D-Cycloserine Application in Psychiatry, Research Paper Example

Question: Is D-Cycloserine needed in combination with exposure based therapy for the treatment of anxiety disorders?

Importance of Research Question. 

D-cycloserine proved efficient in facilitation of fear extinction in animal research; findings summarized from numerous experiments suppose DCS having visible effect on the NMDA receptor complex responsible for resistance to fear extinction, ultimately assisting the exposure therapy process (Rothbaum, 2008; Kushner et al., 2007; Ressler et al., 2004). These positive findings enabled researchers of psychiatry suppose a similar effect on fear extinction with the application of DCS in combination with exposure therapy for humans (Daveney et al., 2009; Hofman, 2007). However, the body of knowledge on the effect of DCS as a potential adjunct for fear extinction in humans is still small; the modern research is focused on finding proper dosing of DCS that shows effect on fear extinction, researching of the DCS effect on the human cognitive and behavioral mechanisms in the long run as well as identifying the set of conditions under which DCS combined with exposure therapy may have positive effect on treatment of anxiety disorders for humans.

Overview

Traditionally, there was a common disapproval of combined pharmacotherapy and psychotherapy in treatment of human anxiety disorders as unimodal treatment appeared more efficient than the mixture of approaches (Zwanzger et al., 2008; Hofmann, 2007). However, initial small-scale and further middle-scale studies reported the comparative advantage of exposure-based CBT and administration of DCS for treatment of described disorders. Though proper dosage of DCS and bounds of the DCs augmentation effects are not yet known, DCS suggests a much more positive effect on fear extinction than the application of exposure therapy alone (Deveney et al., 2009). DCS was found to enhance fear extinction both in animal and human studies, with major gains found in the follow-up treatment (Norberg et al., 2008).

Preclinical studies imply that DCS is effective for blocking the NMDA receptor complex known for its resistance to fear extinction – these findings open a new path for treating DCS not only as an anti-tuberculosis antibiotic, but as an augmentation therapy for psychological treatment procedures for patients suffering from anxiety disorders. This alternative application of DCS may be of substantial value in the field of psychotherapy. Still, it is impossible to deny the range of negative findings both in animal and human studies that either showed no results or suggested the negative impact of DCS on the fear extinction process. Nonetheless, these findings gave a clue to understanding the necessity of acute dosing prevailing over the chronic dosing model as well as sufficient time for memory consolidation upon DCS usage and the necessity of psychological treatment following DCS administration (Hofmann et al., 2006).

Another field of study needed to be accomplished before the decision is made on the DCS application for humans is the extent of generalized extinction that is observed in some experiments. Exposure therapy combined with DCS application shows generalization of extinction to other conditioned stimuli. Such form of extinction proves to be not susceptible to shock-induced reinstatement of fear, which is a great step in psychiatry. This fact found its experimental proof in the work of Davis et al. (2005) – this group of researchers examined several target samples of patients with anxiety disorders and concluded that the fear-potentiated startle of those taking DCS (namely in doses of 15 and 30 mg, without difference in indicators) was the lowest. Even patients who took smaller doses and whose fear-potentiated startle was higher than the one for the most successful group still showed much more progress in fear conditioning than those who did not take DCS at all (Davis et al., 2005).

Positive effect of DCS reported from clinical research

The modern psychotherapy has a great arsenal of drugs that may relieve the patient’s pain, help them overcome their disturbances and personality disorders. However, the majority of drugs is capable of only dealing with the consequences of disorders’ effect on patients and can ease clinical manifestations thereof. An innovative stage in psychiatric treatment has been entered with the start of D-cycloserine (DCS) application. D-cycloserine is a putative nootropic agent known to have profound effect on the N-methyl-D-aspartate (NMDA)-glutamate synapses that are responsible for the functions of learning and memory (Allen, 1996). This unique partial agonist has proven to have profound positive effect in treating tuberculosis, but recent research on animals enabled scientists to assume that DCS will be highly helpful in the facilitation of fear extinction in combination with exposure therapy in treating human patients with anxiety disorders (Hofman et al., 2006).

There are several reasons for the DCS propriety in treating various psychotic disorders from the point of view of NMDA receptors; as noted by Ressler et al. (2004), “some disorders, particularly the anxiety-related disorders exemplified by specific phobia, have an emotional learning component to them that can be facilitated with psychotherapy” instead of dealing with the abnormalities in their ultimate sense. Looking at the mechanism of memory formation and the significance of an emotional element in it, one will clearly realize why NMDA-glutamate synopses’ stimulation has so much potential for the psychiatric treatment progress.

