Gabor I. Keitner, MD

Despite the clinician's goal of treating the depressed patient to the point of remission, this state is generally achieved in only 15% to 30% of patients.

Another 10% to 30% of patients respond poorly to antidepressant treatment, while 30% to 40% have a remitting and relapsing course.

Patients without a major depressive disorder are likely to be treated successfully by primary care physicians and/or other mental health professionals, which leaves psychiatrists to treat patients who have forms of depression that are less responsive to treatment.

Initially, patients may have high expectations of treatment outcome, only to discover that many forms of depression are not readily responsive to even adequate dosages of an antidepressant. Such patients have been described as having difficult-to-treat depression.

Other patients with treatment-resistant forms of depression are defined as having depressions that do not respond to various numbers of treatment trials.

As psychiatrists, how do we help patients who continue to experience significant depressive symptoms, despite the use of evidence-based first-line treatment? Options that are currently available for the treatment of depressive disorders include monotherapy with an antidepressant medication; psychosocial treatment (individual, family, or group therapy); combined pharmacotherapy and psychosocial treatment; substitution of one antidepressant for another; augmentation of an antidepressant with other agents such as lithium, thyroid hormone, or atypical antipsychotic agents; a combination of antidepressants; electroconvulsive therapy; repetitive transcranial magnetic stimulation; and vagus nerve stimulation.

One of the most common options that clinicians recommend is augmentation. In a large-scale study (N = 244,859), 22% of patients with depression were found to have received an augmenting agent; a second antidepressant (11%) or a second-generation antipsychotic (7%) were the most common agents added to treatment.

Most literature on treatment-resistant or difficult-to-treat depression presents findings from clinical trials of various agents that typically have a small number of patients, are open-label studies, and lack control subjects. DeBattista

 noted, "The most common augmentation strategies in depression are those with the least controlled evidence."

Mental health professionals seem as ready as patients to seek easy solutions to difficult problems. Although a variety of alternative pharmacological treatment trials have yielded benefits for some patients, the STAR*D studies have highlighted the limitations of such sequential trials. Sequential and augmentation trials have yielded 15% to 30% remission rates.

Given this evidence, it is important for patients to have realistic expectations about the nature of their depressive illness and for clinicians to help them find ways to cope with depression, even while they continue to test responsiveness to new treatments. Excessively focusing on symptom resolution may paradoxically worsen a patient's psychosocial functioning and quality of life. Disease management approaches that focus on learning how to deal with one's illness in the face of symptom persistence have been used successfully with a number of medical conditions, including chronic fatigue syndrome, diabetes, arthritis, chronic pain, and asthma.

 Evidence-based treatment can be best pursued within the context of a broadly based model for coping with chronic illness.

What evidence exists for the efficacy of atypical antipsychotic augmentation? When is atypical antipsychotic augmentation appropriate, and which agents should be used and for how long? Possible answers to these questions are addressed below.

 added 0.5 to 1 mg/d of risperidone to the treatment regimens of 8 patients with depression who had "incomplete" responses to 16 weeks of treatment with fluoxetine or paroxetine. In this open-label trial, all of the patients' depressive symptoms remitted in less than 1 week.

In a more substantial 8-week, double-blind trial, Shelton and colleagues

 randomly assigned 28 patients with nonpsychotic treatment-resistant depression to olanzapine plus placebo (n = 8), fluoxetine plus placebo (n = 10), or olanzapine plus fluoxetine (n = 10). The symptoms of patients taking a combination of olanzapine and fluoxetine improved significantly more than the symptoms of those receiving either monotherapy.

In the 2 studies cited above, patients had poor responses to treatment with antidepressants before atypical antipsychotic augmentation was initiated. Hirose and Ashby

 conducted an open- label study of 36 patients with depression who were administered a combination of fluvoxamine and risperidone as first-line treatment for 6 weeks. Of the 30 patients who completed the study, 93% had a positive response to the combined treatment (as signified by the percentage of reductions in the Hamilton rating scale for depression).	

In another open-label study of 20 patients with depression who failed to respond to an adequate trial of an SSRI, Papakostas and colleagues

 augmented antidepressant treatment with ziprasidone. Thirteen patients completed the study (suggesting a high discontinuation rate). At completion, 25% of the patients remitted and 50% responded to the augmentation.

