22 PSYCHIATRIC TIMES SEPTEMBER 2011 www.psychiatrictimes.com CLINICAL

Psychodynamic Psychopharmacology Addressing the Underlying Causes of Treatment Resistance

by David Mintz, MD perspective and a proliferation of than they were a quarter of a century stantially is that as the pendulum has safer, more tolerable, and perhaps ago.1 Treatment resistance remains a swung from a psychodynamic uring the past 2 decades, psy- more effective treatments. Despite serious problem across psychiatric framework to a biological one, the chiatry has benefited from an these advances, however, treatment diagnoses.2 One likely reason that impact of meaning (ie, the role of D increasingly evidence-based outcomes are not substantially better outcomes have not improved sub- psychosocial factors in treatment- refractory illness) has been relatively neglected, and psychiatrists have lost some potent tools for working with the most troubled patients. Psychodynamic psychopharma- cology explicitly acknowledges and addresses the central role of meaning and interpersonal factors in pharma- cological treatment.3 This approach recognizes that many of the core dis- coveries of psychoanalysis (the un- conscious, conflict, resistance, trans- ference, defense) are powerful fac- tors in the complex relationships between the patient, the illness, the doctor, and the medications. In many cases, these factors are largely con- cordant with treatment and do not need to be addressed in order for treatment to be effective. However, in patients who are treatment-resis- tant, it is likely that psychodynamic factors (that may well be uncon- scious) are deeply at odds with thera- peutic goals. Dynamic factors in psychopharmacology There is currently a small but im- pressive evidence base that shows that psychological and interpersonal factors play a pivotal role in pharma- cological treatment responsiveness. An analysis of the data from a large, NIMH-funded, multicenter, placebo-controlled trial of the treat- ment of depression found a provoc­ ative treater x medication effect.4 While the most effective prescrib- ers who provided active drug (anti­ depressant) had the best results, it was also true that the most effective one-third of prescribers had better outcomes with placebos than the least effective one-third of prescrib- ers had with active drug. This sug- gests that how the doctor prescribes is actually more important than what the doctor prescribes! A series of meta-analyses of FDA databases (examining an unbiased sample, including negative, unpub- lished studies) shows that although antidepressant medications are ef- fective, the placebo effect accounts for between 76% and 81% of treat- ment effectiveness.5-7 Placebo does not mean imaginary or untrue. Place- bos produce real, clinically signifi- SEPTEMBER 2011 PSYCHIATRIC TIMES 23 CLINICAL www.psychiatrictimes.com

cant, and objectively measurable im- potent than biological effects.4-7,11,13,14 conflicted about getting better, which Patients who are treatment-resis­ provements in a wide range of Just as positive transferences to may manifest as treatment resistance. tant from medication typically pre­ conditions, including psychiatric dis- the doctor or drug lead to positive Patients who need their symp- sent as hungry for medications. Al- orders.8,9 And, placebo responses responses, negative transferences are toms to communicate something that though they take the medications produce measur­able changes in brain likely to lead to negative responses. they cannot put into words will be and may report symptom reduction, activity that largely overlap medica- Patients who have been abused or similarly ambivalent.2 When symp- these patients do not function better tion-induced improvements.10 The neglected by caregivers in the past or toms constitute an important defense with pharmacotherapy; in fact, some patient’s desire to change and a posi- those who otherwise feel vulnerable mechanism, patients are also likely seem to get worse. A psychodynamic tive transference to the doctor and to authority figures (either because to resist medication effects until they psychopharmacologist is mindful his or her medications can mobilize of social disadvantage or a propen- have developed more mature defens- that there are countless ways these profound self-healing capacities— sity to acquiesce) are prone to noce- es or more effective ways of coping.3 medications may serve counterthera- capacities that appear to be even bo responses.15,16 The obverse of the Patients who are not resistant to peutic and/or defensive aims. more potent than the medication’s placebo response, nocebo responses symptom reduction may nonetheless Patients may use pills defensively active ingredient. occur when patients expect (either be motivated to resist the doctor on to disavow responsibility for their Although most of our patients ask consciously or unconsciously) to be the basis of a transference experi- feelings and actions.18 This common- us for help, many are conflicted harmed. Many patients who experi- ence of the doctor as untrustworthy ly occurs in the case of primitively about getting well if their illness has ence intolerable adverse effects to or even dangerous. Such patients of- organized and character-disordered created some