Mental disorders are increasingly understood to be chronic and recurrent conditions. Even when clinicians provide state-of-the-art psychotherapeutic or psychopharmacological treatment, a substantial proportion of patients do not respond, and many others are left with residual symptoms that cause significant distress and impairment (e.g., Judd, Schettlerx, et al., 2003; Kocsis, 2000; Yonkers, Bruce, Dyck, & Keller, 2003). In addition, relapse after successful treatment is all too common (Beshai, Dobson, Bockting & Quigley, 2011; Gitlin et al., 2001; Post et al., 2003; Yonkers, Bruce, Dyck, & Keller, 2003). Clinical researchers have investigated combining medication and psychotherapy as a means of improving response and preventing relapse. Combination treatments are thought to improve outcomes in two ways: by increasing the magnitude of response within individuals, or by increasing the odds that any given person will receive the “correct” treatment. In many cases, combined treatments have been found to provide incremental benefits in average response over medication or psychotherapy alone (e.g., Cuijpers, van Straten, Warmerdam, & Andersson, 2009; Furukawa, Watanabe & Churchill, 2006). On the basis of this evidence, combined treatments are recommended in the American Psychiatric Association (APA) Practice Guidelines, the National Institute of Health and Clinical Excellence (NICE) Clinical Guidelines, and other treatment guidelines, particularly for cases in which symptoms are either unresponsive or partially responsive to monotherapy.
Despite these recommendations and the widespread use of combination therapy (Olfson & Marcus, 2010), little is known about the longer-term risk/benefit and cost/benefit ratios of combination treatments relative to monotherapy. Findings supporting the efficacy of the combination treatment approach are often derived from short-term treatment studies, which provide little information about long-term risk and benefits. When longer-term analyses are conducted, the results are often more equivocal. For example, in the treatment of panic disorder and social anxiety disorder, investigators have found that combined medication and psychotherapy is less effective than psychotherapy alone in preventing relapse (Otto, Bruce, & Deckersbach, 2005; Otto, McHugh, & Kantak, 2010). Issues related to long-term response deserve careful consideration because the costs of combined treatment can be high. Compared to monotherapy, combined treatments are more complex and time-consuming, and they expose individuals to an increased chance of negative effects. Currently, there is little controlled clinic data to guide clinicians as to which monotherapy or combined therapy is most likely to produce a lasting benefit in any specific individual (i.e., there is limited research on prescriptive factors). In the absence of any prescriptive evidence, we argue that treatment selection should be guided by the expected benefit in symptoms or functioning in comparison to other available treatments over the full course of the illness. A review of the evidence suggests that simultaneous initiation of combination treatment is often not indicated when long-term outcomes are considered. Instead, we recommend a strategic approach to combining psychotherapy and medications with the goal of maximizing benefit-to-cost ratios.
In this chapter we examine the empirical evidence for combining therapies, and discuss whether the evidence justifies the additional costs. We confine our review to treatments for adult outpatients with anxiety, depressive, bipolar and schizophrenia spectrum disorders. When available, findings are highlighted pertaining to the long-term efficacy of combination treatments. We also present arguments and evidence for a strategic application of combined therapy, and areas for future research.
Anxiety disorders present numerous treatment challenges, and therefore are a fitting place to begin. Both medications and psychotherapy (in particular, cognitive behavioral therapy, or CBT) are efficacious in the acute treatment of anxiety disorders (Kjernisted & Bleau, 2004; Norton & Price, 2007), but many individuals remain symptomatic (Pollack et al., 2008), and relapse is common (Thuile, Even, & Ruillon, 2009). Strikingly, at least three trials of medications combined with CBT have found that the combined approach is less effective than CBT alone over the longer term, leading authors to suggest that medication can interfere with exposure-based treatments (Foa, Franklin, & Moser, 2002; Otto et al., 2005). These findings call into question the widely held assumption that combined treatments are more effective than single treatments and that the only remaining questions concern the magnitude and mechanisms of the presumed advantage. On the other hand, studies have shown that nonanxiolytic medications such as D-cycloserine can augment exposure therapy by enhancing extinction learning (Hofmann, Smits, Asnaani, Gutner, & Otto, 2011), providing an example of a possible synergy between psychotherapy and medications. We begin by reviewing studies from each of the major anxiety disorders in which combination psychotherapy and medication have been initiated simultaneously. These include the studies showing evidence of treatment interference. This is followed by a discussion of possible drawbacks of this approach, and a description of alternatives such as nonsimultaneous combination strategies.
In panic disorder, both psychotherapeutic and pharmacological interventions have demonstrated short-term efficacy (Batelaan, van Balkom, & Stein, 2011; Hofmann & Smits, 2008). However, the literature provides only modest support for the value of combining them. A recent meta-analysis found that combined treatment for panic disorder was only 1.2 times more likely to produce a response than antidepressants alone (tricyclics or SSRIs) and only 1.2 times more likely to produce a response than psychotherapy alone (Furukawa et al., 2006). Longer-term outcomes were even less impressive; the effects of combined treatment were equal to those of psychotherapy alone after medications were discontinued. Similar short-term findings emerged from a meta-analysis of combined CBT and benzodiazepine treatments (Watanabe, Churchill, & Fukuwara, 2007). In this case, combined treatment was not superior to CBT on primary outcomes, although it showed additional benefit on some secondary measures. An analysis of follow-up data showed that CBT alone was superior both to medications and combination treatment over longer periods, providing some evidence that medications interfere with the enduring effects of CBT.
Evidence for treatment interference in panic disorder is derived from two separate trials. In the first of these, Marks et al. (1993) randomized 154 patients to 8 weeks of exposure (EXP) plus Alprazolam (ALP), EXP plus Placebo (PBO), Relaxation (RLX) plus ALP, and RLX plus PBO. At posttreatment, response rates were 71%, 71%, 51%, 25%, respectively. Groups receiving exposure demonstrated superior short-term response relative to those who received ALP or relaxation. However, at a 43-week medication-free follow-up, the sustained response rate in the combined treatment group fell to 36%, compared to 62% for the EX plus PBO, and 29% for the ALP alone group. EX plus PBO was superior to all other treatments, whereas combined treatment was no different from medication alone. In the second study, Barlow, Gorman, Shear, and Woods (2000) randomized 312 patients to CBT plus imipramine (IMP), CBT plus PBO, CBT, IMP, and PBO. After the 3-month acute phase and 6 months of continuation treatment, CBT plus IMP was superior to CBT and IMP alone (9-month response rates: CBT plus IMP: 57%, CBT plus PBO: 47%, CBT: 40%, IMP: 39%, PBO: 13%). However, at a 6-month medication-free follow-up, groups receiving CBT without IMP evidenced sustained response rates of 41% (CBT plus PBO) and 32% (CBT alone), each of which were numerically superior to the 25% rate in the combined treatment group. Among patients who entered the follow-up phase, both groups receiving CBT without imipramine had significantly better sustained response rates than the CBT plus IMP group, which experienced the highest relapse rate in the study. Thus, in panic disorder, combination treatments appear to be, at best, marginally superior to CBT alone in producing acute response (e.g., Van Apeldoorn et al., 2008), and at worst, associated with a higher probability of relapse in comparison to CBT monotherapy.
Clinical trials in social anxiety disorder offer a mixed picture for the efficacy of combined therapy. Some findings suggest that combined therapy is superior to monotherapy during short-term treatment. For example, in a study of 128 patients randomized to phenelzine (PHEN), cognitive-behavioral group therapy (CBGT), PHEN plus CBGT, and PBO, results showed that PHEN plus CBGT (response rate: 72%) and PHEN monotherapy (54%) were superior to placebo (33%), and CBGT (47%) after 12 weeks (Blanco et al., 2010). Results were similar after 24 weeks of treatment. Responders in the combined group evidenced larger average improvements than responders in each of the monotherapies, suggesting a within-individual additive effect of combined treatment (i.e., combined treatment responders received more benefit on average than monotherapy responders). As impressive as these findings are, a follow-up report is needed to determine the longer-term outcomes. This is particularly important because in a similar study an acute advantage for combined treatment relative to psychotherapy faded after treatment was discontinued. In that trial, Blomhoff et al. (2001) randomized 375 patients in primary care to 24 weeks of combined exposure (EX) plus sertraline (SERT) therapy, EX plus PBO, SERT monotherapy, or PBO. At end of the treatment period, response rates were 46%, 33%, 40%, and 24%, respectively. Active medication treatments were superior to placebo and EX plus PBO was not superior to PBO alone. However, at the end of a 28-weeks medication-free follow-up period, the EX plus PBO and PBO groups had continued to improve, whereas EX plus SERT and SERT monotherapy groups had experienced significant worsening on one symptom measure and indications of deterioration on others, suggesting that, similar to what is seen in panic disorder, medications might interfere with longer-term gains (Haug et al., 2003).
In contrast, three other clinical trials yielded no evidence of interference in social anxiety. However, these studies also failed to demonstrate short-term advantages of combined treatment relative to monotherapy. Davidson et al. (2004) found that fluoxetine (FLU) monotherapy, comprehensive CBT (CCBT), combined FLU plus CCBT, and CCBT plus PBO all yielded similar response rates after 14 weeks of treatment (51%, 52%, 54%, and 51%, respectively). Prasko et al. (2006) found CBT plus PBO and CBT plus moclobemide (MOC) to be superior to MOC alone after 6 months of treatment, and each of the CBT groups had lower rates of relapse after a 24-month treatment free follow-up (CBT + PBO: 48%, CBT + MOC: 64%, MOC: 79%). Finally, in one of only a few studies of combination treatment that did not use CBT, Knijnik et al. (2008) found that medication combined with psychodynamic group therapy did not result in greater symptom reduction than medication alone, but it did result in greater gains on a measure of clinical improvement. So, in social anxiety, there is mixed evidence for the efficacy of combined treatments versus monotherapy, and at least one example of treatment interference.
In the treatment of obsessive compulsive disorder, some studies suggest an advantage for combined treatments versus monotherapies, specifically in individuals with comorbid mood symptoms. In one of these, Cottraux et al. (1990) found no differences between fluvoxamine (FLV), exposure and response prevention (EXRP), and EXRP plus FLV after 24 weeks of treatment, and no differences in relapse-prevention during 48 weeks of follow-up. However, the combined treatment did produce a greater improvement in mood at 24 weeks. In another study, Hohagen et al. (1998) also found no differences in compulsions between those assigned to CBT plus FLV as compared to CBT plus PBO after 9 weeks of treatment, but combined therapy resulted in lower levels of obsessions and a higher response rate (88%) relative to monotherapy (60%). Combined treatment was also more efficacious for patients with substantial co-morbid depressive symptomatology.
In contrast, other studies have found no advantage of combined treatment (e.g., van Balkom et al., 1998). In one trial (Foa et al., 2005), patients were assigned to clomipramine (CMP), intensive EXRP, EXRP plus CMP, or placebo for 12 weeks (N = 122). At the end of acute treatment, EXRP plus CMP (response rate: 70%) and EXRP (62%) were each superior to CMP alone (42%) but not different from one another. After a 12-week treatment discontinuation phase, EXRP plus CLO and EXRP alone were each associated with fewer relapses than CLO alone (sustained response of 39%, 55%, and 17%, respectively), and no different from one another (Simpson et al., 2004). One important criticism of this study is that the period of intensive EXRP (15 2-hour sessions over 3 weeks) was completed before the effects of clomipramine could be realized, perhaps reducing the chance of finding a combined effect (Franklin & Simpson, 2005). Other evidence suggests that there is no difference between combined treatment and psychotherapy alone in preventing relapse and recurrence over a longer-term follow-up (Rufer et al., 2005). Therefore, in OCD, evidence for greater efficacy of combined treatments over the short term is mostly confined to individuals with comorbid depression symptoms. There is little if any evidence suggesting that there are long-term benefits of combined treatment, relative to CBT alone.
