The combination of pharmacotherapy and psychotherapy in the setting of anxiety disorders is often viewed as a potential source of augmentation of clinical effects, with little attention paid to the potential occurrence of negative events. In most of the studies, however, if benefits ensued, they were modest and likely to fade. Further, 4 high-quality and well-designed individual studies suggest that the addition of a benzodiazepine or an antidepressant to cognitive behavioral treatment of anxiety disorders could be detrimental compared to placebo at follow-up. The aim of this review was to outline a novel hypothesis, which needs to be adequately tested but may shed some new light on this interaction. Any type of psychotropic drug treatment, particularly after long-term use, may increase the risk of experiencing additional psychopathological problems that do not necessarily subside with discontinuation of the drug or of modifying responsiveness to subsequent treatments. The changes are persistent and not limited to a short phase, such as in the case of withdrawal reactions, and cannot be subsumed under the generic rubrics of adverse events or side effects. The term ‘iatrogenic comorbidity' refers to unfavorable modifications in the course, characteristics, and responsiveness of an illness that may be related to treatments that were administered previously. The likelihood of iatrogenic comorbidity needs to be considered in clinical practice: The concurrent use of pharmacotherapy and psychotherapy may yield advantages in the short term, but its costs at some later point in time may largely outweigh such benefits.

Iatrogene Komorbidität · Psychotherapie · Antidepressiva · Benzodiazepine · Angststörungen

Die Kombination von Pharmakotherapie mit Psychotherapie bei Angststörungen wird oft als mögliche Ursache einer Verstärkung klinischer Effekte angesehen, ohne das mögliche Auftreten negativer Ereignisse zu beachten. In den meisten Studien waren die Vorteile, die daraus hervorgingen, jedoch nur geringfügig und ließen meist wieder nach. Des Weiteren schlagen 4 qualitativ hochwertige und gut angelegte Einzelstudien vor, dass die zusätzliche Gabe eines Benzodiazepins oder eines Antidepressivums zu einer kognitiven Verhaltenstherapie bei Angststörungen zu einer Verschlechterung im Vergleich zu Placebo beim Follow-up führt. Ziel dieses Übersichtsartikels war die Darstellung einer neuen Hypothese, die zwar noch entsprechend getestet werden muss, die aber ein neues Licht auf diese Interaktion werfen könnte. Jede Art von Behandlung mit einem psychotropen Medikament kann besonders nach längerfristiger Einnahme zu einer Erhöhung des Risikos für das Erfahren weiterer psychopathologischer Probleme, die nicht notwendigerweise mit dem Absetzen des Medikamentes abklingen, oder für ein verändertes Ansprechen auf weitere Behandlungen führen. Diese Veränderungen sind dauerhaft und nicht wie im Falle von Entzugsreaktionen auf eine kurze Phase begrenzt, und sie können auch nicht unter den Oberbegriffen «unerwünschte Ereignisse» oder «Nebeneffekte» zusammengefasst werden. Der Begriff «iatrogene Komorbidität» bezieht sich auf ungünstige Modifikationen im Verlauf, in den Eigenschaften und im Ansprechen einer Krankheit, die mit den vorher angewendeten Behandlungsmethoden in Zusammenhang stehen. Die Wahrscheinlichkeit des Auftretens einer iatrogenen Begleiterkrankung muss in der klinischen Praxis berücksichtigt werden: Die gleichzeitige Anwendung von Pharmakotherapie und Psychotherapie kann kurzfristig Fortschritte erzielen, ihre zu einem späteren Zeitpunkt auftretenden Kosten können diesen Nutzen jedoch weit überwiegen.

The combination of pharmacotherapy and psychotherapy in the setting of anxiety disorders is often viewed as a potential source of augmentation of clinical effects, with little attention paid to the potential occurrence of negative events. Forand et al. [2013] have reviewed the complex literature that is concerned with combining medication and psychotherapy in the treatment of major mental disorders. What emerges from their analysis is the fact that a combined treatment is not necessarily a better treatment and that there is the need of proper assessment tools for evaluating the pros and cons of each approach.