In a retrospective chart review, olanzapine, risperidone, quetiapine, and ziprasidone were given in a fee-for- service setting as augmenting agents to patients with treatment-resistant depression (N = 49).

 found an overall response rate of 65%, based on clinical global impression scale ratings. There was no difference in response rates between the different atypical agents.

The question of whether patients' responses to atypical antipsychotic augmentation are greater in those who have been pretreated with antidepressants than in those in whom antidepressants and atypical antipsychotics are started together continues to be a focus of investigation. Twenty patients with major depression were treated with antidepressants for 2 weeks and showed minimal or no improvement. The patients were then randomly assigned to augmentation with placebo or olanzapine for an additional 4 weeks.	 

Improvement rates between the 2 groups (45% and 43%, respectively) were no different, although of the 12 primary responders, 8 were in the olanzapine group and 4 were in the placebo augmentation groups. Four patients did not improve with placebo augmentation and showed a "distinct and rapid" effect with subsequent olanzapine augmentation.

 This study suggests-as may be the case with lithium augmentation-that pretreatment with an antidepressant may be needed in order for the patient to benefit from augmentation with an atypical antipsychotic.

Another small open-label study (N = 12) reported on the effects of aripiprazole augmentation of SSRIs for patients with treatment-resistant depressive disorders.

 In this 8-week trial, 9 patients completed the study; 5 were classified as "responders." For those who did respond, the improvement was reported as "robust and rapid" by the end of the first week of treatment.

Similarly, in a small open-label study, 15 depressed patients responded poorly to 8 weeks of antidepressant therapy.

 In these patients, treatment was augmented for another 4 weeks with aripiprazole. Remission rates were 40% by the first week and 60% by the second week of treatment. Response rates were faster and higher in patients receiving 10 mg/d of aripiprazole; however, more patients in that group discontinued treatment because of adverse effects than in the group who received 2.5 mg/d.

 conducted a large (N = 500), multisite (71 sites) study of patients with treatment-resistant depression. All patients were treated with nortriptyline for 7 weeks. Those patients who had less than 30% improvement were randomly assigned to 8 weeks of double-blind treatment with olanzapine plus fluoxetine (n = 146), olanzapine plus placebo (n = 144), or fluoxetine plus placebo (n = 142) or were kept on nortriptyline plus placebo (n = 68). In contrast to the small open-label studies described earlier, overall response rates were low; this was similar in all groups (20% to 30%) by week 8. Patients in the olanzapine-plus-fluoxetine group showed quicker response (by weeks 1 through 3) than did those in the monotherapy groups; however, all groups had comparable response rates by week 8.

Another large (N = 386), multicenter study assessed the usefulness of risperidone continuation-phase augmentation for treatment-resistant depression. In a 4- to 6-week open-label phase trial, 63% of patients improved with risperidone augmentation; 241 of these patients then entered a 24-week, double-blind, placebo-controlled continuation-phase trial.

 The mean number of days to relapse was 102 in the risperidone augmentation group and 85 in the placebo augmentation group, which was a nonsignificant difference.

 
Several additional studies have been presented at national meetings but not yet published. Dunner and colleagues

randomized patients with treatment- resistant depression to an 8-week trial of sertraline monotherapy (n = 20) or sertraline plus ziprasidone (n = 40). Patients with a history of non-SSRI treatment resistance (but not those who were poorly responsive to SSRIs) showed significantly greater improvement with combination treatment than with monotherapy.

 presented the results of a large (N = 97) randomized, double-blind, placebo-controlled study of risperidone augmentation for patients with difficult-to-treat depression. Although both study groups improved significantly over a 4-week trial, patients receiving risperidone augmentation had significantly greater odds for remitting (odds ratio, 3.33) and responded faster than those augmented with placebo. The augmented risperidone group also reported having significantly better quality of life and more satisfaction with their medication.

Patients with depression (N = 605) who were not responsive to SSRI treatment were enrolled in 2 parallel 8-week, double-blind studies comparing a combination of olanzapine plus fluoxetine, olanzapine alone, and fluoxetine alone.