Psychotherapy (i.e., CBT) and pharmacotherapy are each efficacious treatments for PTSD (APA, 2004a; NICE, 2005). However, there have been few controlled trials testing their simultaneous combination. In a recent randomized trial, paroxetine, in combination with prolonged exposure (a type of CBT), was more efficacious than prolonged exposure alone after 10 weeks of treatment (Schneier et al., 2012). Although this trial is suggestive of an acute advantage for combined treatment, there is as of yet no follow-up report on the long-term stability of these gains.
In contrast, findings from a study by van Minnen, Arnzt, and Keijsers (2002) suggest that medications might interfere with the beneficial effect of psychotherapy. In this trial of 63 outpatients, self-reported use of concurrent benzodiazepines was associated with poorer outcomes in exposure therapy. Further evidence suggests that a course of CBT is more effective at preventing relapse than is a course of medications of equal duration (Frommberger et al., 2004), and that medication maintenance is necessary for prevention of relapse and recurrence (Davidson et al., 2001). Without further comparisons between monotherapy and combined therapy, however, it remains unclear whether adding medications to CBT either enhances or inhibits the relapse prevention effect of CBT for PTSD.
There is little evidence that combined therapy is more effective than monotherapy in the treatment of GAD. In the largest controlled study, Power et al. (1990) randomized 113 individuals to CBT plus diazepam (DZ), CBT plus PBO, CBT monotherapy, DZ, or PBO. After 9 weeks of therapy, combined treatment was superior to DZ alone but not to CBT plus PBO or CBT alone at reducing anxiety symptoms (response rates: 91% for CBT plus DZ, 83% for CBT plus PBO, 86% for CBT, 68% for DZ, and 37% for PBO). At a 6-month naturalistic follow-up, response rates in all conditions that contained CBT were better than those for DZ-alone conditions. There was no difference observed between the condition that combined CBT with DZ, relative to the CBT conditions that did not include medication, suggesting that DZ neither enhanced nor interfered with CBT's relapse prevention effect (Foa, Franklin & Moser, 2002). In another study, using a naturalistic design (N = 87), Ferrero et al. (2007) found no differences between brief dynamic therapy (BDT), BDT plus medication (i.e., antidepressants plus benzodiazepines), or medication alone after 3, 6, or 12 months of therapy. Overall, the lack of randomized comparisons between combined and monotherapies limits the conclusions that can be made about the relative effectiveness of these approaches in the treatment of GAD.
The findings summarized above suggest that the benefits obtained during combination treatment, which are of modest clinical significance in most trials, fade relative to psychotherapy after treatment is completed (Hofmann, Sawyer, Korte, & Smits, 2009). Even more concerning is the evidence that, in some cases, combined treatment is inferior to CBT alone at preventing relapse (Barlow et al., 2000; Haug et al., 2003; Marks et al., 1993). In these instances, medications appear to block some of the prophylactic benefits of exposure-based CBT.
There are several plausible explanations of treatment interference effects in anxiety disorders, each focusing on how medications might disrupt the presumed therapeutic mechanisms of exposure therapy. One account, provided by Foa, Franklin, and Moser (2002), suggests that the anxiolytic effects of medication suppress the activation of fear-related cognitions during exposure, preventing the encoding of corrective information. Others have suggested that corrective information is encoded, but that this learning does not generalize across the contextual shift that accompanies medication discontinuation, leading to the return of anxiety after treatment (Otto et al., 2005). In a review of evidence from both animal and human neurobiological studies, Otto, McHugh, and Kantak (2010) propose that medications inhibit extinction learning by suppressing acute cortisol secretion. The secretion of cortisol, which normally facilitates the consolidation of memories (Lupien et al., 2005), is inhibited by benzodiazepines and antidepressants (e.g., Pomara, Willoughby, Sidtis, Cooper, & Greenblatt, 2005; Schüle, Sighart, Hennig, & Laakmann, 2006), thus potentially interfering with the consolidation of fear-incongruent learning during exposures.
In each of the proposed mechanisms, the presumed therapeutic effect of the medication disrupts the processes that mediate the effect of exposure. Thus it may be that the beneficial effects of one treatment undermine the beneficial effects of another superior treatment. Notably, interference findings have thus far been observed only when the two treatments are initiated simultaneously, and the interference effects are asymmetric in that there is no evidence that psychotherapy interferes with or inhibits the positive effects of medications.
A reexamination of the rationale for simultaneously combining medication and psychotherapy is required in light of repeated findings that these strategies are not superior to psychotherapy in the treatment of anxiety disorders. Because combination treatments yield little advantage in sustained benefit relative to psychotherapy alone, it is likely that many individuals receive unnecessary treatment with medications. Duration of this unneeded treatment can be lengthy. Evidence suggests that medication use can continue for years after the intial response to combined therapy without providing a benefit in relapse prevention relative to CBT alone (Van Oppen, van Balkom, de Haan, & van Dyck, 2005). Other negative effects of combined treatment relative to psychotherapy have been noted, including increased cost, unwanted side effects, and an increased chance of dropout (Gould, Otto, & Pollack, 1995). Prolonged benzodiazepine use can also result in tolerance (Salzman, 1998; Woods, Katz, & Winger, 1992), and there is emerging evidence that prolonged antidepressant exposure might produce similar problems (Fava & Offidani, 2011; see the depression section). Moreover, individuals who relapse after discontinuation of medication therapy might need to restart and remain on medications indefinitely to prevent further relapses (Thuile et al., 2009).
In addition to the increased costs and risks, the opportunity to learn whether patients would have responded to a monotherapy is missed when both treatments are initiated simultaneously. In other words, when a patient is treated successfully with a combination therapy, it cannot be known if one of the monotherapies would have been sufficient, and if so, which one. On the other hand, if a monotherapy is effective, the patient and the provider acquire information about treatment response that can inform the longer-term management of the illness. Identifying effective and cost-effective treatment options is especially important for patients who seek additional therapy after an incomplete initial response, as well as for those whose symptoms return after treatment. Both scenarios are common in patients who are treated for anxiety disorders (Davidson et al., 2001; Durham et al., 2005; Keller, 2006; Rubio & López-Ibor, 2007; Rufer et al., 2005). Thus, the selection of a simultaneous combination treatment can be seen as disadvantageous when viewed within the context of longer-term care.
An alternative to the simultaneous initiation of combination treatment is treatment sequencing. In sequencing strategies, a monotherapy is the initial treatment, and additional or alternative therapies are introduced only if response is inadequate (Rodrigues et al., 2011). The sequencing strategies that have shown the most promise in the treatment of anxiety are those that involve the addition of psychotherapy or pharmacotherapy (i.e., augmentation) and those in which psychotherapy is used to assist in the tapering of medications.
Rodrigues et al. (2011) provide a systematic review of 17 studies in PTSD, panic disorder, or OCD that used CBT as an add-on treatment for pharmacotherapy non-remitters. In contrast to the common finding that combination treatments do not outperform monotherapies, positive findings have been obtained consistently from studies of CBT augmentation. For example, in a three-phase study of panic disorder, Simon et al. (2009) showed that nonresponders to back-to-back courses of sertraline treatment experienced a reduction in symptoms from either the addition of CBT or clonazepam, which did not differ from each other. In OCD, Simpson et al. (2008) found that partial responders to serotonin reuptake inhibitors showed greater rates of response when EXRP was added, relative to the addition of stress management. In PTSD, Hinton et al. (2005) showed that CBT improved outcomes after an inadequate response to SSRI plus supportive counseling. Benefits accruing from add-on CBT after an inadequate medication response have been observed in several other controlled trials (e.g., Kampman et al., 2002a; Tolin et al., 2007);1 and in uncontrolled naturalistic studies (Heldt, Blaya, et al., 2006; Pollack et al., 1994; Tundo, Salvati, Busto, Di Spigno, & Falcini, 2007).
CBT augmentation might also have other advantages over simultaneous treatment combinations. Franklin (2005) proposed that, in the treatment of OCD, medications plus add-on EXRP might work synergistically, by allowing time for the medications to reach their full effective dose before EXRP is initiated. Once on their therapeutic dose, patients might more readily confront feared stimuli and refrain from engaging in safety behaviors. Add-on CBT might also be less susceptible to treatment interference. Some research indicates that cortisol response normalizes over the course of medication treatment, perhaps leading to a reduction in medication-induced inhibition of extinction learning (Otto, McHugh, & Kantak, 2010). Findings to date on the durability of add-on CBT have been positive (Heldt, Gus Manfro, et al., 2006; Hinton et al., 2005; and Pollack et al., 1994), but large-scale replication is lacking.
In contrast to add-on psychotherapy, surprisingly few controlled clinical trials provide data on the strategy of adding medications to psychotherapy (Albert & Brunatto, 2009). Findings from these studies paint a mixed picture of the benefits of this approach. In one study of panic disorder, paroxetine or pill placebo was added to CBT after a nonresponse (N = 161). At the end of treatment, 74% of patients in the CBT plus paroxetine group were panic free, compared to 47% in the CBT plus placebo group (Kampman et al., 2002b). Findings from two other panic disorder studies suggest that clear but modest gains accrue from the addition of clomipramine to exposure therapy (Hoffart et al., 1993), and from the addition of divalproex sodium (Depakote) to CBT plus standard medications (Baetz & Bowen, 1998). In contrast, Simon et al. (2008) found no benefit for the addition of paroxetine versus placebo to PE after an initial nonresponse to PE in PTSD. Indeed, although non-significant and small (d = 0.35), effect sizes favored the placebo group. A similar finding in panic disorder was reported by Fava, Savron, Grandi, and Rafanelli (1997). In this crossover design, patients were randomly assigned to three balanced treatment blocks involving exposure, exposure plus imipramine, and exposure plus cognitive therapy. Remission was observed most often after exposure alone regardless of treatment order. Moreover, a number of nonremitters to exposure assigned to exposure plus imipramine had difficulty tolerating the drug, and 43% had to be discontinued prematurely. The results of these two studies might suggest that (1) the duration of exposure treatment is inadequate in some psychotherapy nonresponders, and (2) the addition of other treatment “too early” could complicate the therapeutic process of exposure. Because the addition of medications to psychotherapy is popular in general practice (Albert & Brunatto, 2009), further studies are urgently needed, with specific attention paid to mediating and moderating variables that might identify those patients for whom the addition of medications is likely to enhance response, relative to a continuation of psychotherapy, or to a shift in the targets or methods of psychotherapy.
Other sequencing strategies address difficulties with discontinuing anxiolytic medications, a process that is associated with severe discontinuation syndromes, substantially increased anxiety, or relapse (Noyes, Garvey, Cook, & Suelzer, 1991). CBT has proven useful as a means of “bridging the gap,” by preventing relapse during benzodiazepine taper in both panic and GAD (Gosselin, Ladouceur, Morin, Dugas, & Baillargeon, 2006; Otto et al., 1993; Otto, McHugh, Simon, et al., 2010). CBT might also reduce the negative effects of the discontinuation of antidepressant medications after successful treatment for panic disorder (e.g., Schmidt, Wolloway-Bickel, Trakowski, Santiago, & Vasey, 2002). These studies suggest that combination therapy in anxiety might help those who struggle to taper their medications after successful acute treatment.