Uhlenhuth et al. [1969] examined the combinations of pharmacotherapy and psychotherapy in psychiatric disorders. They outlined 4 models of interaction: (a) addition (the effects of 2 interactions combined equals the sum of their individual effects), (b) potentiation (the effect of 2 interventions combined is greater than the sum of their individual effects), (c) inhibition (the effect of 2 interventions combined is less than each individual effect), (d) reciprocation (the effect of the 2 interventions combined equals the individual effect of the more potent intervention). Most of the studies that were reviewed were compatible with the reciprocal concept of interaction, and only a few, with an additive effect.

Subsequent research has substantiated these conclusions in mood and anxiety disorders. In some cases, psychotherapy and pharmacotherapy have partially additive effects, as was found to be the case with the sequential model in depression which consists of the use of pharmacotherapy in the acute phase and of psychotherapy in its residual phase [Guidi et al., 2016]. In most cases, the effects of the 2 interventions combined were equivalent to the effect of 1 intervention, particularly when follow-up evaluations were performed [Friedman and Thase, 2009; Forand et al., 2013; Biesheuvel-Leliefeld et al., 2015]. There are, however, some high-quality and well-designed individual studies in anxiety disorders that suggested that the addition of a benzodiazepine or an antidepressant to cognitive behavioral treatment could be detrimental compared to placebo at follow-up [Marks et al., 1993; Barlow et al., 2000; Haug et al., 2003; Nordahl et al., 2016]. We will briefly describe these studies and we will then discuss a recent conceptualization, subsumed under the rubric of iatrogenic comorbidity, which needs to be adequately tested but may shed some new light on the interaction between pharmacotherapy and psychotherapy. Finally, we will provide some cautionary clinical notes on the concurrent use of pharmacotherapy in the psychotherapeutic setting of anxiety disorders.

In the literature, we can find 4 randomized placebo-controlled trials in which a combination of medication (benzodiazepine [Marks et al., 1993] or antidepressant [Barlow et al., 2000; Haug et al., 2003; Nordahl et al., 2016]) and cognitive behavioral treatment was compared with each treatment alone in the management of different forms of anxiety disorders and yielded a detrimental interaction. These studies represent only part of the randomized controlled trials (RCT) that were performed with such a combination in anxiety disorders. In most of the cases benefits did not ensue or were modest and faded after treatment was completed [Forand et al., 2013].

The first of these studies is a cross-national trial conducted by Marks et al. [1993] in 2 centers, London and Toronto. In this research, 154 patients with a diagnosis of chronic panic disorder with agoraphobia were randomized to receive alprazolam and exposure (AE group), alprazolam and relaxation (AR group), placebo and exposure (PE group), or placebo and relaxation (PR group), the latter being a form of psychological placebo. The study was double-blind for drug and single-blind for psychological treatment. During a total period of 10 months, the patients had individual outpatient treatment for 8 weeks, taper of medication from week 8 to 16, and then follow-up to week 43. At the end of the treatment, both alprazolam and exposure were effective on non-panic measures, with exposure having twice the effect size of alprazolam. Interestingly, during tapering and follow-up, PE patients maintained and slightly increased their gains, whereas patients receiving alprazolam (whether in combination with exposure or relaxation) lost theirs, with AE being significantly worse than PE. This pattern is well represented by rates of relapse. Indeed, according to an index of global improvement, the percentages of patients who improved and did not relapse at the end of the study (week 43) were 36% in AE, 62% in PE, 29% in AR, and 18% in PR.

Subsequently, Barlow et al. [2000] conducted a 5-arm multicenter double-blind trial in which 312 patients affected by panic disorder with or without mild agoraphobia were treated with cognitive-behavioral therapy (CBT) alone, imipramine and medical management, CBT and imipramine, placebo and medical management, or CBT and placebo. The patients were assessed at the end of both an acute and a maintenance phase of 3 and 6 months, respectively, and after 6 months of follow-up. At the end of the treatment, all active groups were significantly better than the placebo group. However, after treatment discontinuation, only CBT alone and the combination of CBT and placebo were significantly superior to placebo, whereas imipramine-treated patients, with or without the addition of CBT, were significantly worse than those who received CBT, either alone or in combination with placebo. In particular, according to the intention-to-treat analysis of the Panic Disorder Severity Scale (PDSS) [Shear et al., 1997], the response rates at follow-up were 41% for CBT and placebo, 32.4% for CBT alone, 25% for CBT and imipramine, 19.7% for imipramine, and 9.1% for placebo.