 Response rates were 40%, 30%, and 26%, respectively. Pooled results from the 2 studies demonstrated significantly greater symptomatic improvement in the combination group. Patients taking olanzapine had greater weight gain and an increase in cholesterol level.

Treatment was augmented with quetiapine in an 8-week, double-blind, placebo-controlled trial of patients with treatment-resistant depression.

 Significantly more patients who received treatment with the quetiapine augmentation responded to treatment (67%) or achieved remission (43%) than did those whose treatment was augmented with placebo (27% and 15%, respectively). A smaller (N = 15) randomized, double-blind, placebo-controlled study with quetiapine augmentation also found significantly greater improvement in the quetiapine group than in the placebo-augmented group.

In the only study comparing the efficacy and tolerability of atypical antipsychotics, Ravindran and associates

 conducted a 6-week randomized, double-blind study of low and high doses of risperidone or olanzapine in 43 patients who had difficult-to-treat depression. Both low-dose groups (risperidone 0.5 to 1 mg/d and olanzapine 2.5 to 5 mg/d) did better than the high-dose groups (risperidone 2 to 3 mg/d and olanzapine 10 to 15 mg/d) but were comparable to each other. Interestingly, there was no reported difference in adverse effects between the low- and high-dose groups, while patients in the olanzapine group reported more adverse effects than did those in the risperidone groups.

 
What can we conclude from these studies about when and how to use atypical antipsychotics for patients with depression? Overall, it appears that some patients respond well to augmentation with atypical antipsychotics. To date, no study has been able to identify predictors of which patients are more likely to benefit from such augmentation. One study has suggested that patients whose symptoms failed to improve on non- SSRIs are likely to have better responses than those whose symptoms failed to improve on SSRIs,

 but most studies have noted symptom improvement in SSRI nonresponders as well.

The most clinically useful and reasonably consistent finding is that treatment augmentation with an atypical antipsychotic is associated with a faster response than continuing the primary antidepressant alone. A majority of the studies suggest that a significant ben-efit to augmentation is evident with- in 1 to 2 weeks after initiating the treatment.


The data suggest that atypical augmentation may be most useful when a rapid response is desirable. Such situations may arise when patients become particularly discouraged by lack of response, when safety considerations are paramount, and when psychosocial functioning is excessively compromised. The literature also suggests that pretreatment with antidepressants may lead to a better outcome than starting combination therapy from the outset.

 However, this may not be the case for all patients.

Which antipsychotic should psychiatrists prescribe? Two studies comparing one antipsychotic to another as an augmentative agent in patients with depression did not find any differences in effectiveness between the two.

 Given the comparable efficacies, the choice of antipsychotic should be made according to the agent's adverse-effect profile, patient preference and his or her past history with a particular drug, and cost. In general, the studies cited have found the atypicals to be well tolerated in patients with poorly responsive depressions. The most problematic adverse effect reported was weight gain with olanzapine, ranging from 3 to 6 kg over a 4- to 8-week treatment period. Examples of potential antipsychotics and effective dosages are provided in the 

 
Only one study to date has looked at the effectiveness of a continuation of treatment with atypical antipsychotic augmentation over a 24-week period.

 The study did not find significant benefits for delaying relapse with risperidone augmentation. Most of the studies have ranged from 4 to 6 weeks and have reported measurable benefits within 1 to 2 weeks. Based on these findings, it seems reasonable to use atypical antipsychotics for a 2- to 4-week treatment trial. Past this point, the financial cost and side- effect burden may not be justifiable. To date, augmentation with atypical antipsychotics for short periods in patients who relapse has not been studied.


Atypical augmentation of antidepressants for patients with difficult-to-treat and/or treatment-resistant forms of depression appears to be a reasonable treatment option, particularly when a faster response is desirable. Most research evidence points to the use of low dosages of an antipsychotic agent for a 2- to 4-week trial period. As with antidepressants, the choice of the antipsychotic agent should depend on the patient's history of previous response to medication, the adverse-effect profile, patient preference, and additional cost.	