Most augmentation strategies for anxiety add one anxiolytic therapy, whether psychotherapeutic or pharmaceutical, to another. In contrast, the glutamatergic N-Methyl-D-Aspartate (NMDA) partial agonist D-cycloserine (DCS) has no anxiolytic properties on its own, but has been shown to enhance response when combined with exposure therapy (Deveney et al., 2009). Specifically, DCS is thought to enhance extinction learning and thereby facilitate response to exposure therapy (Hofmann et al., 2011). Across several brief placebo controlled trials, DCS administered before exposures has been associated with greater symptom improvement in acrophobia (Ressler et al., 2004), social anxiety disorder (Guastella et al., 2008; Hofmann et al., 2006) and panic disorder (Otto, Tolin, et al., 2010). Although these results are promising, findings from some studies suggest that DCS becomes less effective with prolonged use, possibly due to drug tolerance (Kushner et al., 2007; Wilhelm et al., 2008). Further work is therefore needed to determine the limitations and durability of the enhancing effects of DCS and other putative memory enhancers (e.g., yohimbine hydrochloride; see Hofmann et al., 2011).
Results for simultaneously combined treatments in anxiety vary by the specific anxiety disorder under study, but on the whole the evidence for improved efficacy over monotherapies is lacking. Thus, combination treatments are best reserved for cases that are refractory to monotherapy, and then used in such a way to maximize their benefit. Evidence suggests that adding psychotherapy for individuals who are non-responders to medication is efficacious acutely (Rodrigues et al., 2011), and that CBT is effective in helping individuals taper medications while maintaining treatment gains. Fewer studies assess adding medications to psychotherapy, and the benefits of this approach are not yet determined. In each case, more research is needed to identify prognostic and prescriptive factors for combination treatments (e.g., Maher et al., 2010) and to determine the durability of these approaches.
The prospect of increasing the potency of exposure therapy with pharmacological agents such as DCS is exciting and important. At this time, DCS is not widely available; however, as researchers refine the procedures and identify the populations for whom application of DCS is most effective, practitioners might be provided with a powerful tool. These approaches appear to retain the best features of CBT treatments (enduring effects, limited side effects), while at the same time increasing their efficacy.
Findings from research on combined therapies for depression share several features with those for anxiety disorders. Psychotherapy and antidepressant medication appear to have similar efficacy in short-term treatment trials (Cuijpers, van Straten, van Oppen, & Andersson, 2008; Spielmans, Berman, & Usitalo, 2011). Psychotherapeutic treatments, in particular CBT, might also confer an enduring benefit by preventing relapse and recurrence when compared to discontinuing medication (Dobson et al., 2008; Hollon, DeRubeis, et al., 2005; Imel, Malterer, McKay, & Wampold, 2008). However, as is true of antianxiety therapies, antidepressant therapies are only modestly effective during initial short-term treatment, with remission rates of less than 50% (Fava, Ruini & Belaise, 2007). Moreover, rates of recurrence after successful treatment for depression range from 40% to 85%, with an average time to recurrence of 3.2 years (Hughes & Cohen, 2009). Recent large-scale trials (e.g., Keller et al., 2000) and meta-analytic studies (Friedman, et al., 2004; Pampallona, Bollini, Tibaldi, Kupelnick, & Munizza, 2004) have revealed a small to moderate short-term advantage for combined therapy over various monotherapies of depression. As a result, treatment guidelines recommend the use of combined therapy as initial treatment for severe, chronic, and recurrent depression, as well as for individuals who have not responded to prior monotherapy (Davidson, 2010). We briefly review these positive findings, and then turn our attention to concerns with common combination approaches and discuss evidence for possible alternatives.
In head-to-head comparisons, estimates of the short-term advantage for combined treatment in depression are d = 0.31 versus medications (Cuijpers, Dekker, Hollon, & Andersson, 2009), and d = 0.35 versus psychotherapy (Cuijpers, van Straten, et al., 2009); although a large portion of the latter advantage could be accounted for by the placebo effect (Cuijpers, van Straten, Hollon, & Andersson, 2010). Further meta-analytic findings suggest that chronicity, rather than severity, might be the best predictor of an advantage of combined treatment (Cuijpers, Dekker, et al., 2009; Cuijpers, van Straten, Schuurmans, et al., 2010; see also Cuijpers, van Straten, Hollon, et al., 2010).
In addition to improving rates of response, combined treatment might increase the “breadth” of response relative to monotherapy by providing more rapid symptom reduction or improvements in a greater number of functional domains (Hollon, Jarrett, et al., 2005). In early studies of Interpersonal Therapy (IPT), a combination of IPT and medication was associated with greater gains in social functioning compared to medication alone (Weissman, Klerman, Paykel, Prusoff, & Hanson, 1974, Weissman, Klerman, Prusoff, Sholomskas, & Padian, 1981). Cognitive behavioral analysis system of psychotherapy (CBASP; a variant of CBT) combined with medication also appears to enhance the breadth of response relative to monotherapy. In a trial of 656 patients with chronic depression, Keller et al. (2000) found the combination of CBASP and nefazodone to be more efficacious than either monotherapy (rates of remission for combined treatment: 48%, CBASP: 33%, and nefazadone: 29%). Secondary analyses from this trial revealed that combined treatment was associated with faster time to remission (Manber et al., 2008), and greater improvements in psychosocial functioning relative to either monotherapy (Hirschfeld et al., 2002).
Combination therapy with brief dynamic psychotherapy (BDT) might also be associated with added functional benefits. To date, two controlled clinical trials and one mega-analysis of combined therapy with BDT have shown short-term advantages of combined therapy over monotherapy (Burnand et al., 2002; de Jonghe, Kool, van Aalst, Dekker, & Peen, 2001; de Maat et al., 2008). Molenaar et al. (2007) also found that patients receiving BDT plus medications improved on more dimensions of social functioning than did those receiving medication monotherapy, although it is possible that these advantages were due to the superior effects of the combined treatment on symptoms of depression.
Thus, in addition to small advantages in symptoms, short term combined treatment has been shown to improve rate of response and some dimensions of social functioning relative to monotherapy.
As we have argued in our review of anxiety disorders, the long-term benefits of combination treatments must equal or exceed the benefits derived from monotherapies to justify their use as an initial treatment. Maintenance medications (Geddes et al., 2003), as well as initial and maintenance psychotherapy (Blackburn & Moore, 1997; Dobson et al., 2008; Hollon, DeRubeis, et al., 2005), have shown moderate efficacy in preventing relapse and recurrence of depression. The available evidence, although limited in scope, suggests that longer-term efficacy of combined treatments is on a par with but not superior to that of either monotherapy (e.g., Cuijpers, Dekker, et al., 2009; Vittengl, Clark, Dunn, & Jarrett, 2007). Comparisons between discontinued combination therapy with CBT versus discontinued CBT alone show no difference with respect to relapse prevention, with each condition being superior to discontinued medication (Blackburn, Eunson, & Bishop, 1986; Evans et al., 1992; Simons, Murphy, Levine, & Wetzel, 1986). Vittengl et al. (2007) estimated the risk of relapse or recurrence in individuals with prior CBT combined with medications to be 61% lower than in those with prior medication monotherapy. Again, prior combined therapy did not differ from prior CBT.
Data from a recently completed study also support the benefit of CBT combined with medications in producing a sustained response. The study comprised a large (N = 452) trial of CBT plus medications versus medication monotherapy for recurrent and/or chronic major depression. The aim of the trial was to treat patients to recovery, defined as a 26-week period without relapse, allowing for the detection of speed of recovery and therefore a comparison of combined treatment versus medications alone. Preliminary results show that rates of recovery were higher in combined therapy (73%) versus medication alone (62%) while rates of attrition were lower in combined therapy (18%) versus medication alone (27%; S. D. Hollon, R. J. DeRubeis, R. C. Shelton, J. Zajecka, & J. Fawcett, personal communication, May 7, 2011).
IPT or BDT in combination with medication might also provide some protection against relapse. Cuijpers et al. (2011) estimated that maintenance IPT in combination with medications is superior to medication maintenance alone, with an effect size of d = 0.37. Interestingly, the method that produced the acute response might be important for predicting recurrence. Frank et al. (2007) found that women on maintenance IPT who had remitted on IPT alone were less likely to have a recurrence than women who had remitted on IPT plus add-on medications. Other findings suggest that maintenance IPT plus medications is superior to IPT maintenance alone in preventing relapse (Reynolds et al., 1999). In regards to BDT, Maina, Rosso, and Bogetto (2009) found that the combination treatment resulted in a lower rate of relapse (28%) than the medication group (47%) over a 48-month naturalistic follow-up.
Taken together, the evidence for combined therapy of depression is largely positive. Unlike combined therapy for anxiety disorders, there is little evidence that treatments interfere with one another. However, the possibility of obtaining incremental gains from combined treatment must be balanced against other potential disadvantages.
One concern in combination therapy is the long-term care of depressive illness. Increasingly, depression is recognized as a chronic and recurrent disorder, suggesting that the longer-term management of the disorder should be considered during initial treatment selection (Fava & Ruini, 2006). As with anxiety disorders, having information about an effective treatment for any particular individual is potentially cost-reducing. If a patient evidences a good response to simultaneously initiated combination treatment, no information is obtained about how to prevent relapse or recurrence in that individual; that is, whether or not to continue to provide both, one, or neither of the therapies. An incorrect choice can have negative consequences: If medications produced the response, discontinuation could leave the individual vulnerable to relapse (Bockting et al., 2008). On the other hand, a decision to continue both treatments might leave an individual on two expensive and possibly unnecessary maintenance treatments. As previously noted, successful combination treatment also provides no information for selecting subsequent (and less costly) monotherapies if symptoms recur. Faced with these uncertainties, a common and recommended maintenance strategy in clinical practice is prolonged continuation of medication treatment (Petty, House, Knapp, Raynor, & Zermansky, 2006; Piek, van der Meer, & Nolen, 2010), which is expensive (Vos, Corry, Haby, Carter, & Andrews, 2005) and often ineffective (Bockting et al., 2008).
Moreover, the increased potential for negative or iatrogenic effects during combined treatment needs to be considered. Side effects during medication treatment (Warden et al., 2009) and the increased chance of relapse upon discontinuation of medications (Viguera, Baldessarini, & Friedberg, 1998), are well documented. There is also increasing evidence that prolonged antidepressant maintenance can worsen the course of depressive illness, at least in some cases (Fava & Offidani, 2011). Findings from long-term studies suggest that the efficacy of maintenance medication fades over time, with little additional benefit accruing after 3 to 6 months of maintenance (Kaymaz, van Os, Loonen, & Nolen, 2008; Reimherr et al., 1998). Other studies have found evidence for tachyphylaxis, or progressive tolerance, defined as the recurrence of depressive symptoms during adequate maintenance treatment (Solomon et al., 2005). Tachyphalaxis might be functionally related to treatment resistance, in which individuals fail to respond to previously effective medications after a drug-free period (Amsterdam et al., 2009). Tolerance to antidepressant therapy may become more likely as the number of prior medication exposures increases (Amsterdam et al., 2009; Amsterdam & Shultz, 2005; Leykin et al., 2007). Discontinuation of medications can also result in “discontinuation syndromes,” marked by worsening mood, agitation, and multiple somatic symptoms (Rosenbaum, Fava, Hoog, Ascroft, & Krebs, 1998). Fava and Offidani (2011) hypothesize that these effects are caused by compensatory changes in neurotransmitter systems, collectively known as “oppositional tolerance.” Similar to iatrogenic effects in antipsychotic medications (e.g., tardive dyskinesia), oppositional tolerance is hypothesized to result from adaptations in synaptic structure and activity induced by the presence of antidepressant agents. Progressive change in these mechanisms might result in the return of depressive symptoms during treatment, or a rebound effect upon discontinuation.
