During the past 2 decades, psychiatry has benefited from an increasingly evidence-based perspective and a proliferation of safer, more tolerable, and perhaps more effective treatments. Despite these advances, however, treatment outcomes are not substantially better than they were a quarter of a century ago.1 Treatment resistance remains a serious problem across psychiatric diagnoses.2 One likely reason that outcomes have not improved substantially is that as the pendulum has swung from a psychodynamic framework to a biological one, the impact of meaning (ie, the role of 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 psychopharmacology explicitly acknowledges and addresses the central role of meaning and interpersonal factors in pharmacological treatment.3 This approach recognizes that many of the core discoveries of psychoanalysis (the unconscious, conflict, resistance, transference, defense) are powerful factors in the complex relationships between the patient, the illness, the doctor, and the medications. In many cases, these factors are largely concordant with treatment and do not need to be addressed in order for treatment to be effective. However, in patients who are treatment-resistant, it is likely that psychodynamic factors (that may well be unconscious) are deeply at odds with therapeutic goals.
Dynamic factors in psychopharmacology
There is currently a small but impressive evidence base that shows that psychological and interpersonal factors play a pivotal role in pharmacological treatment responsiveness.
An analysis of the data from a large, NIMH-funded, multicenter, placebo-controlled trial of the treatment of depression found a provocative treater x medication effect.4 While the most effective prescribers who provided active drug (antidepressant) 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 prescribers had with active drug. This suggests 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A series of meta-analyses of FDA databases (examining an unbiased sample, including negative, unpublished studies) shows that although antidepressant medications are effective, the placebo effect accounts for between 76% and 81% of treatment effectiveness.5-7 Placebo does not mean imaginary or untrue. Placebos produce real, clinically significant, and objectively measurable improvements in a wide range of conditions, including psychiatric disorders.8,9 And, placebo responses produce measurable changes in brain activity that largely overlap medication-induced improvements.10 The patient’s desire to change and a positive transference to the doctor and his or her medications can mobilize profound self-healing capacities—capacities that appear to be even more potent than the medication’s active ingredient.
Although most of our patients ask us for help, many are conflicted about getting well if their illness has created some conscious or unconscious benefit. If a patient is not “ready to change,” it is unlikely that a medication, however potent, will produce a therapeutic effect. Beitman and colleagues11 found, in a placebo-controlled trial, that patients who received a benzodiazepine for anxiety and who were highly motivated to change had the most robust response. However, placebo recipients who were highly motivated to change had a greater reduction in anxiety than patients who took the active drug but were less ready to change. Readiness to change was found to be the single most powerful determinant of treatment effectiveness—even more potent than type of therapy (ie, active vs placebo).
In 1912, Freud12 noted that the unobjectionable positive transference (consisting of such things as the patient’s belief in the doctor’s salutary intentions, the wish to use the doctor to get better, and the desire to win the doctor’s love or esteem by genuinely trying to get better) was a key factor in the patient’s ability to overcome symptoms. This unobjectionable positive transference, ie, the therapeutic alliance, is one of the most potent ingredients of treatment.12,13 In a large, placebo-controlled, multicenter trial of treatments of depression, Krupnick and colleagues14 showed that patients were most likely to respond when they received the active drug and had a strong therapeutic alliance. Those least likely to respond when given placebo had a poor therapeutic alliance. Patients who received placebo and who had a strong treatment alliance had a significantly more robust therapeutic response than patients who received an antidepressant but had a poor therapeutic alliance. Taken together, these studies examining the relative effectiveness of biologically and symbolically active aspects of the medication suggest that meaning effects in psychopharmacology are more potent than biological effects.4-7,11,13,14
Just as positive transferences to the doctor or drug lead to positive responses, negative transferences are likely to lead to negative responses. Patients who have been abused or neglected by caregivers in the past or those who otherwise feel vulnerable to authority figures (either because of social disadvantage or a propensity to acquiesce) are prone to nocebo responses.15,16 The obverse of the placebo response, nocebo responses occur when patients expect (either consciously or unconsciously) to be harmed. Many patients who experience intolerable adverse effects to medications are nocebo responders. It comes as no surprise that these patients are likely to become treatment-resistant.
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