It is important to highlight the reality that even atypical augmentation leads to a 15% to 40% remission rate, leaving a significant number of patients with continuing and bothersome depressive symptoms. Pharmacological treatment continues to have its limitations. In addition to pharmacological therapy, patients need to learn to cope with their illness in a way that improves their social and vocational functioning, as well as their quality of life, despite persistent symptoms.

 Keitner GI, Ryan CE, Solomon DA. Realistic expectations and a disease management model for depressed patients with persistent symptoms. 

Rush AJ, Thase ME, Dube S. Research issues in study of difficult-to-treat depression. 

Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. 

Valenstein M, McCarthy JF, Austin KL, et al. What happened to lithium? Antidepressant augmentation in clinical settings. 

 DeBattista C. Augmentation and combination strategies for depression. 

 Trivedi MH, Rush AJ, Wisniewski SB, et al. Evaluation of outcome with citalopram for depression using measurements-based care in STAR*D: implications for clinical practice. 

 Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. 

Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. 

 Shelton R, Tollefson GB, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. 

Hirose S, Ashby CR Jr. An open pilot study combining risperidone and a selective serotonin reuptake inhibitor as initial antidepressant therapy. 

 Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. 

Barbee JG, Conrad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. 

Parker G, Brotchie H, Parker K. Is combination olanzapine and antidepressant medication associated with a more rapid response trajectory than antidepressant alone? 

Papakostas GI, Petersen TJ, Kinrys G, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depression disorder. 

Simon J, Nemeroff CB. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. 

 Shelton R, Addington S, Thakker V. Risperidone vs bupropion combined with SSRIs in treatment resistant unipolar major depression. Presented at: 44th Annual Meeting of the American College of Neuropsychopharmacology; 2005; Waikoloa, Hawaii.


Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation. 

 Dunner DA, Amsterdam JD, Shelton RC, et al. Adjunctive ziprasidone in treatment-resistant depression: a pilot study. Poster presented at: American Psychiatric Association Annual Meeting; May 17-22, 2003; San Francisco.


Keitner GI, Garlow S, Ryan CE, et al. Risperidone augmentation for patients with difficult-to-treat major depression. Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.


Thase ME, Corya SA, Olawale O, et al. Olanzapine/ fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. Presented at: American Psychiatric Association Annual Meeting; May 23, 2006; Toronto.


 Mattingly G, Ilivicky H, Canale J, Anderson R. Quetiapine augmentation for treatment-resistant depression. Presented at: American Psychiatric Association Annual Meeting; May 22, 2006; Toronto.


Khullar A, Chokka P, Fullerton D, et al. Quetiapine as treatment of non-psychotic unipolar depression with residual symptoms: double-blind, randomized, placebo controlled study. Presented at: American Psychiatric Association Annual Meeting; May 22, 2006; Toronto.


Ravindran L, Lam R, Chaput Y, et al. A. Impact of low vs high dose olanzapine or risperidone on outcome and side effects in non-psychotic treatment-resistant depression. Presented at: the New Clinical Drug Evaluation Unit; June 12-15, 2006; Boca Raton, Fla.

Articles

Despite the clinician's goal of treating the depressed patient to the point of remission, this state is generally achieved in only 15% to 30% of patients. Another 10% to 30% of patients respond poorly to antidepressant treatment, while 30% to 40% have a remitting and relapsing course.1 Patients without a major depressive disorder are likely to be treated successfully by primary care physicians and/or other mental health professionals, which leaves psychiatrists to treat patients who have forms of depression that are less responsive to treatment.

Atypical Antipsychotic Augmentation in the Treatment of Depression

The current most commonly used model for the understanding and treatment of depression is a biomedical one that emphasizes symptom resolution. The mainstay of contemporary psychiatric treatment is pharmacotherapy, and of contemporary psychological treatment, cognitive-behavioral therapy. Both pharmacotherapy and psychotherapy can be effective treatments for depression, but, in spite of their efficacy, a significant minority of patients with depression do not respond well and continue to experience problematic residual symptoms (Hirschfeld et al., 2002; Thase et al., 2001). Double-blind, controlled trials for outpatients with mild-to-moderate depression have reported remission rates of 46% for medications, 46% for psychotherapy and 24% for control conditions (Casacalenda et al., 2002), leaving up to 50% of patients with some degree of persistent symptoms.