There are also possible negative effects of psychotherapy. Research on harmful effects in psychotherapy has been hindered both by neglect (Lilienfeld, 2007) and by methodological difficulties (Dimidjian & Hollon, 2010), thus the identification of these effects in psychotherapy lags behind that of pharmacological interventions. However, a review of the literature indicates that 5% to 10% of adults deteriorate while in psychotherapy (Hansen, Lambert, & Forman, 2003), indicating that negative effects are possible. In established therapies for depression, findings regarding moderators of treatment outcome might suggest conditions under which treatment is toxic to some individuals, for example, in cases of comorbid personality disorder (Fournier et al., 2008) or low levels of therapist competence in CBT (Strunk, Brotman, DeRubeis, & Hollon, 2010).2 Unethical or inappropriate actions by therapists, such as sexual relations with patients, are also an unfortunate and serious cause of potential harm (Berk & Parker, 2009). However, even presumably ethical and well-meaning therapists can produce negative outcomes. Okiishi et al. (2006) found that outcomes in outpatient treatment varied widely by therapist. Furthermore, Kraus, Castonguay, Boswell, Nordberg, and Hayes (2011) found that a surprising number of community therapists produced reliable deterioration in specific functional domains. For example, 10% of therapists reliably increased anxiety symptoms and 14% of therapists reliably decreased social functioning. This alarmingly high rate of deterioration (although largely domain specific, i.e., therapists might produce poor outcomes in one domain but not others) suggests that harmful effects of therapy might be more common than once thought. Even if it is innocuous, ineffective courses of psychotherapy are associated with more substantial “opportunity costs” relative to ineffective medications, because they require a greater investment in time and effort (Lilienfeld, 2007).
The findings that point to these problems in both medications and psychotherapy are not definitive; therefore, further investigation is required. However, the possibility of incurring one or more of these negative effects increases when two therapies are prescribed together. Treatment providers should consider this increased chance of harm when selecting initial treatment strategies.3
Similar to anxiety disorders, better cost/benefit and risk/benefit ratios might be achieved from sequenced treatment strategies, which might produce, on average, similar benefit with a lower chance for negative effects. Evidence exists regarding the effects of several sequencing strategies in depression, including (a) switching between therapies, (b) augmenting one therapy with another, and (c) clinical staging (Fava & Tomba, 2010). These strategies have been examined for their ability to improve both short-term and long-term responses.
Switch strategies involve a planned change from one treatment to another for patients who fail to respond adequately to the initial treatment. Evidence in favor of switching strategies has emerged from Keller et al. (2000) and the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D). In Keller et al., individuals who did not respond to CBASP or nefazodone alone after 12 weeks were crossed over to the other treatment (Schatzberg et al., 2005). Individuals who were switched from nefazadone to CBASP experienced a significantly greater rate of response (57%) than individuals who were switched from CBASP to nefazadone (42%), a difference that the authors attributed to a lower rate of dropout in CBASP. In Stage 2 of STAR*D, nonresponders to citalopram could be assigned to switch to CBT or have citalopram augmented with CBT. Among those who were switched to CBT, 25% remitted, compared to 28% of those who were switched to another medication (Thase et al., 2007). Moreover, the switch-to-CBT group reported significantly fewer side effects than did the medication switch group. Thus, switching from medications to psychotherapy appears to be about as efficacious as the opposite strategy, but the longer-term efficacy of each strategy is unknown.
Add-on treatments have been studied for their ability to improve both short-term response and long-term efficacy. In STAR*D, add-on CBT at Stage 2 was equivalent to add-on medications in producing remission (rates of 23% versus 33%, respectively), although medication augmentation was associated with faster time to remission (Thase et al., 2007).4 In one of the only studies to compare two different strategies for combining treatments, Frank et al. (2000) randomized women to IPT or combination IPT plus medications. In the IPT alone group, medications were added at 24 weeks if remission was not achieved. At the end of treatment, the augmentation treatment group showed a higher rate of remission (79%) than the combination treatment group (66%). Interestingly, in another study comparing IPT alone versus IPT plus sequential medication augmentation, maintenance IPT was less efficacious at preventing recurrence in the augmentation group after the medication was discontinued (Frank et al., 2007). Other studies show less positive results for short-term augmentation. In the Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP) trial, nonresponders or partial responders to 12 weeks of sertraline treatment received equal—and surprisingly low levels of—benefit from each of the following treatments: 12 weeks of continued medication, add-on CBASP, and add-on supportive therapy (Kocsis et al., 2009). The authors conjectured that the lack of benefit from add-on CBASP could have occurred because individuals who preferred psychotherapy might have been discouraged from entering a trial that required an initial course of medication.
In trials testing relapse prevention strategies, the long-term efficacy of medication maintenance is consistently improved by add-on CBT. For example, mindfulness-based cognitive therapy (MBCT), a treatment designed to prevent depressive relapse by teaching patients to become mindful of and disengage from ruminative cognitive processes (Teasdale et al., 1995), appears to be particularly useful for preventing relapse in patients with recurrent depression. Two studies found that remitted depressed individuals with three or more previous episodes (but not those with two or fewer) receiving MBCT plus treatment as usual (TAU) were less likely to relapse over 60 weeks than those receiving TAU (Ma & Teasdale, 2004; Teasdale et al., 2000). Other studies suggest that the protective effect of add-on CBT for recurrent depression is durable. CBT added to maintenance medication was associated with decreased relapse rates versus medication monotherapy at 68 weeks (Paykel et al., 1999) and at 3.5 years (Paykel et al., 2005). CBT was also associated with cost-benefit advantages over medication monotherapy (Scott, Palmer, Paykel, Teasdale, & Hayhurst, 2003). Furthermore, Bockting et al. (2005) found that remitted depressed individuals with five or more depressive episodes had lower relapse rates in group CBT plus TAU than did those who received TAU alone (46% versus 72%, respectively). The enduring effects of CBT continued for individuals with four or more episodes at a 5.5-year follow-up (Bockting et al., 2009).
Similar to the Frank et al. (2007) finding reported above, evidence suggests that patients who require augmentation to achieve acute remission are more likely to relapse than those who remit after unaugmented treatment. Rucci et al. (2011) reported that remitters to IPT or SSRI alone were one third as likely to relapse over 6 months of continued treatment as those who required add-on medications or IPT to achieve remission. These studies suggest that difficult-to-treat individuals might require more robust maintenance therapy in order to achieve recovery.
The augmentation literature, although promising, provides little guidance for making treatment decisions about when—or if—one should initiate psychotherapy or terminate medication treatment, and so on. A possible alternative to unguided augmentation is theory-guided staging of treatments. These approaches are derived from clinical staging models commonly used in medicine, and are receiving increasing attention in the psychiatric literature (McGorry et al., 2007; McGorry, Nelson, Goldstone, & Yung., 2010; Tomba, Fabbri, & Fava, 2009). Clinical staging defines the progression of the disorder and the individual's stage within this progression, allowing the selection of interventions best suited to these conditions (Fava & Tomba, 2010; McGorry et al., 2010). Proponents of staging models for depression hypothesize that the needs of patients change over the course of treatment. For example, patients might initially require acute relief of distress, but during the residual phase they would benefit from interventions to improve functioning and prevent relapse (Tomba et al., 2009). In Fava and Ruini's (2002) “sequential model,” patients are treated to response with medications, and then switched to a variant of CBT, called well-being therapy (Fava, 1999), as medications are tapered. According to Fava and Ruini (2002), sequential treatment with CBT might (a) alleviate residual symptoms (known to be related to relapse), and (b) provide a prophylactic effect without the need for maintenance medications, eliminating the potential drawbacks of long-term medication use.
Some evidence is emerging to substantiate the clinical applicability of this and similar staging algorithms. Fava, Grandi, Zielezny, Canestrari, and Morphy (1994) found that, after successful antidepressant treatment, individuals randomly assigned to CBT during medication discontinuation had lower residual symptoms at the end of the discontinuation period than individuals assigned to clinical management. They also had lower rates of relapse at 4-year follow-up (35% versus 70%; Fava, Grandi, Zielezny, Rafanelli, & Canestrari, 1996), although these differences had faded after 6 years (50% versus 75%; Fava, Rafanelli, Grandi, Canestrari, & Morphy, 1998). In a similar study of individuals with recurrent depression, a group recieving CBT plus well-being therapy during antidepressant discontinuation evidenced lower relapse rates than a clinical management group at both the 2 year (25% versus 80%; Fava, Rafanelli, Grandi, Conti, & Belluardo, 1998) and 6 year (40% versus 90%; Fava et al., 2004) follow-ups. In another study of staged treatment using MBCT, remitted individuals were randomized to discontinued medications plus MBCT, maintenance medications, or placebo (Segal et al., 2010). The two active conditions were each superior to placebo and equal to one another in preventing relapse in “unstable” remitters (individuals who experienced brief symptom recurrence after remission) over 18 months, but they did not differ from placebo among “stable” remitters.
Staged approaches offer the possibility of a prescribed series of treatments that maximize the benefits of each (e.g., rapid symptom relief for medications, relapse prevention for CBT), while minimizing their potential weaknesses. Currently, though, the literature provides a somewhat limited investigation of possible staging strategies, as only medications have been tested as the first step in the sequence. Fava and Tomba (2010) suggest that state-dependent learning and cognitive deficits might inhibit depressed individuals from benefitting from acute CBT (e.g., Reus, Weingartner, & Post, 1979). Moreover, evidence that medications consistently outperform psychotherapy in producing an acute response, even severe depression, is equivocal (Cuijpers et al., 2008; DeRubeis et al., 2005; Elkin et al., 1989). Current staging models might therefore be based on an incorrect premise: That early stages of depression treatment require pharmacological intervention. One consequence of the limited scope of these investigations is that they provide little information about options for individuals refractory to medication treatment. Nevertheless, staging strategies are the first well-researched treatments for depression that integrate psychotherapy and medications into a coherent treatment model.
There is little doubt that combined treatments for major depression provide incremental improvements in response over monotherapies, particularly in subgroups such as those with chronic depression. At the same time, there is little reason to offer combined treatment for mild or moderate depression unless individuals do not respond to monotherapy. Concerns about the effectiveness and safety of medications over the long term and possible negative effects of psychotherapy suggest that the best strategy for implementing combined treatments is a nonsimultaneous and time-limited approach (e.g., switching, augmentation, or staging). However, more research is needed to determine optimal treatment selection and timing of treatment changes. Particularly needed are studies that assess the efficacy of adding medications to psychotherapy when a course of psychotherapy does not lead to remission, given the somewhat surprising finding from one such study, in which the remission rate was higher for the augmentation strategy relative to a simultaneous combination (Frank et al., 2000). Despite the larger evidence base for medication-first strategies, there is no reason not to conduct research on psychotherapy-first strategies (e.g., Frank et al., 2011). In particular, acute remission on psychotherapy would offer the benefits associated with this treatment without requiring exposure to medication treatment and its associated risks. Finally, moderators of response for combination therapy versus monotherapy, that is, prognostic and prescriptive factors (e.g., Fournier et al., 2009; Frank et al., 2011), have also yet to be identified.
