antidepressant medication in the treatment of chronic depression (). Although CBASP has not yet been specifically applied to the treatment of personality disorders, the cognitive, interpersonal, and behavioral skills techniques that are used may be relevant to this patient population. For example, a chronically depressed person with a long-standing pattern of allowing others to make decisions, lacking initiative, having difficulty disagreeing with others, and feeling helpless when alone may have a comorbid dependent personality disorder, and CBASP might be very effective in targeting the patient’s chronic depressive symptoms and associated personality traits. Of interest in this respect, cognitive-behavioral analysis system of psychotherapy alone was found to have significant effects on psychosocial function in chronically depressed patients, and this improvement was relatively independent of changes in depressive symptoms ().
Most patients with refractory or chronic depression and comorbid personality disorders will benefit from some combination of pharmacotherapy and psychotherapy, which will often require coordination between a nonmedical psychotherapist and a pharmacotherapist (). Pharmacotherapy and psychotherapy can each be provided within a clearly focused and rigorous conceptual model of treatment (). Close collaboration will be needed, however, to avoid problems with treatment splitting that may undermine or contradict the efforts of each provider. Obviously, this problem is more likely to occur in the treatment of patients with comorbid personality disorders.
Although there are no formal controlled studies of combined treatment in refractory or chronic depression specifically addressing comorbid personality disorders, there is some evidence that combination treatment may be more effective than pharmacotherapy alone in these patients (). In addition, many studies have demonstrated the relative benefits of combining psychotherapy and pharmacotherapy in patients with chronic and refractory depression, who are more likely to suffer from comorbid personality pathology ().
A recent large randomized study comparing the antidepressant nefazodone alone, cognitive-behavioral analysis system of psychotherapy, and their combination in 681 patients with chronic major depression or double depression found that the treatment response rate to nefazodone or to CBASP alone was approximately 50% after 12 weeks (). This response rate was impressive for a very chronically depressed group of patients (the average duration of their current episode of dysthymia was approximately 23 years and approximately 8 years for their current episode of major depression) but was significantly less than the astounding 70% response rate seen in the combined treatment group. Those patients receiving nefazodone (either alone or in combination) responded to treatment significantly earlier than the cognitive-behavioral analysis system of psychotherapy only group. Moreover, combination treatment resulted in relatively greater improvements in psychosocial functioning (). An ongoing study is currently investigating the efficacy of adjunctive CBASP (compared with a supportive psychotherapy) in the treatment of patients with chronic depression who have not responded fully to antidepressant medication.