A biopsychosocial model that draws attention to the social environment in which the depressive episode evolves may be a more helpful way of approaching the management of major depression. There are many reasons to pay attention to the social context of depression in addition to the generally insufficient effectiveness of biological and/or psychological treatments by themselves.

More than half of patients with major depression experience distressing and problematic family functioning (Coyne et al., 2002; Keitner et al., 1995). Families of patients with chronic forms of depression experience similar levels of family dysfunction as patients with acute depression (Keitner et al., 2003). Changes in the social environment and the level of social support have a clear association with depression (Paykel and Cooper, 1992). Marital difficulties, especially arguments, are the most frequently reported events prior to the onset of depression (Paykel et al., 1969). Lack of support and inability to confide in a spouse can in itself increase the risk for depression (Parry and Shapiro, 1986). Even within a maritally distressed group of subjects, couples comprised of one partner with depression tended to have the lowest level of marital cohesion (Beach et al., 1988). During interactions between people with depression and their spouses, both parties experience their partners as more negative, hostile, mistrusting and detached than controls (Kahn et al., 1985). Patients who are depressed exert aversive control over their spouses' behaviors (Nelson and Beach, 1990; Schmaling and Jacobson, 1990). Conflicted social interactions are associated with depression, and depression may lead to family stresses and burdens.

Family Functioning and the Course of Depression

Interpersonal stress is not only a precursor to depression, but marital/family dysfunction during the acute phase of a depressive episode is common and often leads to difficulties in multiple family domains. Communication, problem solving and role functioning are particular areas of family life that are disrupted (Keitner et al., 1995). There is significant family burden with financial worries, a sense of social isolation, loss of status, chronic tension and fears of recurrence (Fadden et al., 1987; van Wijngaarden et al., 2004). Problematic family functioning during the acute episode is not only distressing for the family but also has an impact on the course of the depression. Patients who are depressed and have marital distress show slower responsiveness to treatment (Rounsaville et al., 1979). Poor family functioning has a negative impact on both short- and long-term recovery from depression (Keitner et al., 1997, 1995). However, the depression may last for a shorter period of time in those families who are able to improve their family functioning (Keitner et al., 1987).

Often, there is improvement in family functioning as the depression remits. Nonetheless, families with a member who is depressed still report worse family functioning at remission of the depression than do control families (Keitner et al., 1995). Family functioning is also related to the likelihood of maintaining wellness or relapsing. High levels of criticism toward the patient are associated with a greater likelihood of relapse (Vaughn and Leff, 1976). In addition to perceived criticism, marital distress is also strongly related to the tendency to relapse.

We do not know the causal sequence between depression and problematic family functioning. It is likely that there are mutually reinforcing patterns of interactions between a patient's vulnerability to depression and the family's ways of coping with the illness (Figure) 

(Due to copyright concerns, this Figure cannot be reproduced online. Please see p40 of the print edition--Ed.).

 A patient's vulnerability to depression may include genetic predisposition, early life experiences, personality variables, current life events and/or persistent family conflicts. Regardless of the etiology of the episode, the patient's family and/or significant others have to respond to and deal with the depression. If the family and social support system respond effectively, the depressive illness may be relatively brief and may remit more readily. If the family is unable to respond adequately to the patient's illness because of the family's own difficulties, then the illness may be more prolonged, with the patient less likely to recover and more likely to relapse into subsequent episodes. Pharmacotherapy and psychotherapy may be helpful in dealing with genetic vulnerability, early life experiences and current life stresses, while family intervention can reinforce the family's competence in responding to the illness (Keitner and Miller, 1990).

A number of self-reported and interview-based family assessment instruments have been developed and described. Many of these family assessment tools were designed for research purposes. They are standardized and provide numerical summaries of various aspects of family functioning that can then be more systematically analyzed. Some may be adapted for clinical use.