Combination treatment of bipolar and psychotic disorders presents a different set of issues. Unlike anxiety and depression, medications are known to be more efficacious than psychotherapy for reducing acute manic or psychotic symptoms. Medications are also the recommended treatment for prevention of relapse and recurrence of these disorders. However, medication monotherapy is often inadequate as an acute and preventive therapy for these disorders, and is often associated with poor compliance and side effects. These problems have led researchers to explore an expanded role for psychotherapy. Because medications are considered the mainstay therapy, the majority of studies have examined psychotherapy as adjunctive treatment, and controlled trials of psychotherapy-first or staging strategies are therefore rare. The utility of add-on psychotherapy in these disorders depends upon whether the addition of second (or third, fourth, etc.) treatment is worth the additional cost and effort. Often, this appears to be the case, as adding psychotherapy to medication appears to improve acute outcome and provides some protection against relapse and recurrence relative to medications alone. In contrast, there is some emerging evidence that acute medication treatment might be contraindicated in some cases of psychosis, possibly indicating a larger role for psychotherapy as initial treatment. In the following sections we present the evidence regarding the acute and long-term efficacy of combined treatments in these disorders.
Antipsychotics are recommended for the acute and maintenance treatment of schizophrenia and other psychotic disorders (APA, 2004a; NICE, 2009). However, up to 30% of individuals show a poor initial response and an additional 30% of patients continue to experience symptoms (Lehman et al., 2004). In addition, medication side effects can be debilitating, resulting in poor adherence and reduced effectiveness (Lieberman et al., 2005). Schizophrenia spectrum disorders are also heterogeneous in their presentation and clinical course, suggesting that a “one-size-fits-all” treatment strategy is inapprorpriate (McGorry et al., 2010). A variety of adjunctive psychosocial treatments have been developed to enhance the effectiveness of medications at different phases of treatment, for example, to hasten recovery in acute psychosis, or to relieve chronic medication-resistant symptoms. Other treatments target comorbid problems such as substance use and weight gain. Some researchers have also examined the efficacy of delaying medication therapy, often in conjunction with psychosocial treatment, as an intervention for early episode psychosis.
Several well-established psychosocial treatments for schizophrenia are not readily classified as “psychotherapy” per se, but rather as rehabilitation or skills-training programs. Although a full description of these studies is outside the purview of this chapter, we briefly present some relevant evidence. Because combined treatments for schizophrenia are often delivered in inpatient settings, we broaden our review to incorporate studies that include inpatients.
CBT for schizophrenia was developed to treat persistent, medication-resistant positive psychotic symptoms. Since its initial trials, it has also been examined for its efficacy in treating acute psychosis and in preventing relapse. In CBT models, cognitive and behavioral strategies are used to treat positive and negative symptoms directly. For example, individuals are taught to reappraise the power and source of halucinations (e.g., internal versus external), evaluate the veracity of delusions, or address motivational and other deficits (Gaudiano, 2006; Tarrier, 2010).
Findings from several trials suggest that CBT reduces symptoms of schizophrenia (e.g., Kuipers et al., 1997; Sensky et al. 2000; Tarrier et al., 1998). In one meta-analysis, effect sizes for CBT versus standard care5 were estimated at d = 0.40 for targeted symptoms, d = 0.37 for positive symptoms, and d = 0.38 for general functioning, suggesting that CBT produces significant small to moderate effects (Wykes, Steel, Everitt, & Tarrier, 2008).6 On the basis of these findings, CBT is classified as a recommended adjunctive treatment in NICE (2009) and by the Schizophrenia Patient Outcomes Research Team (PORT; Dixon et al., 2010).
The most compelling evidence for CBT effectiveness comes from treatment of chronic positive symptoms of schizophrenia. In a 3-arm, 87-subject trial comparing CBT plus standard care versus supportive therapy plus standard care versus standard care alone, Tarrier et al. (1998) found that CBT was superior to both groups in reducing the number and severity of positive symptoms after 3 months of treatment and at a 12-month follow-up (Tarrier et al., 1999). In another study, Sensky et al. (2000) randomized 90 individuals with persistent symptoms to either CBT or a befriending intervention (described as empathic and nondirective). At the end of the 9-month treatment, there were no differences between groups, but at an 18-month follow-up, CBT was superior to befriending on schizophrenia symptoms. At a 5-year follow-up, the CBT group maintained superiority to befriending on overall symptoms (Turkington et al., 2008). Other evidence suggests that CBT can be helpful for more specific applications, such as increasing control over command hallucinations (Trower et al., 2004). Findings from a recent trial also suggest that CBT can reduce negative symptoms of schizophrenia in the most severely ill individuals. In a group of 60 low-functioning chronic schizophrenia patients, a type of patient that typically is excluded from CBT trials, Grant, Huh, Perivoliotis, Stolar, and Beck (2011) found that a modified form of CBT was superior to standard care at improving functional outcomes, as well as decreasing the severity of avolition, apathy, and positive symptoms.
Less evidence has accrued in support of CBT for speeding recovery from early (or first episode) psychosis. Lewis et al. (2002) randomized 315 individuals with early episode psychosis to standard care, CBT plus standard care or supportive counseling plus standard care. At Week 4, the CBT group showed a nonsignificant trend toward faster improvement than did the standard care group; however, these differences did not persist to the end of the 5-week treatment. At an 18-month follow-up, both CBT and supportive counseling were superior to standard care in relieving symptoms, but not different from each other (Tarrier et al. 2004). Notably, patients received only 9 hours of the CBT intervention on average, which, as the authors acknowledged, might have been insufficient to promote enduring change. Two studies by Jackson and colleagues conducted in the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne, Australia, also provide mixed evidence of CBT's efficacy. In the first, Cognitively Oriented Psychotherapy for Early Psychosis (COPE) was added to EPPIC's standard rehabilitation services (N = 91). This treatment did not improve symptoms or readmissions relative to EPPIC alone (Jackson et al., 2005). A second study examined a befriending intervention versus acute symptom intervention called Active Cognitive Therapy for Early Psychosis (ACE; N = 62). Participants receiving ACE showed a trend toward improvement in negative symptoms and overall functioning relative to befriending early in treatment, but there were no differences between groups at a 1-year follow-up (Jackson et al., 2008).
Two trials adapted CBT treatment for relapse prevention. Gumley et al. (2003) randomized 144 subjects at high risk for relapse to standard care plus 12 weeks of CBT (plus additional CBT if signs of relapse were detected) versus standard care alone. At 12 months, CBT was associated with significantly lower relapse rates (18% versus 35%), and more improvement in symptoms and functioning. In contrast, a more recent study of 128 recently relapsed individuals found similar and suprisingly low rates of remission (< 50%) after 9 months of standard care or standard care plus CBT (Garety et al., 2008). Relapse, defined as a reemergence or a significant worsening of positive symptoms, did not differ by treatment condition at either 12 or 24 months. In light of these conflicting results, further research is needed to determine the efficacy of CBT in reducing schizophrenic relapse.
Despite the broad application of CBT for schizophrenia, the evidence suggests that CBT is most effective for chronic medication resistant symptoms. Improvements in chronic symptoms following CBT also appear to be relatively enduring (Tarrier et al., 1999; Turkington et al., 2008). Currently, CBT does not appear to be more efficacious than supportive treatment for acute symptom relief, and evidence regarding relapse prevention is equivocal. Newer applications of CBT, such as CT for negative symptoms (Grant et al., 2011) and acceptance and commitment therapy in acute schizophrenia (Bach & Hayes, 2002; Gaudiano & Herbert, 2006) have shown promise, and are likely a fruitful area for continued inquiry.
Family psychoeducation treatments are intended to improve coping, reduce stress within the family, and encourage within-family behaviors that promote recovery (e.g., reduction in conflict and high expressed emotion). Interventions include psychoeducation, consultation, and elements from supportive and cognitive behavioral therapies (McFarlane, Dixon, Lukens, & Lucksted, 2003). More than 50 trials of family psychoeducation have been conducted, generally with relapse prevention as the primary outcome. Efficacy estimates are impressive, with early studies achieving an estimated reduction in relapse risk of as high as 40% by the end of treatment, although the estimates are lower in comparisons of family treatments verus other adjunctive psychosocial treatments (Bustillo, Lauriello, Horan, & Keith, 2001; Pilling et al., 2002). In a recent Cochrane review, Pharoah, Mari, Rothbone, and Wong (2010) estimated that family interventions reduce the risk of relapse at 12 months (relative risk = 0.55), 18 months (relative risk = 0.64) and 24 months (relative risk = 0.64) relative to all comparison treatments.
Some research indicates that the prophylactic effects of family treatments can extend even longer. For example, one family treatment study found that patients in the treatment group whose families were judged to be high in expressed emotion had significantly lower relapse rates compared to subjects who received psychoeducation or standard care at 5 and 8 years (Tarrier, Barrowclough, Porceddu, & Fitzpatrick, 1994). In another study, Barrowclough et al. (1999) assigned patients and carers to a needs-based program with access to a family support worker, problem solving, behavioral family management, and/or CBT components. At 6 months, members of the control group, who also received a family support worker, were 2.6 times more likely to relapse than those in the treatment group (46% versus 24%). The advantage for the treatment group remained at 12 months (hazard ratio = 2.8; 72% versus 37%; Sellwood et al., 2001), and at 5 years (Sellwood, Wittkowski, Tarrier, & Barrowclough, 2007). Importantly, evidence suggested that the prophylactic benefits of the treatment were sustained across the full course of the 5-year follow-up.
Family interventions have also been found to improve outcomes for caregivers (Cuijpers, 1999; Hazel et al., 2004) and have been successfully implemented in a number of different ethnic groups and nationalities (Pharoah et al., 2010). Some preliminary work suggests that family treatments are also efficacious in preventing relapse in early psychosis (Bird et al., 2010).
However, family treatments do require the willing participation of a caregiver in close contact with the patient, making them inappropriate for some. At least one study has had difficulty recruiting enough families to adequately power a family treatment arm (Garety et al., 2008), and others have enrolled only a small percentage (22%) of potentially eligible families (Schooler et al., 1997). Thus, despite promising outcomes, family treatments have limited clinical utility for individuals whose family members are unable or unwilling to participate in treatment.
Studies of other adjunctive psychotherapies have produced mixed results. Recent meta-analyses of psychodynamic and supportive therapies for schizophrenia suggest that these treatments do not improve outcome relative to standard care (Buckley & Pettit, 2007; Malmberg, Fenton, & Rathbone, 2010; respectively). Furthermore, Hogarty's personal therapy (Hogarty et al., 1997a), which was designed specifically as an intervention for schizophrenia, produced some positive results with respect to relapse prevention (albeit only among those patients living with their families) and social adjustment (Hogarty et al., 1997b). However, despite these promising findings, no subsequent trials have been conducted to test this intervention.
Psychosocial treatments have also been tested for reducing medication side effects or treating comorbid conditions in schizophrenia. For example, psychosocial treatments have proven effective for addressing weight gain and metabolic dysfunction, which are common and potentially serious side effects of second-generation atypical antipsychotics (Falissard et al., 2011). Positive outcomes have been reported for both weight loss and weight gain prevention programs (for a review, see Alvarez-Jimenez, Hetrick, González-Blanch, Gleeson, & McGorry, 2008). In an example of the latter, Evans, Newton, and Higgins (2005) found individuals in a 3-month nutritional psychoeducation program had significantly less weight gain (4.4 pounds) than a TAU group (13.2 pounds). Lower weight relative to TAU was maintained at 6 months (4.4 versus 21.8 pounds).