Much experimental work has been conducted regarding the effect of DCS on phobia treatment, e.g. acrophobia as examined in the works of Ressler et al. (2004) and Davis et al. (2006). Both studies are dedicated to the DCS role in treating acrophobia and assessment of the overall DCS impact on the progress of corrective psychopathology. Ressler et al. (2004) used DCS as an adjunct in the extinction learning processes of humans in the period of virtual reality exposure (VRE) therapy proven successful for treatment of phobias and disorders. The task was to find out whether acute treatment with DCS would augment extinction of fear for patients having acrophobia. The results showed significant differences in fear reduction in groups with placebo and drug groups, which proves the indiscriminate role of DCS in fear extinction. Some other findings include: the conclusion that DCS does not reduce the level of fear or avoidance of fear during the therapy, DCS enhances extinction of fear within the virtual environment, and that the DCS extinction effect may last for about 3 months (Ressler et al., 2004). Generally, Ressler et al. (2004) make conclusions on the reduction of general acrophobia measures with the help of DCS and the scope of overall subjective and functional improvement.

Davis et al. (2006) support these findings; the researchers also base their research theoretically, exploring the role of DCS in fear conditioning. Authors also examine the potential for causing generalized extinction and prove its possibility, which means that “DCS facilitates extinction by enhancing the devaluation of the US representation elicited by the presentation of light CS” (Davis et al., 2006). The US stands here for the unconditioned stimulus, and CS is a conditioned stimulus. Generalized extinction may lead to loss of fear to any cue, which is potentially dangerous. Nonetheless, DCS has proven to reduce reinstatement of fear after extinction and successfully combines with behavioral exposure therapy (Davis et al, 2004). It is surely not the only study that supports the combined usage of behavioral therapy and DCS, which will be clear further.

Possible assistance of DCS in fear conditioning in combined usage with CBT is proven in the discussion of obsessive-compulsive disorder treatment in the article of Rothbaum (2008). The arguments that the author uses are the serious role of DCS in fear conditioning with further help in learning new behaviors that can be provided by CBT (Rothbaum, 2008).

Rothbaum (2008) utilizes data from previous successful cases of treating three anxiety disorders by CBT and medications. If one discusses medicines alone compared to CBT in treating diverse anxiety disorders, OCD included, no prevalence was found. Besides, prevalence of CBT combined with medications does not also reveal itself experimentally; but this is true only about traditional medicines like alphrazolan, buspirone, imipramine etc. However, as soon as experiments were pursued under the same conditions but with the application of DCS, much more positive results were shown. The author assumes their dependence on the mechanism of DCS effect and makes positive evaluations of the discovered perspective (Rothbaum, 2008).

There are many positive results reported in relation to studies of DCS in combination with exposure therapy alone to treat social anxiety disorder (Guastella et al., 2008) and obsessive-compulsive disorder (Kushner et al., 2007) as well as the application of DCS in combination with CBT (Otto et al., 2010). In all three cases the positive effect on fear conditioning provided by DCS is proven, despite the fact that different doses are applied (50 and 125 mg). Guastella et al. (2008) report greater improvement on symptoms’ severity, dysfunctional cognitions and like-impairment from social anxiety disorder, which speaks in favor of the medication. Otto (2010) also find DCS helpful in achievement of improvement in 77% of participants with no adverse effects of the drug registered. Kushner et al. (2007) experimented with the larger dose, 125 mg of DCS, but still reported more progress in exposure therapy achieved in the DCS group as compared to the placebo group.

Another DCS-related research direction is the investigation of prolonged effect it can produce, i.e. multiple exposures to the drug and this practice’s connection with the success of fear conditioning. To illustrate current findings, one can consider a study conducted by Parnas et al. (2004) – this group of researchers bases their argument on the success of exposure therapy both for people and animals due to the extinction phenomenon. Since the NMDA blockade becomes the major barrier for extinction and it is overcome pharmacologically, through the usage of DCS, Parnas et al. (2004) explore how the one-time application of this drug differs from repetitive, long-term usage thereof.