Self-report scales, which are cost effective to administer, provide information on how family members evaluate their own functioning. The Dyadic Adjustment Scale (DAD), for example, is a 32-item measure of marital quality and marital adjustment. Four subscales measure marital satisfaction, cohesion, consensus and affective expression. The Family Environment Scale (FES) is a 90-item true/false measure assessing how family members perceive their family environment along the three domains of relationships, personal growth and system maintenance. The Family Questionnaire (FQ) is a brief measure of perceived criticism and overinvolvment. The Family Assessment Device (FAD) is a 60-item scale that assesses the six dimensions of the McMaster Model of Family Functioning (communications, problem solving, affective responsiveness, affective involvement, roles and behavior control) in addition to having a general functioning subscale. The FAD has high levels of internal consistency, acceptable levels of test-retest reliability, low correlations with social desirability and good discriminative validity.

Interview-based family assessment instruments are more labor intensive and require rater training. They provide an outside perspective on how a family functions compared to other families. The Camberwell Family Interview requires extensive training and is used to assess levels of criticism and overinvolvment. The Five Minute Speech Sample is a brief method of assessing expressed emotion in relatives of patients with psychiatric disorders. The McMaster Clinical Rating Scale (MCRS) is based on a family interview conducted by a rater, and it assesses the same six dimensions of family functioning as the FAD in addition to assessing the overall health/pathology of a family. The MCRS has acceptable interrater and test-retest reliability as well as concurrent and discriminative validity. The family assessment interview can take from 45 to 90 minutes depending on the experience of the rater.

Marital and family therapies share very similar therapeutic principles and can be considered the same for the purpose of this article. There are many schools of marital/family therapy (e.g., strategic marital therapy, behavioral marital therapy, cognitive marital therapy, the problem-centered systems therapy of the family, inpatient family, inpatient family intervention). None have been shown superior to the others. Studies of marital/family therapy for depression are faced with the same limitations that other treatment studies face, making comparisons between different types of therapies very difficult. These limitations include differences in patient group studied (diagnosis, severity, chronicity, gender, level of marital distress) and designs used (with or without controls, different comparison groups, variable number of therapy sessions, length of follow-up evaluations).

In spite of these limitations, a number of studies testing a variety of marital therapy approaches to patients with depression have been undertaken and reviewed (Beach, 2003; Kung, 2000). Behavioral marital therapy appears to be comparable to individual therapy in improving depressive symptoms and better than individual therapy in improving marital functioning. Family therapy may be particularly helpful when family distress is present as a component of the depression. Wives who are depressed and are in maritally distressed relationships were randomly assigned to behavioral marital therapy (BMT), cognitive therapy (CT) or a wait-list control condition. In reducing depressive symptoms, BMT and CT were equally effective (and better than the wait-list condition), but BMT was significantly better at reducing the wife's marital distress than was CT (Beach and O'Leary, 1992).

In a randomized, controlled trial, 77 couples, of which one partner had mild-to-moderate depression, were assigned to either antidepressant medication or couples therapy (Leff et al., 2000). Both groups were treated for one year, at which point treatment was discontinued and participants were followed for an additional year. Couples therapy was much more acceptable to the participants in this trial than medication, with a dropout rate of 57% from the drug treatment and 15% from the couples therapy. Both treatment groups improved during the first year, although patients who received couples therapy showed a greater improvement on the Beck Depression Inventory (BDI) than did the couples on medication. The advantage for couples therapy was maintained over the second year after treatments had been discontinued. The Hamilton Rating Scale for Depression (HAM-D) did not differentiate between the two groups. In this study, couples therapy was found to be at least as efficacious as antidepressant drugs for both the treatment and the prevention of relapse of depression.

Another study randomly assigned 121 patients with more severe depression, recruited from the inpatient or partial hospital units of a hospital, to pharmacotherapy alone; combined pharmacotherapy and cognitive therapy; combined pharmacotherapy and family therapy; or combined pharmacotherapy, cognitive therapy and family therapy (Miller et al., in press). The family therapy provided was the Problem Centered Systems Therapy of the Family (PCSFT), which is based on the McMaster Model of Family Functioning. The PCSFT is a structured, short-term family systems intervention that is based on the following principles: an emphasis on "macro" stages of treatment (assessment, contracting, treatment, closure) as opposed to the idiosyncratic "micro" moves of each therapist; emphasis on assessment; inclusion of the entire family; active collaboration between therapist and family members; open, direct communication with the family; focus on the family's responsibility for change; emphasis on current problems; focus on behavioral change; time-limited nature. Compared to no family therapy treatment, the addition of family treatment to pharmacotherapy and/or cognitive therapy led to greater proportions of patients who improved and to significant reductions in interviewer-rated depression and suicide ideation.