In the study of Haug et al. [2003], 375 patients affected by generalized social phobia were treated for 24 weeks with sertraline and exposure (SE group), sertraline and general medical care, placebo and exposure (PE group), or placebo and general medical care. Exposure was given in 8 sessions for the first 12 weeks of treatment. The patients were evaluated at post-treatment (week 24) and at follow-up (week 52). At post-treatment, only sertraline and the combination of sertraline and exposure were significantly superior to placebo. At follow-up, patients in the PE and in the placebo groups had a significant improvement on several scales assessing social phobia and daily functioning, whereas patients treated with sertraline, either alone or in combination with exposure, had a significant deterioration as compared to treatment with both PE and placebo.

Most recently, Nordahl et al. [2016] conducted a comparative trial in which 102 patients with a primary diagnosis of social anxiety disorder with or without avoidant personality disorder were allocated to 4 different conditions: paroxetine and clinical management, cognitive therapy (CT), paroxetine and CT, or placebo and clinical management. The study was double-blind for the medication and placebo groups. Treatment with paroxetine and placebo lasted for 26 weeks, with tapering that commenced at week 23. All patients were assessed at post-treatment (week 12) and at the 12-month follow-up. At post-treatment, the results with CT did not differ significantly from those with the combination of CT and paroxetine. However, while the CT group improved significantly more than the groups treated with both paroxetine and placebo, no differences were observed between the results achieved with the combination of CT and paroxetine and with paroxetine alone. At follow-up, CT maintained its benefits and was significantly better than the combination of CT plus paroxetine on the Liebowitz Social Anxiety Scale (LSAS) [Liebowitz, 1987]. The groups treated with paroxetine (alone or in combination with CT) were no longer different from those treated with placebo. Furthermore, the recovery rates were greater with CT both at post-treatment and at follow-up. Specifically, the share of patients who achieved recovery at the 12-month follow-up was 68% in the CT group, 40% in the combination group, 24% in the paroxetine group, and 4% in the placebo group.

The results of all these studies are consistent in challenging the idea that the combination of pharmacotherapy and psychotherapy may improve the outcome in the treatment of anxiety disorders. Even when drugs may be more effective than placebo, and the combination of drugs and cognitive behavioral treatment may have some advantages over psychotherapy alone during treatment, only benefits obtained with psychotherapy are maintained and slightly improved thereafter. On the contrary, the effect of medications strictly depends on their administration and is lost after treatment discontinuation. Adding a benzodiazepine or an antidepressant to cognitive-behavioral treatment was found to be associated with greater rates of relapse at follow-up. This means not only that the combination of pharmacotherapy and psychotherapy is ineffective in the long-term treatment of anxiety disorders, but also that its effect could be detrimental. These results are rather important if we consider that anxiety disorders are often a disabling and chronic condition, necessitating a treatment that entails long-term efficacy.

There are adverse events that are limited to the period of psychotropic drug administration and effects that may persist long after their discontinuation. Any type of psychotropic drug treatment, particularly after long-term use, may increase the risk of experiencing additional psychopathological problems that do not necessarily subside with discontinuation of the drug or of modifying responsiveness to subsequent treatments [Fava et al., 2014; Offidani et al., 2014; Fava et al., 2016]. The term ‘iatrogenic comorbidity' refers to unfavorable modifications in the course, characteristics, and responsiveness of an illness that may be related to treatments administered previously [Fava et al., 2014; Offidani et al., 2014; Fava et al., 2016]. Such vulnerabilities may occur during treatment administration and/or manifest themselves after its discontinuation. The changes can be persistent and not limited to a short phase, such as in the case of withdrawal reactions [Fava et al., 2015a], and cannot be subsumed under the generic rubrics of adverse events or side effects.

We will illustrate some examples that are concerned with the use of antidepressant drugs; yet, similar phenomena have been described with other types of psychotropic drugs [Fava et al., 2014].