Psychosocial treatments are also available for comorbid substance use disorders, which occur in 20% to 40% of individuals with schizophrenia (Mueser, Bellack, & Blanchard, 1992). In a small study (N = 36), Barrowclough et al. (2001) found that individuals with psychosis and substance use had better global functioning, a lower percentage of days using any substance, and somewhat better symptoms in a 9-month treatment that combined CBT, motivational interviewing, and family intervention, compared to those in a standard care group. Relapse rates were also significantly lower in the treatment group at 12 months, but this difference was not maintained at 18 months (Haddock et al., 2003). Various other interventions for substance use in schizophrenia appear to produce some benefits in substance use and other relevant domains (for a review, see Dixon et al., 2010).
In addition to traditional psychotherapies, there is a strong tradition of multidisciplinary rehabilitation programs in the psychiatric literature, many of which include psychosocial interventions. These programs are intended to promote rehabilitation or address various deficits common in psychotic disorders (e.g., work functioning, social skills). Although these efforts do not always include psychotherapy, per se, they are firmly rooted in the biopsychosocial model, and thus deserve consideration. Examples include intensive case management and community support. Reviews indicate that these services are effective for increasing contact with service providers and reducing rehospitalizations and homelessness (Coldwell & Bender, 2007; Nelson, Aubry, & Lafrance, 2007). Other efforts emphasize behavior management or teach skills needed for good functioning. Interventions such as token economies (Dickerson, Tenhula, & Green-Paden, 2005), supported employment (Bond, Drake, & Becker, 2008), social skills training (Kurtz & Mueser, 2008), social cognitive training (Kurtz & Richardson, 2011), cognitive remediation (Wykes, Huddy, Cellard, McGurk, & Czobor, 2011), metacognitive training (Moritz, Vitzthum, Randjbar, Veckenstedt, & Woodward, 2010), and social rehabilitation (Horan, Kern, Green, & Penn, 2008) have each shown beneficial effects in improving important skills or in reducing the targeted deficits.
In general, research suggests that skills based approaches are promising methods of improving deficits, but similar to other psychosocial interventions for schizophrenia, more research is needed to determine their durability and their generalization to wider domains of functioning. Those interested in learning more about the various other rehabilitation approaches are directed to reviews by Kurzban, Davis, and Brekke (2010) and Dieterich, Irving, Park, and Marshall (2010).
As noted previously, there is a large body of evidence supporting the efficacy of antipsychotic medications in reducing acute positive symptoms of schizophrenia, especially in first-episode psychosis (Kahn et al., 2008). However, long-term maintenance of individuals on these medications can be problematic. Toxicities associated with first generation antipsychostics (tardive dyskinesia, akathesia, drowsiness; Bhattacharjee & El-Sayeh, 2008; Bola, Kao, & Soydan, 2012; Wirshing, 2001) and second generation atypical antipsychotics (diabetes, weight gain, metabolic syndrome; Asenjo Lobos et al., 2010; Gautam & Meena, 2011; Haddad, 2004) can be severe, and noncompliance with medications is common (Lieberman et al., 2005). Treatment with antipsychotics, especially clozapine, has been associated with rapid and severe relapse on medication discontinuation, suggesting that these medications have iatrogenic effects (for a review see Moncrieff, 2006). Although treatment guidelines recommend the immediate initiation of antipsychotic medication for nearly all individuals showing signs of psychosis (American Psychiatric Association, 2004b; NICE, 2010), there is evidence that a subgroup of individuals can recover without them. Indeed, the placebo response rate in controlled trials has been 25% or higher (Kemp et al., 2010; Kinon, Potts, & Watson, 2011). Evidence also suggests that some individuals can obtain stable functional recovery or prolonged periods of remission from schizophrenia without continued medication maintenance (Harrow & Jobe, 2007). These findings suggest that neuroleptics might not be the best intervention for all individuals in the early stages of psychotic illness (Francey et al., 2010).
Despite the prospect of medication free recovery, withholding medications is controversial in part because longer periods of untreated psychosis have been associated with a worse course of illness (Bottlender et al., 2003; Harrison et al., 2001). Nevertheless, a handful of studies have investigated the efficacy of intensive psychosocial interventions in combination with delayed medication. In these approaches, medications are postponed for a prescribed period and initiated only in the case of nonresponse or symptom worsening. Although these studies are of varying quality, their results are promising. A preliminary meta-analysis of studies with placebo or other medication free arms found no evidence of long-term harm in comparison to groups receiving medications (Bola, 2006). In a review of medication delay studies, Bola, Lehtinen, Cullberg, and Ciompi (2009) described the outcomes of five experimental or quasi-experimental programs that provided active psychosocial treatment in combination with medication delay: the Agnews State Hospital Project (Rappaport, Hopkins, Hall, Belleza, & Silverman, 1978), the Soteria project in San Francisco (Mosher & Menn, 1978), the Soteria-Berne project (Ciompi et al., 1992), the Needs-Adapted Project in Finland (Lehtinen, Aaltonen, Koffert, Räkköläinen, & Syvälahti, 2000), and the Parachute Project in Sweden (Cullberg, Levander, Holmqvist, Mattsson, & Wieselgren, 2002). In the experimental conditions, 27% to 61% of treatment completers received no antipsychotic medications. The analysis revealed a small advantage for the experimental treatments in comparison to treatment as usual (composite advantage, weighted by sample size = 17%). At 2- to 3-year follow-up, 27% to 43% of individuals in the experimental groups were not receiving medications.
Other evidence supporting the effectiveness of psychotherapeutic treatment has emerged from a recent trial of cognitive therapy for individuals with schizophrenia who refused or discontinued medications. In a 9-month open trial (N = 20), Morrison et al. (2011) found CT to have significant medium to large uncontrolled effect sizes on all outcome measures, and response rates of 35% and 50% after acute treatment and 15 months of follow-up, respectively. A full-scale controlled trial is currently underway. In light of these preliminary findings, it seems likely that for some individuals with psychotic disorders, intensive psychosocial treatment alone is equally as effective as, or superior to, standard medication treatment.
Based in part on the evidence for medication delay approaches, some clinical researchers have called for the development of clinical staging approaches in psychotic disorders (McGorry et al., 2007; McGorry, et al., 2010). As in depression (Tomba et al., 2009), clinical staging approaches offer treatments tailored to the stage of the disorder as well as the individual's progression within the course of illness. In McGorry and colleagues' model, earlier, less severe stages are treated with simpler and more benign treatments, whereas later stages are treated more aggressively. Because the future course of psychosis cannot be known at onset (i.e., some patients will become chronically ill, others will recover), clinical staging treatments begin with milder psychosocial interventions, and step up the level of care in the case of worsening or nonresponse. In other words, clinical staging approaches reduce the chance of “overtreating” conditions that are benign but phenotypically similar to more severe pathologies. Some preliminary evidence on staging approaches suggests that programs using CBT alone (Morrison et al., 2004) or in conjunction with low dose antipsychotics (McGorry et al., 2002) can prevent so-called ultra-high risk individuals from transitioning to full-blown psychosis. Viewed in this way, a medication delay approach is a two-phase staging treatment.
At present, these approaches lack well-controlled clinical data to support them. However, a large controlled trial of a staging treatment with a medication-free arm is curently underway at the EPPIC program in Melbourne, Australia (Francey et al., 2010). It is hoped that this trial will provide much needed data on the efficacy of medication free treatment, including prognostic and prescriptive factors that might predict medication free response.
Overall, adjunctive psychosocial treatments appear to improve symptomatic and functional outcomes in individuals with schizophrenia spectrum disorders, and we recommend their use. Each of the available psychosocial treatments has specific strengths, however, and clinicians are advised to select treatments carefully based on these characteristics. CBT is best suited for treating chronic positive symptoms (and perhaps chronic negative symptoms, Grant et al., 2012), but its effect on relapse or recurrence is equivocal. Individuals judged to be at risk for relapses are likely to benefit from family psychoeducation, but only if they have close caregivers who are willing to participate in treatment. There are also several treatment options for individuals suffering from comorbid conditions.
Unfortunately, evidence for moderators of response to combined treatments is lacking. One exception is Hogarty et al. (1997a), who found that individuals in personal therapy living with their families had lower relapse rates compared to psychological treatment controls, whereas those living alone had higher relapse rates than controls. Because little is known about who will benefit from which treatments in schizophrenia, including those who might benefit from less intensive treatments during the early course of the illness, future trials should include planned analyses of theory-specific mediators and moderators.
The recommended treatments for bipolar depression and mania for initial and long-term therapy are mood stabilizers or anticonvulsants (APA, 2002; NICE, 2006). However, remission during medication monotherapy is not common, with only about one in four patients achieving symptomatic or functional recovery after 1 year of treatment (Keck et al., 1998). Medication responders often require complex medication regimens to achieve sustained response (Post et al., 2010). Relapse rates are also high, reaching and exceeding 70% after 4 to 5 years (Gitlin, Swendsen, Heller, & Hammen, 1995; Tohen, Waternaux, & Tsuang, 1990). In addition, adherence to medication treatment has often been poor, with up to 75% of individuals discontinuing or otherwise interrupting treatment (Keck et al., 1996; Unützer, Simon, Pabiniak, Bond, & Katon, 2000).
Psychotherapy has been studied as an adjunctive treatment for bipolar depression and mania (Frank et al., 2005; Miklowitz et al., 2007; Scott et al., 2006), and for preventing relapse (Colom et al., 2003; Lam et al., 2003; Miklowitz et al., 2000). The psychotherapy interventions with the most empirical support are CBT (e.g., Lam et al., 2003), Family Focused Therapy (FFT; Miklowitz & Goldstein, 1997), Interpersonal and Social Rhythm Therapy (IPSRT; Frank et al., 1994), and psychoeducation (e.g., Colom et al., 2003). Although each contains unique elements, several interventions are common across these treatments. All target known risk factors for relapse, such as poor medication adherence (Otto, Reilly-Harrington, & Sachs, 2003), and environmental triggers such as sleep-wake cycle disruptions and stressful life events (Johnson et al., 2000; Johnson & Roberts, 1995). They also promote self-monitoring as a means of normalizing routines and recognizing signs of relapse (Lam, Burbeck, Wright, & Pilling, 2009). Promising findings have been obtained in tests of these therapeutic models. In a large trial, CBT, IPSRT, and FFT combined with medications were associated with significantly higher rates of recovery over 1 year than medications combined with collaborative care (Miklowitz et al., 2007). With regard to relapse prevention, Scott, Colom, and Vieta (2007) estimated that adjunctive psychotherapy decreases relapse rates by 40% relative to pharmacotherapy alone.
Although CBT is the best-studied of these adjunctive therapies, trials of CBT as an initial treatment for bipolar disorder have produced mixed findings. A recent 5-month trial of CBT combined with medications in patients with treatment refractory bipolar disorder showed that CBT was of modest benefit, with a lower frequency of hospitalizations at a 12-month follow-up, as well as lower levels of depressive, manic, and anxiety symptomatology compared to medications alone at 6 and 12 months (Isasi, Echeburúa, Limiñana, & González-Pinto, 2010). In contrast, an earlier large-scale trial produced very different results. In that study, Scott et al. (2006) assigned 253 patients with severe and recurrent bipolar disorder (32% in active episode) to CBT plus TAU or TAU. Rates of relapse did not differ between the groups at any point during treatment or over follow-up (18 months). The authors did find an interaction between treatment and number of previous episodes, such that CBT was superior for individuals with 12 or fewer, perhaps suggesting that CBT is more efficacious for those with less chronic forms of bipolar disorder. Lam (2006) argued that, despite its large sample and good methodological controls, this trial is not indicative of CBT's efficacy in preventing relapse, because the inclusion of acutely ill patients might have interfered with treatment delivery.