Family therapy can be provided in a multifamily group format (Keitner et al., 2002). This format combines family therapy and psychoeducational group therapy and is complementary to pharmacotherapy. In addition to obtaining information and dealing with their own issues, families in a group format not only learn from each other, but also experience an additional important source of social support from others who understand their concerns. The multifamily group format also has the potential to be more cost effective.

Some general principles may be useful to consider when meeting with families of patients with depression (

). Meet with all available/interested family members. One never knows which family member is most involved in the care of the patient and most in need and open to outside support. It is important to be supportive and nonjudgmental. Many families have had the experience of being blamed for their loved one's depression, thus making them defensive and less likely to join in a collaborative effort to deal with ongoing problems. A thorough assessment of the family is important. This is best achieved by listening to all perspectives and by exploring a broad range of family functions, including how they communicate, solve problems, allocate roles and responsibilities, engage emotionally with each other, and set rules and expectations (Ryan et al., 2005). It is helpful to try to identify a major problem/conflict area as opposed to trying to deal with every issue that the family may bring up.

Sharing information about the illness, its treatment, and the early signs and symptoms of relapse, as well as the impact of residual symptoms, can be very helpful for families. A discussion of illness characteristics and available treatments should lead to an emphasis on compliance. The more family members know about the depression and the more they feel like collaborative partners in the management of the illness, the more likely they are to support ongoing treatment efforts with their loved one.

One of the most difficult tasks that a family has is to find a balance between not pushing the member with depression beyond their capability versus passively accepting the negative outlook and self-doubt of the family member who is depressed. A therapist can be very helpful in guiding the family to recognize the realistic limitations that a person with depression may experience in terms of being able to concentrate or having sufficient energy or motivation to carry out more complicated tasks, while at the same time helping to determine the kinds of positive steps that the person with depression can take in terms of reconceptualizing their illness and making small changes that can help to minimize feelings of hopelessness and helplessness.

Not all families of patients with depression need family therapy, but all can benefit from the opportunity of meeting together with a mental health professional (

). At the minimum, useful information can be exchanged, potential difficulties identified, and plans can be made for addressing agreed-upon problems. Families can be encouraged to become knowledgeable about the illness, to learn about local mental health laws, to recognize prodromal and residual symptoms, to establish an ongoing collaborative relationship with health care providers, to support treatment compliance, to reach out for help early in the onset of an episode, and to become familiar with local support groups.

A comprehensive, biopsychosocial approach, which combines a judicious use of pharmacotherapy, psychotherapy and family intervention, may not only provide a good likelihood of positive response to acute and maintenance treatment of depression, but can also help patients and families cope with those depressive symptoms that may persist in spite of optimal treatment.

Dr. Keitner is professor of psychiatry at Brown University and director of adult psychiatry and the Mood Disorders Program at Rhode Island Hospital.

Beach S (2003), Affective disorders. J Marital Fam Ther 29(2):247-261.

Beach SRH, Nelson GM, O'Leary K (1988), Cognitive and marital factors in depression. Journal of Psychopathology and Behavioral Assessment 10:93-105.

Beach SRH, O'Leary KD (1992), Treating depression in the context of marital discord: outcome and predictors of response for marital therapy vs. cognitive therapy. Behavior Therapy 23:507-528.

Casacalenda N, Perry JC, Looper K (2002), Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry 159(8):1354-1360 [see comments].

Coyne JC, Thompson R, Palmer SC (2002), Marital quality, coping with conflict, marital complaints, and affection in couples with a depressed wife. J Fam Psychol 16(1):26-37.

Fadden G, Bebbington P, Kuipers L (1987), Caring and its burdens. A study of the spouses of depressed patients. Br J Psychiatry 151:660-667.