conscious or uncon- medications are nocebo responders. ten pains­takingly negotiate the medi- patients who rely on splitting and scious benefit. If a patient is not It comes as no surprise that these cation, dosing, and timing of medi- projective dynamics. Such patients “ready to change,” it is unlikely that patients are likely to become treat- cations (so as not to feel under the tend to see things strictly in black a medication, however potent, will ment-resistant. control of the malevolently experi- and white and frequently defend produce a therapeutic effect. Beit- enced doctor) or surreptitiously man- against feeling intolerably and com- man and colleagues11 found, in a Pharmacological treatment age their own regimen (by taking pletely bad by displacing all of placebo-controlled trial, that patients resistance more or less than the prescribed the “badness” onto the “other” in a who received a benzodiazepine for From a psychodynamic perspective, dose). Needless to say, if they are not relationship. anxiety and who were highly moti- patients may be seen as resistant to taking a therapeutic dose, they lessen After receiving a prescription for vated to change had the most robust medication or resistant from medica- their chances of a therapeutic re- mood stabilizers for bipolar disorder, response. However, placebo recipi- tion. These 2 broad categories of sponse. As noted, if these patients a patient prone to splitting as a de- ents who were highly motivated to pharmacological treatment resis- cannot resist the doctor’s orders, fense will often experience an imme- change had a greater reduction in tance tend to have different underly- then their bodies may unconsciously diate reduction in dysphoria. A psy- anxiety than patients who took the ing dynamics and may require differ- do the resisting for them, which leads chopharmacologist who is inclined active drug but were less ready to ent kinds of interventions. to nocebo effects. (Please see Treatment Resistance, page 24) change. Readiness to change was Patients who are resistant to med- found to be the single most powerful ications have conscious or uncon- determinant of treatment effective- scious factors that interfere with the ness—even more potent than type of desired effect of medications. Often, therapy (ie, active vs placebo). resistance in this category takes the In 1912, Freud12 noted that the un- form of nonadherence but also in- objectionable positive transference cludes patients who repeatedly expe- (consisting of such things as the pa- rience adverse responses to medica- tient’s belief in the doctor’s salutary tions (ie, nocebo responders). intentions, the wish to use the doctor In contrast, patients who are resis- to get better, and the desire to win the tant from medications more typically doctor’s love or esteem by genuinely are eager to receive the medication trying to get better) was a key factor or some benefit that the patient as- in the patient’s ability to overcome cribes to the medication. For such symptoms. This unobjectionable patients, pills may appear to relieve positive transference, ie, the thera- symptoms, but they do not contribute peutic alliance, is one of the most to an improvement in the patient’s potent ingredients of treatment.12,13 In quality of life. Resistance to med­ a large, placebo-controlled, multi- ications and resistance from medi­ center trial of treatments of depres- cations are not mutually exclusive, sion, Krup­nick and colleagues14 and some patients present with both showed that patients were most like- dynamics. ly to respond when they received the In 1905, Freud17 described the active drug and had a strong thera- psychodynamic concept of resis- peutic alliance. Those least likely to tance and concluded that many pa- respond when given placebo had a tients were unconsciously reluctant poor therapeutic alliance. Patients to relinquish their symptoms or were who received placebo and who had a unwittingly driven, for transference strong treatment alliance had a sig- reasons, to resist the doctor. These nificantly more robust therapeutic same dynamics may apply in phar- response than patients who received macotherapy. Although suffering an antidepressant but had a poor greatly, patients may find good uses therapeutic alliance. Taken together, for their symptoms. Patients who de- these studies examining the relative rive significant secondary gains from effectiveness of biologically and sym­ their symptoms (eg, they are relieved bolically active aspects of the medi- from various burdens, or they re- cation suggest that meaning effects ceive care rather than neglect as a in psychopharmacology are more result of their illness) can be deeply 24 PSYCHIATRIC TIMES SEPTEMBER 2011 www.psychiatrictimes.com CLINICAL

