False Negative Impacts on Drug Trial Outcomes

In the pharmacological research literature, much has been made about the placebo effect and its impact on drug effectiveness measures.  Individuals who might be highly suggestible may respond positively to a drug even though it may have no appreciable biological effect on them.  Thus, a drug trial that did not take this effect into account could report effectiveness results that are biased upward because of these false positives.

On the other hand, little attention has been devoted to the adverse impact that false negatives can have on drug effectiveness measures.  Some trial participants may be treatment resistant, and even though a drug might have biological benefits, various psychosocial factors prevent these benefits from showing up.

There are complex relationships among the trial participant, the malady, the medication, and the treatment provider.   For some trial participants, factors such as conflicts, defense mechanisms, resistance, and transference at the subconscious level may contribute to false negatives.  These psychodynamic factors can be deeply at odds with positive therapeutic outcomes and should be taken into account in any drug trials.

A large NIMH-funded study has shown a medication/treatment-provider effect*.  The most effective providers who administered an active antidepressant had the best outcomes, but the most effective one-third of providers had better outcomes with placebos than the least effective one-third of providers administering the active drug.

This study strongly suggests that the relationship between treatment provider and trial participant can play an important role in drug trial outcomes.   A trial participant’s positive transference to the treatment provider can mobilize self-healing capacities (i.e., placebo effect) while a negative transference may lead to a nocebo effect.

Furthermore, participants, who are not manifestly resistant to symptom reduction, may nevertheless be motivated to resist virtually any treatment provider on the basis of a transference experience whereby the provider is regarded as untrustworthy or in some way dangerous. Such participants might surreptitiously not adhere to the trial protocol  so as not to feel under the control of what they perceive to be a “malevolent” provider.

Then there are trial participants, psychologically resistant to medications themselves, who may have conscious or subconscious factors that interfere with the medication’s effect.  Resistance can once again take the form of drug trial protocol non-adherence but also includes participants who are nocebo responders experiencing adverse responses to a medication.

A trial participant’s desire to change is an important determinant of outcomes.  Even for participants who enter a trial ostensibly to be helped, some may be conflicted about improving if their malady has created some conscious or subconscious benefits**. Trial participants perceiving significant benefits for their symptoms may, consequently, be reluctant to relinquish these symptoms.  Symptoms, in these cases, may thus be an important defense mechanism inhibiting positive outcomes.

For example, a study*** showed that patients receiving a benzodiazepine for anxiety, who were highly motivated to change had the most robust response to the drug, while placebo recipients who were highly motivated had a greater reduction in anxiety than patients taking the active drug who were less ready for change.

The observations above have implications for pharmacological research applied to stuttering.  While the root cause of stuttering is some neurological malfunction of the brain, nevertheless various psychological factors eventually come into play.  And these factors may interact with a treatment protocol affecting trial outcomes.

In a following post, we will discuss a framework for the correction of false negatives in pharmacological trials.

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*  McKay KM, Imel ZE, Wampold BE. Psychiatrist effects in the psychopharmacological treatment of depression. J Affect Disord. 2006;92:287-290.

**  See an interesting blog post in this regard:

 http://thestutteringbrain.blogspot.com/2007/10/who-says-stuttering-has-no-benefit.html

***  Beitman BD, Beck NC, Deuser WE, et al. Patient Stage of Change predicts outcome in a panic disorder medication trial. Anxiety. 1994;1:64-69.


Copyright 2011

Stuttering and Gene Therapies

Stem cell therapies are generally oriented toward the remediation of some chemical deficiency in a living organism.  For example, Parkinson’s victims are deficient with regard to the production of dopamine and Type 1 diabetics lack a capability for producing insulin.

The hope of stem cell therapy is that stem cells can be used to make cells producing the vital chemical that is lacking.  These cells can then be injected into the relevant organs and, as they took hold, the symptoms of the disease would disappear (hopefully permanently). 

 A recent study in the journal Nature (November 6, 2011), describes research in which stem cells derived from human embryos were used to treat Parkinson’s disease in rodents.  Previous approaches had failed because human derived dopamine cells did not perform efficiently when transplanted into animals; in addition, the transplantations triggered the growth of unwanted tumor-like structures.

In these past experiments, two specialized proteins, known as growth factors, were added to turn embryonic stem cells into dopamine-producing nerve cells.  But the recent  Nature study added a third substance that activated a crucial biological pathway in the embryonic cells, leading to human dopamine cells that functioned more effectively and that did not lead to tumor-like structures. 

What does this study have to do with stuttering?  In many cases, stuttering is a result of excessive dopaminergic activity in parts of the brain dealing with speech and its timing rather than some neurochemical deficiency.  So, at first glance, it may appear that stem cell therapies might not be relevant.

However, an insufficiency of GABAergic activity in these areas of the brain may be a contributing factor leading to the dopaminergic overactivity (see the blog post entitled “Stuttering and Neurotransmitters,“ August 25, 2010).  So if stem cells could be coaxed into generating GABA-producing cells, then, in principal a gene therapy approach to stuttering might be feasible.

The problems with gene therapies applied to stuttering are that there are essentially no animal models with which to test these therapies (perhaps the “stuttering mice?”) and that such intrusive treatments may not be deemed warranted for a “mild” malady such as stuttering.  At any rate, we should expect a relatively long time horizon before any such treatments become available.  And when they do, we might expect them to be a byproduct of therapies for the treatment of conditions such as schizophrenia.