Other trials have focused on CBT for relapse prevention in individuals whose symptoms have stabilized. Scott, Garland, and Moorehead (2001) found that CBT led to improved symptoms and functioning compared to a wait-list control, and resulted in a decrease in relapse rates of 60% relative to relapse rates prior to the trial. Lam et al. (2003) also found that a 6-month CBT treatment reduced relapse rates, and that this benefit extended to a 12-month follow-up (44% in CBT versus 75% in TAU). By the 30th month, the CBT group still showed significantly lower bipolar affective relapses (64% versus 84%), however, most of this benefit was seen during the first 12 months (Lam, Hayward, Watkins, Wright, & Sham, 2005). A similar finding emerged from Ball et al. (2006), who randomized 52 patients to 6 months of CBT plus TAU versus TAU. At the end of treatment, patients in the CBT group had, on average, lower scores on measures of depression and dysfunctional attitudes, and a trend toward lower relapse rates (CBT: 20%, TAU: 33%) was also observed. However, this difference had faded by the 18-month follow-up. Findings from these trials suggest that the efficacy of CBT in preventing bipolar relapse might not be robust over longer periods (Szentagotai & David, 2010). Thus, further research is required to determine the conditions under which CBT interventions are most effective.
Family treatments enlist patients' relatives in relapse prevention by targeting risk factors such as lack of social support or high levels of familial expressed emotion (Miklowitz & Goldstein, 1997). Like family treatments in schizophrenia, family therapies for bipolar disorder require the involvement of a close caregiver. In the treatment of acute bipolar symptoms, two studies provide evidence for the efficacy of family therapies. The first is the NIMH's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial, in which Family Focused Therapy (FFT) was numerically (but not significantly) superior at one year to the other psychosocial treatments in individuals whose family members agreed to participate (recovery rates, FFT: 77%, IPSRT: 57%, CBT: 59% and collaborative care: 58%; Miklowitz et al., 2007). In the second study, Miller, Solomon, Ryan, and Keitner (2004) randomized 92 actively depressed or manic patients to TAU in combination with individual family therapy (one patient and family members), multifamily group psychotherapy (a group of patients and family members), or TAU. The authors found no differences between any of these groups on rates of recovery at 28 months. However, a follow-up analysis showed that only 5% of patients undergoing multifamily group therapy required hospitalization compared to 31% in individual family patient and 38% in TAU, suggesting that group family treatment might protect against hospitalization (Solomon, Keitner, Ryan, Kelley, & Miller, 2008).
Findings from other randomized studies suggest that FFT confers protection against bipolar relapse. In one study, Rea et al. (2003) randomized 53 patients to 9 months of FFT or individually focused patient treatment (described as supportive, problem-focused, and educational). Over the 2-year study period, there were no differences between groups on time to first relapse. However, a secondary analysis revealed that patients receiving FFT were less likely to relapse over the 1-year follow-up (28% versus 60%)—but not during the acute period—and that they had fewer relapses overall. In the other study, Miklowitz, George, Richards, and Simoneau (2003) randomized 101 patients to 9 months of either clinical management or clinical management plus FFT. They found that patients receiving FFT were less likely to relapse by the end of 24 months (35% versus 54%), and had longer mean relapse-free intervals (74 weeks versus 53 weeks). A difference in depressive symptoms favoring FFT was also found, but this difference emerged only after 6 months of treatment. The delay in relapse protection in Rea et al. (2003) and symptom improvement in Miklowitz et al. (2003) led Miklowitz and Otto (2007) to suggest that time is needed for patients and families to “absorb” the skills central to family treatments.
Interpersonal Social Rhythm Therapy (IPSRT) is based on Interpersonal Therapy (IPT) for depression (Klerman, Weissman, Rounsaville, & Chevron, 1984). In addition to IPT principles such as the identification of interpersonal problem areas, the treatment focuses on correcting disruptions in social and circadian rhythms that can lead to bipolar relapse (Frank et al., 1994).
IPSRT has been examined in two large-scale bipolar trials: the STEP-BD trial, the acute findings from which are reported above, and the University of Pittsburgh Maintenance Therapies in Bipolar Disorder trial. In the latter, Frank et al. (1999) randomized 82 patients in an acute affective episode to medication management plus IPSRT or intensive clinical management (CM). After an acute stabilization phase, patients were reassigned either to remain in the same psychosocial treatment or to switch to the other treatment over a 2-year relapse prevention phase. This created four treatment groups: CM/CM, CM/IPSRT, IPSRT/IPSRT, and IPSRT/CM. There were no differences over the first 52 weeks between the groups; however, relapse rates were significantly higher for those who switched treatments (41%) relative to those who remained in the same treatment (18%). The authors interpreted this result as evidence that stable treatment routines are important for preventing bipolar relapse. Notably, although no differences emerged on rates of relapse, monthly symptom scores were worse in the group that had lost IPSRT, relative to the groups that gained IPSRT, stayed in IPSRT, or never had IPSRT at all. At 2 years, Frank et al. (2005) found that patients treated acutely with IPSRT had longer time to recurrence than those treated acutely with CM. Additional analyses indicated that acute IPSRT was associated with improved social rhythms, and that improved social rhythms were associated with a lower probability of recurrence across conditions, supporting the idea that IPSRT protects against recurrence by stabilizing interpersonal and circadian rhythms.
Psychoeducational treatments for bipolar disorder focus on improving medication adherence, stabilizing chaotic lifestyles, and promoting the early detection of prodromal symptoms (e.g., Colom et al., 2003; Perry, Tarrier, Morriss, McCarthy & Limb, 1999). In the first major randomized trial of psychoeducation for bipolar disorder, 7 to 12 sessions of psychoeducation plus TAU or TAU alone were provided to 69 individuals (Perry et al., 1999). Over an 18-month follow-up, the psychoeducation group had a longer time to manic relapse and a 30% lower rate of manic relapse than the TAU group. Other psychoeducational treatments have been provided in a group therapy format. Colom et al. (2003) randomized 120 euthymic bipolar individuals to medications plus a 20-week group psychoeducational treatment or an unstructured support group. Patients in the psychoeducation condition recurred at a lower rate during acute treatment (38% versus 60%) as well as during the 2-year follow-up (67% versus 92%). The treatment also extended time to recurrence for depressive, manic, and mixed episodes, and reduced the number and duration of hospitalizations, relative to the unstructured group. At a 5-year follow-up, the psychoeducation group continued to have fewer recurrences and a longer average time to recurrence for all episode types. Treatment had no effect on medication adherence. The durability of this treatment is particularly impressive considering that the prophylactic effects of other psychotherapies appear to fade over time (e.g., Lam et al., 2005; Ball et al., 2006). Indeed, Colom et al. (2003) found that the size of the prophylactic effect increased between 2 and 5 years. These results have yet to be replicated, but suggest that a group psychoeducational format might be a powerful intervention for prevention of relapse.
Other group psychoeducation treatments enlist patients' family members or close companions in relapse prevention. Reinares et al. (2008) compared a 12-session group intervention for caregivers of individuals with bipolar disorder to a group control treatment (N = 113). Patients did not attend the group meeting in either condition. The psychoeducation group was associated with a lower relapse rate (42% versus 66%), and a longer time to relapse over a 12-month follow-up, although this effect was primarily confined to manic episodes. Other group formats, including one in which a close companion of each patient is included in the group, have also shown positive effects for relapse prevention (D'souza, Piskulic, & Sundra, 2010).
Overall, group treatments have been shown to be effective in the prevention of relapse in bipolar disorder. Outside of Colom and colleagues' studies, the prevention effect has been evident primarily in regard to manic episodes. Because of the potential for these programs to improve outcomes to a larger number of individuals at a relatively low cost, group treatments are worthy of greater research attention.
As is the case with schizophrenia, medication treatment outcomes for bipolar disorder remain relatively poor overall (Post et al., 2010). Even with high adherence to medication treatment regimes, individuals experience frequent depressive, manic, and mixed episodes, and residual symptoms between episodes are common (Judd, Akiskal, et al., 2003; Judd, Schettler, et al., 2003). It is also uncertain whether medication maintenance is superior to placebo in preventing relapse (Bowden et al., 2000). Considering that delayed or low dose medication in combination with appropriate psychosocial management can be successful in early psychosis (Bola, 2009), the potential role for reduced medication use in some cases of bipolar illness is worthy of study. The reviewed trials provide some suggestive results. One of the mechanisms through which psychosocial interventions are hypothesized to prevent relapse is by improving medication adherence. Surprisingly, several trials demonstrating positive prophylactic effects found no differences in adherence between treatment and control conditions (Colom et al., 2009; Frank et al., 2005; Rea et al., 2003; Reinares et al., 2008). In another trial, differences in adherence were obtained, but they did not account for the benefits conferred by psychotherapy (Lam et al., 2005). Of all reviewed trials, only in Milkowitz et al. (2003) was a reduction in mania fully mediated by better medication adherence in the experimental condition.
Despite the widely held belief that mania is a “biological” mood state, placebo response rates in mania range from 11% to 43% (Charney et al., 2002) and psychosocial treatments also appear to prevent and shorten time in manic episodes (Colom et al., 2009; Perry et al., 1999; Reinares et al., 2008). These findings suggest that there might be a larger role for psychotherapeutic treatments in bipolar disorder, especially for individuals who cannot tolerate prolonged medication maintenance. Treatment might begin with stabilization on medication, followed by careful withdrawal of medications while the patient undergoes an intensive relapse prevention treatment, similar to clinical staging treatments in depression (Tomba et al., 2009). If manic relapse occurs, medications can be reintroduced as needed. Alternate possibilities include medication delay and intensive inpatient management for early episodes of mania, similar to the medication delay models for early psychosis (Bola et al., 2009; Francey et al., 2010). Such programs, if successful, could improve long-term outcomes for some individuals.
On the whole, empirically supported adjunctive psychotherapy is recommended in treatment of bipolar disorder. Current evidence suggests that CBT and IPSRT provide acute benefits, with some research suggesting longer-lasting effects. Perhaps the most promising treatments are family therapies and group psychoeducation, each of which has been shown to reduce acute symptoms and protect against relapse. Family interventions might be especially helpful for individuals who are unable to recognize the signs of an impending relapse. Indeed, it appears that patients do not have to participate in these treatments for them to be effective in preventing relapse (Reinares et al., 2008). Preliminary research on group psychoeducation has also yielded impressive long-term results (Colom et al., 2009). As with the other reviewed disorders, there is little research on predictors of treatment response in combination treatments of bipolar disorder. Some evidence suggests that patients who are acutely ill or those with more chronic illnesses might benefit less from adjunctive psychotherapy (Solomon et al., 2008; Scott et al., 2006), but these findings are not consistent (Frank et al., 2005; Lam et al., 2009). Further research is needed to identify the conditions under which combined treatments are most effective. Also, the overlap in the interventions between these treatments (Lam et al., 2009) makes it difficult to determine whether common or specific treatment elements are related to efficacy. Randomized head-to-head trials such as STEP-BD can be useful to determine moderators of treatment response, and we encourage researchers to look into these questions.