Treatment Resistance uses of medications (resistance potential sources of resistance to the understand complex situations that Continued from page 23 from medications) medication or the doctor are under- more than anything else lends its par- • Identify and contain countertrans- stood, they must be addressed. If they ticular power to our discipline and to think both psychodynamically and ference involving prescribing19 are clear at the outset, they must be gives us skills for working with par- biologically will recognize that the Avoid a mind-body split. A psy- addressed preemptively. In this way, ticularly troubled patients. reduction in dysphoria may be oc- chodynamic psychopharmacologist an alliance is made with the patient curring not because of the medica- recognizes that a rigid mind-body before massive resistance is sparked. Dr Mintz is Director of Psychiatric Education at tion but because it allows the patient dualism is a fantasy. Experiences, Negative transferences must be iden- the Austen Riggs Center in Stockbridge, Mass. to create a stable split within which feelings, ideas, and relationships tified and worked through. Empathic The author reports no conflicts of in­terest he can remain good while all badness change the structure and function of interpretation of nocebo responses concerning the subject matter of this article. is located in “my bipolar.” the brain just as the state of the brain can resolve adverse effects.21 References While patients may feel better, influences experience. A psychody- Be aware of countertherapeutic uses of medications (resistance 1. Kessler RC, Berglund P, Demler O, et al; National they actually do worse. No longer namic psychopharmacologist con- from Comorbidity Survey Replication. The epidemiology of feeling personally responsible for siders that a positive or negative medications). Countertherapeutic major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. symptomatic behavior, they give medication response may be a direct uses of medications should also be 2003;289:3095-3105. their worst instincts free rein, exacer- action of the pill or may be mediated interpreted. As a prescriber, you 2. Plakun EM. A view from Riggs—treatment resis- bating personal and interpersonal by the meanings the patient attaches might tolerate some irrational use of tance and patient authority: I. A psychodynamic per- spective. J Am Acad Psychoanal Dyn Psychiatry. chaos. It is important not to collude to the pill. medications if the patient is working 2006;34:349-366. unwittingly with these legally com- Mind-body integration also means through an issue that interferes with 3. Mintz D, Belnap B. A view from Riggs: treatment resistance and patient authority—III. What is psy- petent patients whose treatment re- that psychotherapy and psychophar- a healthier use of those medications. chodynamic psychopharmacology? An approach to sistance relates to defensive use of macology will need to be well-inte- There comes a time, however, when pharmacologic treatment resistance. J Am Acad Psy- choanal Dyn Psychiatry. 2006;34:581-601. medications. Rather, it is crucial to grated so that psychopharmacologi- discontinuation of a counterthera- 4. McKay KM, Imel ZE, Wampold BE. Psychiatrist ef- empathically help them understand cal interventions facilitate the psy- peutic medication may become a fects in the psychopharmacological treatment of that although they are ill, they remain chotherapy and so that the therapy condition of continued pharmaco- depression. J Affect Disord. 2006;92:287-290. 5. Kirsch I, Sapirstein G. Listening to Prozac but hear- responsible for their choices. helps the patient become conscious logical treatment. ing placebo: a meta-analysis of antidepressant Medications can be used defen- of psychological sources of pharma- Identify and contain counter- medication. June 26, 1998. http://psycnet.apa. org/?fa=main.doiLanding&doi=10.1037/1522- sively in myriad ways. Patients who cological treatment resistance. Ef- transference in prescribing. When 3736.1.1.12a. Accessed June 24, 2009. experience people as dangerous and fective psychopharmacological in- patients struggle with overwhelming 6. Khan A, Warner HA, Brown WA. Symptom reduc- tion and suicide risk in patients treated with placebo unreliable may attempt to replace terventions to treatment nonresponse dysphoric affects, they often evoke in antidepressant clinical trials: an analysis of the people with pills. Still other patients might include an increase in frequen- corresponding effects in their pre- Food and Drug Administration database. Arch Gen 2 Psychiatry. 2000;57:311-317. may feel that any “negative” feeling cy of appointments rather than an scribers. It seems likely that a medi- 7. Kirsch I, Moore TJ, Scoboria A, Nicholls SS. The 20 is pathological and should be extin- increase in medication dosage. cation regimen made up of, for ex- emperor’s new drugs: an analysis of antidepressant guished. If accepted at face value, Know your patient. Sir William ample, 3 antidepressants, 4 mood medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5, Article 23. this can lead a well-meaning psy- Osler, the father of modern medi- stabilizers, 3 antipsychotics, and 1 or 2002. http://www.journals.apa.org/prevention/ chiatrist toward an ever more com- cine, remarked that “it is much more 2 anxiolytics, has in part been shaped volume5/pre0050023a.html. 8. Brody H. Placebos and the Philosophy of Medicine. plex and burdensome medication important to know what sort of pa- by countertransference. Such a regi- Chicago: University of Chicago Press; 1977. regimen that actually contravenes tient has a disease than to know what men is unlikely to be effective and is 9. Moerman DE, Jonas WB. Deconstructing the pla- cebo effect and finding the meaning response. Ann healthy developmental aims. sort of disease a patient has.” This is perhaps aimed at treating the doc- Intern Med. 2002;136:471-476. When pills are used to manage de- a central tenet of psychodynamic tor’s anxiety rather than the patient’s; 10. Mayberg HS, Silva JA, Brannan SK, et al. The velopmentally appropriate feelings, psychopharmacology. Practically, the patient is not the only source of functional neuroanatomy of the placebo effect. Am J Psychiatry. 