The best-known manifestation involves the phenomenon of switching into mania or hypomania; this is a well-known complication of the use of antidepressant drugs (ADs) in bipolar disorder [Tondo et al., 2010]. The occurrence of mania and other forms of behavioral activation in unipolar depression may unveil unrecognized bipolar illness or may be drug induced, since they may also occur in allegedly unipolar patients. A systematic review and meta-analysis concerned with excessive mood elevation and behavioral activation of children and adolescents disclosed that the rates of excessive arousal/activation with antidepressants were very high both in anxiety (13.8%) and in depression (9.8%), and much lower with placebos (5.2% vs. 1.1%, respectively) [Offidani et al., 2013a]. Furthermore, in almost half of the pediatric patients who participate in antidepressant trials, such reactions occur in the absence of a family history of bipolar disorder [Joseph et al., 2009]. Hence, the risk of developing behavioral activation may occur also with the use of ADs in anxiety disorders, particularly in younger patients, and the symptoms do not necessarily subside upon discontinuation of the AD [Joseph et al., 2009; Tondo et al., 2010; Offidani et al., 2013a]. Such findings are in line with the contraindications that occur with the use of ADs in bipolar disorder [Tondo et al., 2010].

Further, several side effects of ADs are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later. They encompass gastrointestinal symptoms (e.g., nausea, diarrhea, gastric bleeding, dyspepsia), hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disturbances (e.g., heart rate, QT interval prolongation, hypertension, orthostatic hypotension), genitourinary symptoms (e.g., urinary retention, incontinence), sexual dysfunction, hyponatremia, osteoporosis and risk of fractures, bleeding, central nervous system (CNS) disturbances (e.g., lowering of the seizure threshold, extrapyramidal side effects, cognitive disturbances), sweating, sleep disturbances, affective disturbances (e.g., apathy, switches, paradoxical effects), ophthalmic manifestations (e.g., glaucoma, cataract), and hyperprolactinemia [Carvalho et al., 2016]. At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity. For instance, long-term use of antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) may induce weight gain, after an initial period characterized by reduced appetite, and the increased weight does not necessarily recede upon AD discontinuation [Carvalho et al., 2016]. It has been suggested that an increase in exposure to antidepressants via a multitude of mechanisms may be a driving force for the obesity pandemic [Lee et al., 2016]. Similarly, the prevalence of sexual side effects can be as high as 50-70% among individuals taking SSRIs, and such effects may persist even after AD discontinuation [Carvalho et al., 2016].

Negative effects may also occur as a result of psychotherapeutic treatment, whether due to technique, patient or therapist variables, or inappropriate use [Barlow, 2010; Linden, 2013; Scott and Young, 2016]. Side effects of psychotherapy are difficult to recognize because of the number of variables that are involved, including the various stages of the psychotherapeutic process [Linden, 2013]. It has been underscored how much research on the negative aspects of psychotherapy is insufficient [Scott and Young, 2016].

Two other manifestations of iatrogenic comorbidity related to the use of ADs are, however, less known and may have particular importance in interpreting the interaction between pharmacotherapy and psychotherapy.

One is concerned with the fact that, in some cases, long-term use of ADs may enhance the biochemical vulnerability to depression and worsen its long-term outcome and symptomatic expression, decreasing both its likelihood of subsequent response to pharmacological treatment and the duration of symptom-free periods [Fava, 2003]. Clinical evidence has been found indicating that, even though ADs are effective in treating depressive episodes, they are less efficacious in recurrent depression and in preventing relapse. In many cases, antidepressants have been described as inducing adverse events such as withdrawal symptoms at discontinuation, onset of tolerance and resistance phenomena, and switch and cycle acceleration in bipolar patients. Unfavorable long-term outcomes and paradoxical effects (depression inducing and symptomatic worsening) have also been reported [Fava, 2003]. All these phenomena may be explained on the basis of the oppositional model of tolerance. Continued drug treatment may recruit processes that oppose the initial acute effect of a drug. When the drug treatment ends, these processes may operate unopposed, at least for some time, and increase vulnerability to relapse [Fava and Offidani, 2011]. In a meta-analysis concerned with the sequential use of pharmacotherapy and psychotherapy in depression, patients randomized to psychotherapy who had their antidepressants tapered and discontinued were significantly less likely to experience relapse/recurrence compared to patients with continuation of antidepressant medication [Guidi et al., 2016]. In an RCT of mindfulness-based cognitive therapy (MBCT) versus a waiting list control group [Bakker et al., 2016], the patients who increased their positive affects the most were the ones who did not take an AD.