Finally, current models of treatment in bipolar are highly constrained, with only multiple combinations of medications and adjunctive psychotherapy available as alternatives in the case of nonresponse. This approach is inappropriate for a disorder that is increasingly recognized as heterogeneous (e.g., Angst, Gerber-Werder, Zuberbühler, & Gamma, 2004). We encourage the development and testing of alternative strategies that do not rely solely on indefinite medication use.
A central concept in any discussion of mental health treatment is the heterogeneity of psychiatric disorders. Recognition of heterogeneity, particularly in regard to therapeutic response, has contributed directly to the increase in research on combined treatments. These treatments are often considered a means to “correct” for diverse responses. As we have argued, however, a nonstrategic use of combined treatments often trades rather small average advantages in short-term response against effective longer-term management for specific individuals, while also increasing risks and costs. In light of these concerns, we have encouraged clinicians to think carefully about how to combine psychotherapy and medications to meet various patient needs. Recently, evidence has emerged to support a number of strategic approaches for combining therapies. Sequenced approaches, in which additional treatment is provided only when it is necessary or when it is known to improve longer-term outcomes (e.g., Rodrigues et al., 2011; Tomba et al., 2009), are likely associated with improved risk/benefit ratios over simultaneously combined therapies. Taken a step further, theory-derived clinical staging protocols presume that treatment needs correspond to the clinical progression of the disorder, and thus promote the use of less intensive treatments at earlier or less severe stages (McGorry, 2010). A flexible, long-sighted approach to treatment using these or other treatment algorithms is better suited for treatment of heterogeneous disorders than are fixed, one-size-fits-all methods.
We acknowledge that some of our recommendations run counter to beliefs that are commonly held by clinicians and clinical scientists. For example, we argue that a potential delay in short-term response, as can occur in a sequenced or staged treatment, might be superior to an accelerated response produced by a simultaneous combination treatment (as in Manber et al., 2008). Although rapid relief of distress is appreciated by patients and clinicians, there is currently little evidence that rapid symptom relief is associated with improved longer-term outcomes. Indeed, emerging evidence indicates that, in some contexts, rapid early improvement in depression can be associated with increased risk of relapse (Forand & DeRubeis, under review). Thus, a prolonged period of recovery might be beneficial for longer-term stability in some individuals.
We also argue that possible complications arising from long-term medication management indicates that the use of these approaches might best be minimized. This argument is contrary to the recommendations of some practice guidelines and the clinical impressions of many. However, there is reason to believe that the design of clinical trials and typical clinical practices might lead to biased estimates of the safety and effectiveness of medications. For example, there is evidence that the probability of relapse is elevated over baseline rates when medications are discontinued (Baldessarini et al., 1999; Frank et al., 2011; Moncrieff, 2006). However, evidence supporting the use of long-term maintenance medication is based on comparisons between groups that continue medications versus groups that discontinue, sometimes abruptly, which invariably produce large effects in favor of the medications. The natural conclusion is that the likelihood of sustained recovery is maximized by aggressive, long-term medication use. This biased understanding of medication effects has likely fostered the prolonged use of maintenance medications in clinical practice (Petty et al., 2006; Piek et al., 2010) despite the questionable effectiveness of this practice (Bockting et al., 2008). We believe it is essential for clinicians to challenge their conceptions about treatment based on a careful (re)reading of the available evidence. Conceptualizing the goal of treatment as long-term recovery, as opposed to rapid symptom reduction and tenuous stability, might prove helpful in this endeavor.
Although sequenced and staging approaches represent advances over simple and inflexible treatment models, the literature supporting their use has limitations that must be addressed before definitive recommendations can be made. One concern is that sequencing trials often provide evidence for only one possible treatment algorithm even though other procedures might be equal or superior. In clinical staging, the research is limited by incomplete knowledge about disease progression, as well as by unreliable and insensitive diagnostic instruments. For example, although some have called for interventions at the prodromal stage of bipolar and depressive disorders (Berk et al., 2010; Fava & Tossani, 2007), efforts to identify sensitive and specific markers of progression from prodromes to full-blown disorders have produced equivocal results (e.g., Fava & Tossani, 2007; Howes et al., 2011). Thus, the development of valid sequencing or staging treatments presents a number of new challenges.
Recent advances in trial design and analysis might help address some of these problems (Collins, Murphy, & Strecher, 2007). One promising design is “sequential multiple assignment randomized trials” or SMART. SMART designs are used to develop “adaptive” sequenced treatments, in which treatment dose and type are adjusted repeatedly based on time-varying information such as treatment response (Collins, Murphy, & Bierman, 2004; Murphy, 2005). The goal of SMART is to develop a series of decision rules that optimizes overall outcome. These trials comprise multiple treatment phases, with randomization to various next-step treatments at each phase. Posttrial analyses determine the most efficacious treatment path as well as predictors of response to initial and subsequent treatment steps. Replication and refinement of decision rules occurs in subsequent trials (Murphy, 2005). SMART designs are well-suited to analyzing difficult-to-treat disorders because they can identify effective sequences of treatments for individuals with particular prognostic or prescriptive features, including up-to-the-moment information about treatment adherence and response (e.g., Brooner et al., 2007; Marlowe, Festinger, Dugosh, Lee, & Benasutti, 2007).
Despite the promise of these designs, recent examples of SMART trials such as the STAR*D trial in depression (Rush et al., 2004), and the Clinical AntipsychoticTrials of Intervention Effectiveness (CATIE) for schizophrenia (Stroup et al., 2003) have produced somewhat disappointing results (Lieberman et al., 2005; Rush et al., 2006). Why promote these designs when two influential SMART trials have failed to improve overall outcomes? For one, more efficacious treatment algorithms might be identified if a greater variety of possible interventions are studied. These trials relied heavily (or in CATIE, completely) on sequences of pharmacological agents, all of which have similar mechanisms of action. In one sense, poor outcomes are not surprising, because non-responders to one drug are not likely to respond to another similar drug. Some evidence suggests that psychotherapy and medication work via different neurological pathways (Etkin, Pittenger, Polan, & Kandel, 2005; Linden, 2008; Roffman, Marci, Glick, Dougherty, & Rauch, 2005), perhaps indicating that response to one is poorly predicted by response to the other. Combining these approaches in a SMART design, in sequence or combination, allows a test of the relative strengths and weaknesses of medications and psychotherapy for different stages of treatment. Other treatment-enhancement methods, such as progress monitoring and practitioner feedback systems (e.g., Finch, Lambert, & Schaalje, 2001), have also been shown to improve outcomes in comparison to usual treatment (Shimokawa, Lambert, & Smart, 2010). Methods such as these could be integrated into combination treatment algorithms as a means of identifying those who might require a switch or adjunctive treatment, or redoubled efforts in their current treatment. Even though these approaches are time and resource intensive, they represent our best current option for optimizing and individualizing our treatments, and we encourage future investigators to consider them.
Throughout this chapter we have argued that the evidence supports a prominent role for evidence-based psychotherapy, either alone or in combination with medications. Although most studies of stepped treatments assume a medication-first approach (e.g., Fava & Ruini, 2006; Rodrigues et al., 2011), psychotherapy is an appropriate and advantageous first-phase treatment for many conditions. Nevertheless, the use of psychotherapy decreased in the United States from 16% in 1998 to 11% in 2007, while use of medications alone increased from 44% to 57%. Combined treatment with medications and psychotherapy has also decreased (Olfson & Marcus, 2010).
Several factors contribute to these trends. First, efforts of pharmaceutical companies to promote and market their products directly to the public have been extremely successful at increasing awareness and acceptance of medication treatments (An, Jin, & Brown, 2009; Bell, Taylor, & Kravitz, 2010; Wilkes, Bell, & Kravitz, 2000). Other factors include large differences in accessibility and availability between medication and psychotherapy (Hoge et al., 2007; Mark, Levitt, Buck, Coffey, & Vandivort-Warren, 2007), and limitations on coverage of psychotherapy by third-party payers (Teich & Buck, 2007). Still other factors, such as financial disincentives for psychiatrists to provide therapy (because medication management sessions are reimbursed at a higher pay per unit time), or cultural factors such as a wish for a “quick fix” might also contribute to this decline.
Clearly, improving access to psychotherapy in the United States would require extensive changes in culture, dissemination, and regulation. One model for such changes might be found in the United Kingdom's “improving access to psychological therapies” (IAPT) program, which is a national dissemination and training effort designed to increase access to government-mandated psychological services. As of 2011, IAPT has trained more than 3,600 CBT providers, and initial findings from evaluation studies of IAPT are encouraging (Clark, 2011). However, until such efforts achieve widespread support in the United States, the most feasible stepped treatments will be medication-first strategies, with psychotherapy used as an add-on, switch, or staged treatment when available. Insofar as short-term medication use is safe and efficacious for most individuals (Melnik, Soares, Puga, & Atallah, 2010; Papakostas, 2010; Vieta et al., 2010), these strategies are appropriate. However, we reiterate that long-term care must be considered carefully. Clinicians should develop plans for both inadequate response and maintenance treatment, and these should include options for decreasing or discontinuing medications, especially if psychosocial treatment is also available. We recommend that medications be used in ways that emphasize their relative strengths (i.e., short term symptom relief), and minimize their relative weaknesses (the costs, financial and otherwise, of long-term maintenance).
Our review has been limited to outpatient treatment of anxiety, mood, and psychotic disorders; however, there is little doubt that other psychiatric conditions would benefit from strategic thinking about combining medication and psychotherapy. Of particular importance are conditions that can be treated efficaciously with either medications or psychotherapy, such as substance use disorders (McHugh, Hearon, & Otto, 2010; Ross & Peselow, 2009). Childhood disorders also deserve careful attention. Recent high-profile research has highlighted the short-term efficacy of combined psychotherapy and medication for depression and anxiety in children (March et al., 2004; Walkup et al., 2008). However, because of the largely unknown effect of long-term treatment in children, concerns about increased risk of combination treatments are amplified, and more research in this area is urgently needed. As above, we encourage the development of strategic, adaptive treatment strategies for children designed to maximize long-term outcome while minimizing risk.
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1 For an exception see Rothbaum et al., 2006, who found that adding PE to sertraline did not significantly improve response compared to continuing sertraline in PTSD. It should also be noted that, with the exception of Hinton et al. (2005) and Rothbaum et al. (2006) these studies lack comparison groups who continue their previous treatment, making it difficult to separate the effects of augmentation versus the passage of time.
2 These findings do not provide evidence for harmful outcomes, per se. Rather, they identify conditions under which some individuals respond less well. It is possible that extreme values on these dimensions could make CBT toxic in some cases.
3 It is not always the case that combination treatment increases the chance of harm. Some evidence suggests that combined treatments have lower dropout rates than medication monotherapy (Cuijpers, Dekker, Hollon, & Anderson, 2009).
4 Unfortunately, due to the randomization strategy in STAR*D, too few patients were either augmented or switched to CT to permit a generalizable estimate of its efficacy as a second stage treatment.
5 Unless otherwise noted, all participants in the reviewed studies were treated with antipsychotic medications. Experimental treatments were generally added to “standard care,” which at minimum consisted of medication management and regular treatment visits, and in some cases also included case management and other services.
6 The estimates for the benefit of CBT are more modest when only higher-quality studies are considered (e.g., d = 0.22 for targeted symptoms; Wykes et al., 2008).