2002;159:728-737. such as loneliness, disappointment, this means that the pharmacologist treatment resistance. A psychody- 11. Beitman BD, Beck NC, Deuser WE, et al. Patient sadness, frustration, or anger, pa- should get a thorough developmental namic psychopharmacologist recog- Stage of Change predicts outcome in a panic disor- der medication trial. Anxiety. 1994;1:64-69. tients lose important opportunities and social history to make reason- nizes that the psychiatric relationship 12. Freud S. The dynamics of transference. The that might lead to improved internal able hypotheses about the psychoso- is an encounter between a big mess Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol 12. London: Hogarth controls and increased affective or cial origins of the patient’s treatment and an even bigger mess. An attitude Press; 1912/1958. interpersonal competence. Patient- resistance. The prescriber should al- of humility along with periodic con- 13. Blatt SJ, Zuroff DC. Empirical evaluation of the hood may be reinforced. so directly assess the patient’s atti- sultation about difficult cases helps assumptions in identifying evidence-based treat- ments in mental health. Clin Psychol Rev. 2005;25: tudes about medications (fears of manage irrational prescribing. 459-486. Elements of psychodynamic dependency, worries about being 14. Krupnick JL, Sotsky SM, Simmens S, et al. The role of therapeutic alliance in psychotherapy and psychopharmacology “turned into a zombie,” and so on). Conclusion pharmacotherapy outcome: findings in the National Psychodynamic psychopharmacol- This not only helps assess potential There are many sources of pharma- Institute of Mental Health Treatment of Depression Collaborative Research Program. J Consult Clin Psy- ogy represents an integration of sources of resistance, but it also lets cological treatment resistance. When chol. 1996;64:532-539. biolog­ical psychiatry and psychody- the patient know the prescriber is in- treatment resistance arises from the 15. Hahn RA. The nocebo phenomenon: scope and foundations. In: Harrington A, ed. The Placebo Effect: namic insights and techniques. terested in him as a person, which level of meaning, interventions are An Interdisciplinary Exploration. Cambridge, MA: Psycho­dy­namic psychopharmacol- may enhance the alliance. not likely to be successful unless Harvard University Press; 1997. ogy provides little guidance about Attend to ambivalence about loss they address problems at the level of 16. McNair DM, Fisher S, Kahn RJ, Droppleman LF. Drug-personality interaction in intensive outpatient what to prescribe; instead, it helps of symptoms. Identify potential mean­ing. Psychiatric care providers treatment. Arch Gen Psychiatry. 1970;22:128-135. prescribers know how to prescribe to sources of ambivalence about symp- who operate from either a dogmatic 17. Freud S. A case of hysteria. The Standard Edition of the Complete Psychological Works of Sigmund improve outcomes. toms, such as secondary gains, and psychotherapeutic paradigm or a Freud. Vol 7. London: Hogarth Press; 1905/ 1958. There are 6 principles for psycho- communicative or defensive value of psychopharmacological paradigm 18. Gibbons FX, Wright RA. Motivational biases in causal attributions of arousal. J Pers Soc Psychol. dynamically informed pharmaco- symptoms. It may be helpful at the are hobbled by having access to only 1981;40:588-600. logical practice with treatment-resis- point of intake to ask the patient what half the patient. Psychodynamic psy­ 19. Kayatekin MS, Plakun EM. A view from Riggs: tant patients3: he would stand to lose if treatment cho­pharmacology combines rational treatment resistance and patient authority, Paper X: from acting out to enactment in treatment resistant • Avoid a mind-body split was successful. (The same question prescribing with tools to identify and disorders. J Am Acad Psychoanal Dyn Psychiatry. • Know your patient posed in the middle of a treatment address irrational interferences with 2009;37:365-382. 20. Ankarberg P, Falkenström F. Treatment of depres- • Attend to the patient’s ambiva- may be colored by the doctor’s frus- healthy and effective use of medica- sion with antidepressants is primarily a psychologi- lence about the loss of symptoms tration and is more likely to produce tions. We should not neglect psycho- cal treatment. Psychother Theory Res Pract Training. 2008;45:329-339. • Address negative transferences a negative response.) dynamic contributions that enhance 21. Mintz D. Meaning and medication in the care of and resistance to medications Address negative transferences the integration of meaning and biol- treatment-resistant patients. Am J Psychother. • Be aware of countertherapeutic and resistance to medications. Once ogy. It is the capacity to integrate and 2002;56:322-337. ❒