The second manifestation of iatrogenic comorbidity involves persistent post-withdrawal symptoms after discontinuation of SSRIs. Chouinard and Chouinard [2015] have recently provided a classification of symptoms that may ensue upon discontinuation of psychotropic drugs, with particular reference to SSRIs and serotonin and noradrenalin reuptake inhibitors (SNRIs). They differentiated between withdrawal syndromes (i.e., symptoms occurring with a decrease or discontinuation of a drug that are new and not part of the original illness), rebound syndromes (i.e., a rapid return of the original symptoms at a greater intensity than before treatment), and post-withdrawal or tardive receptor sensitivity disorders (i.e., return of the original illness at a greater intensity and/or with additional features and/or symptoms related to emerging new disorders). Withdrawal symptoms following discontinuation of antidepressant treatment have been described with any type of AD, but particularly with SSRIs, venlafaxine, and duloxetine [Chouinard and Chouinard, 2015; Fava et al., 2015b]. They have been generally defined as ‘discontinuation syndromes', with the aim of avoiding any hint to the dependence potential of SSRIs that may affect marketing, but such definition is misleading since they are actually withdrawal reactions. The withdrawal syndrome is characterized by a broad range of somatic symptoms, such as headache, dizziness, fatigue, diminished appetite, sleep disturbances (i.e., vivid dreams and insomnia), somnolence, flu-like symptoms, nausea and vomiting, and genital hypersensitivity. Less common physical symptoms include myalgia, Parkinsonism, balance difficulties, and cardiac arrhythmias. Psychological symptoms may ensue as well: agitation, anxiety, panic attacks, dysphoria, confusion, and worsening of mood [Chouinard and Chouinard, 2015; Fava et al., 2015b]. Symptoms typically appear within 3 days of stopping antidepressant medication, even if this is done gradually, or initiating a medication taper. They may be easily misinterpreted as a sign of impending relapse or a need of keeping the same dosage. Untreated symptoms may be mild and resolve spontaneously in 1-3 weeks; in other cases, they may persist for months or even years, leading to what has been defined as persistent post-withdrawal disorder [Chouinard and Chouinard, 2015]. This latter form of iatrogenic comorbidity has been described with different classes of CNS drugs or substances (e.g., protracted insomnia for alcohol and benzodiazepine withdrawal, supersensitivity psychosis from antipsychotic drug treatment, dysphoria after cocaine and amphetamine use). Post-withdrawal disorders may resemble rebound syndromes, but these disorders persist for at least 6 weeks, in contrast to rebound symptoms, and may include new illness features [Chouinard and Chouinard, 2015]. Their prevalence is not known at the moment, due to their very recent definition. The high prevalence of mental disorders in the general population may also be an effect of the presence of disorders that are a consequence of previous pharmacological treatments [Cosci et al., 2015]: iatrogenic comorbidity that would require removal of drug treatment and is then interpreted as a justification for new treatment. For instance, much of the refractoriness to treatment of anxious depression may be actually due to secondary post-withdrawal disorders that are secondary to the use of ADs in anxiety disorders [Fava and Tomba, 2014].

Let us consider the psychotherapy/pharmacotherapy combination that resulted in detrimental effects in the 4 studies we synthesized [Marks et al., 1993; Barlow et al., 2000; Haug et al., 2003; Nordahl et al., 2016] in light of these new insights we have discussed.

All studies involved cognitive-behavioral treatment, albeit with somewhat different protocols. In all 4 studies, the detrimental effects occurred during follow-up and not at the end of the study. This may have 2 different interpretations. Either the process of learning during psychotherapy was decreased by the concurrent pharmacotherapy (e.g., exposure with the concurrent use of alprazolam may entail less enduring effects than with placebo) or iatrogenic comorbidity (to be fully disclosed after drug discontinuation) might have ensued. For instance, a patient who suffers from panic disorder may be successfully treated with a medication but, when the drug is tapered and discontinued, may manifest withdrawal syndromes that do not subside in a few weeks but persist for months or years and/or a rebound syndrome (e.g., panic that is far worse than that characterizing the pretreatment phase) and/or a new syndrome (e.g., depression) which he/she never experienced before drug treatment.