Hirschfeld RM, Montgomery SA, Aguglia E et al. (2002), Partial response and nonresponse to antidepressant therapy: current approaches and treatment options. J Clin Psychiatry 63(9):826-837.

Kahn J, Coyne JC, Margolin G (1985), Depression and marital conflict: the social construction of despair. Journal of Social and Personal Relationships 2:447-462.

Keitner GI, Archambault R, Ryan CE, Miller IW (2003), Family therapy and chronic depression. J Clin Psychol 59(8):873-884.

Keitner GI, Drury LM, Ryan CE et al. (2002), Multifamily group treatment for major depressive disorder. In: Multifamily Group Treatment for Severe Psychiatric Disorders, McFarlane WR, ed. New York: Guilford Publications, pp244-267.

Keitner GI, Miller IW (1990), Family functioning and major depression: an overview. Am J Psychiatry 147(9):1128-1137.

Keitner GI, Miller IW, Epstein NB et al. (1987), Family functioning and the course of major depression. Compr Psychiatry 28(1):54-64.

Keitner GI, Ryan CE, Miller IW et al. (1995), Role of the family in recovery and major depression. Am J Psychiatry 152(7):1002-1008 [see comment].

Keitner GI, Ryan CE, Miller IW, Zlotnick C (1997), Psychosocial factors and the long-term course of major depression. J Affect Disord 44(1):57-67.

Kung WW (2000), The intertwined relationship between depression and marital distress: elements of marital therapy conductive to effective treatment outcome. J Marital Fam Ther 26(1):51-63.

Leff J, Vearnals S, Brewin CR et al. (2000), The London Depression Intervention Trial. Randomised controlled trial of antidepressants v. couple therapy in the treatment and maintenance of people with depression living with a partner: clinical outcome and costs. [Published erratum Br J Psychiatry 177:284.] Br J Psychiatry 177:95-100 [see comment].

Miller IW, Keitner GI, Ryan CE et al. (in press), Treatment matching in the post-hospital care of depressed patients. Am J Psychiatry.

Nelson GM, Beach SRH (1990), Sequential interaction in depression: effects of depressive behavior on spousal aggression. Behavior Therapy 21:167-182.

Parry G, Shapiro D (1986), Social support and life events in working class women. Stress buffering or independent effects? [Published erratum Arch Gen Psychiatry 1987;44(2):168.] Arch Gen Psychiatry 43(4):315-323.

Paykel ES, Cooper Z (1992), Life events and social stress. In: Handbook of Affective Disorders, 2nd ed., Paykel ES, ed. New York: Guilford Publications, pp149-170.

Paykel ES, Myers JK, Dienelt MN et al. (1969), Life events and depression. A controlled study. Arch Gen Psychiatry 21(6):753-760.

Rounsaville BJ, Weissman MM, Prusoff BA, Herceg-Baron RL (1979), Marital disputes and treatment outcome in depressed women. Compr Psychiatry 20(5):483-490.

Ryan CE, Bishop DS, Keitner GI, Epstein NB (2005), Evaluating and Treating Families: The McMaster Approach. New York: Taylor and Francis.

Schmaling KB, Jacobson NS (1990), Marital interaction and depression. [Published erratum J Abnorm Psychol 99(4):439.] J Abnorm Psychol 99(3):229-236.

Thase ME, Entsuah AR, Rudolph RL (2001), Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 178:234-241 [see comments].

van Wijngaarden B, Schene AH, Koeter MW (2004), Family caregiving in depression: impact on caregivers' daily life, distress, and help seeking. J Affect Disord 81(3):211-222.

Vaughn C, Leff J (1976), The measurement of expressed emotion in families of psychiatric patients. Br J Soc Clin Psychol 15(2):157-165.

When a family member is diagnosed with depression the whole family is affected. Additional family and marital stresses imposed on the patient with depression can add to the severity of depression and affect long-term remission rates. In order to ensure the best possible success in treatment, the therapist should integrate the family into the patient’s treatment.

Author | Gabor I. Keitner, MD

Articles

Atypical Antipsychotic Augmentation in the Treatment of Depression

Family Therapy in the Treatment of Depression