SSRIs [Belaise et al., 2014; Chouinard and Chouinard, 2015; Fava et al., 2015b], which were used in 2 studies, and alprazolam [Fava, 1988; Cloos et al., 2015; Zito, 2015] have been specifically linked to iatrogenic comorbidity and addictive properties. In one of the studies [Marks et al., 1993], the effects of discontinuing alprazolam were specifically investigated [O'Sullivan et al., 1996]. Alprazolam patients deteriorated on anxiety, panic, depression, and phobia, whereas serious withdrawal symptoms did not occur (probably due to slow tapering). The deterioration in patients treated with alprazolam persisted up to 6 months post-taper [O'Sullivan et al., 1996].

It is thus conceivable that the concurrent use of pharmacotherapy and psychotherapy may yield advantages in the short term, but its costs in terms of iatrogenic comorbidity at some later point in time largely outweigh such benefits. However, this is simply a hypothesis that needs to be considered among various other potential explanations, such as the possibility that medications may suppress the activation of fear-related cognitions and/or may interfere with the consolidation of fear-incongruent learning during exposure [Forand et al., 2013].

Richardson and Doster [2014] suggested the consideration of 3 dimensions in the process of evidence-based decision: baseline riskof poor outcomes from an index disorder without treatment, responsiveness to the treatment option, and vulnerability to the adverse effects of treatment. A rational approach to treatment takes into account the balance between potential benefits and adverse effects applied to the individual patient [Fava et al., 2015c]. Unfortunately, the prescribing clinician is driven by an overestimated consideration of potential benefits, paying little attention to the likelihood of responsiveness and to potential vulnerabilities in relation to the adverse effects of treatment [Fava et al., 2015c]. Appraisal of adverse effects relies primarily on observational studies and data from routine clinical practice and may not emerge from RCTs, unless these effects occur early in the course of treatment and are specifically investigated [Vanderbroucke and Psaty, 2008]. Further, detection of adverse events requires sensitive clinimetric indices that depart from conventional assessment strategies geared to demonstrating efficacy against placebo [Fava and Bech, 2016; Bech, 2016; Piolanti et al., 2016]. Finally, the role of financial conflicts of interest in shaping the literature appraisal is an increasing source of concern [Fava, 2016]. While the dependence potential of benzodiazepines is widely acknowledged, the clinician is less likely to be aware that the same, if not worse, phenomenon may occur with ADs [Chouinard and Chouinard, 2015; Fava et al., 2015b; Starcevic et al., 2015]. Discontinuation syndromes of SSRIs and SNRIs are actually withdrawal reactions [Chouinard and Chouinard, 2015; Fava et al., 2015b] and at least as bad as those that may occur with benzodiazepines. In a systematic review of the direct comparison between ADs and benzodiazepines in anxiety disorders, the superiority of benzodiazepines, both in terms of efficacy and side effect profile, emerged [Offidani et al., 2013b]. This was in sharp contrast with meta-analyses and guidelines that were based on such meta-analyses [Cosci et al., 2015; Starcevic et al., 2015].

Despite the fact that, in real-world clinical practice, most of the patients with anxiety disorders already assume some form of psychotropic drug treatment, clinical psychologists have little familiarity with psychopharmacology and are substantially unaware of subtle and yet pervasive potential effects of psychotropic drugs in their patients [Guidi and Fava, 2014]. It is a major flaw in their clinical training that appears to occur around the world and which requires urgent attention.

The concept of iatrogenic comorbidity has heuristic value and may alert the clinician to the potential occurrence of detrimental effects during treatment of anxiety disorders.

No funding was received by the authors to carry out the present review. G.A.F. and G.B. have no conflict of interest to declare. F.C. received in 2010 an award from Pfizer in the framework of the Global Research Awards for Nicotine Dependence (GRAND).

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