Results of three experiments with rats that were disposed to extinction training for different periods of time and took DCS in different doses, i.e. for a different number of times gave the possibility for the researchers to find out that the effect of DCS was not permanent, with the drug losing its properties over NMDA receptors upon a certain limit. These findings appeared particularly important and initiated the design of an interrupted schedule for DCS treatment. This way, nowadays a 28-day period is observed between five DCS exposures and the dose that is given immediately after extinction training. This scheme shows successful application and increased effect of DCS (Parnas et al., 2004).

The reverse side of the DCS medal

Despite much positive feedback on the transition from studies on animals to the supposed effect of DCS in fear conditioning for humans, there are also experimental findings that report no effect of DCS or renewal of fear as soon as the original context of fears returns. Articles of Storch et al. (2007) and Guastella et al. (2007b) report the absence of effect for patients with OCD and various anxiety disorders. Storch et al. (2007) used the 250-mg doses taken by patients 4 hours before the session of exposure and response prevention therapy. The final results in the placebo group and the DCS-group were equal. Consequently, the authors of the experiment suggest that lack of knowledge on the limitations of DCS-related research is the reason for failure. Being pioneers in the field, the researchers suppose that more information on specific conditions and dosing of DCS are necessary to achieve more fruitful results.

Similarly, Guastella et al. (2007b) conducted several experiments with study groups taking 50 and 500 mg of DCS 2-3 hours before extinction training with the following differential shock conditional paradigm. DCS did not have any effect in several experiments even with patients with different levels of symptom severity. The conclusion made by researchers was the necessity of clearer understanding of DCS therapeutic effect and peculiarities of its usage for fear extinction (Guastella et al., 2007b). The researchers do not deny the possible positive effect from DCS combined with exposure therapy to treat anxiety disorders for humans, but they agree that more in-depth knowledge is vital for positive results achievement.

Some researchers report about another dimension of DCS failure to achieve fear conditioning in humans – they agree on the positive effect from combination of DCS and exposure therapy, but report fear renewal (Bouton et al., 2008; Woods & Bouton, 2006). Bouton et al. (2008) emphasize the fact that the mechanism of DCS effect on the human brain as well as behavioral consequences of DCS application are yet not well understood to allow its wide-scale usage. More than that, they assume that the short-term effect of DCS in rats is really positive as compared to conventional fear extinction methods; however, DCS does not prevent fear renewal under the conditions of fear context resumption ((Bouton et al., 2008). The same results were achieved two years before by Woods and Bouton (2006) – using the 30-mg/kg dose of DCS for rats, the researchers found positive effect on fear extinction but recorded renewal of fear in renewed context.

In connection with reported failures Grillon (2009) made a set of conclusions on the differences in DCS research on animals and its transition to humans from which absence of positive results for the latter occurs. The main point the researcher makes is that DCS acts only on low-level mechanisms of fear conditioning that are in effect for animals (e.g. rodents). Humans also have the reflexive low-order system acting on the unconscious level; but their cognitive system has two levels, and DCS fails to affect the higher-order cognitive system that is responsible for danger and expectation. The recommendations they offer for DCS research on humans are to conduct experiments with fear-relevant stimuli, short conditioned stimulus-unconditioned stimulus intervals and further unconditioned stimulus exposure to promote conditioning processes (Grillon, 2009). These recommendations will serve a guideline for further design of DCS-related research on humans for examination of fear extinction on the example of patients with diverse anxiety disorders. Since at the present moment research findings are controversial, it is essential to review supplementary recommendations that can clarify the controversy and suggest clearer guidelines for DCS research design.

Rationale for the Study

Thus, it is possible to summarize that research in DCS administration continues opening new conditions for DCS efficiency guarantee, e.g. the discovery that DCS administration for a limited number of times and conducted immediately before or after the exposure therapy/extinction training series showing more resultant outcomes on long-term fear extinction (Norberg et al., 2008). Some other directions for clinical research that will enable researchers to design a more efficient and reasonable model for DCS administration include processes in extinction specifically targeted by DCS, long-term consequences of DCS usage, the range of effects produced by DCS on the cognitive and behavioral mechanisms of humans, optimal administration of DCS, timing and dosage thereof etc. (Hofmann, 2007). These issues should be continually addressed in clinical research to find out the optimal conditions in DCS administration to ensure its positive effect for treating humans with anxiety disorders. This idea will become the guiding line for the proposed experiment.

Thesis Statement: D-Cycloserine is needed to enhance the exposure based therapy for the treatment of anxiety disorders.

Proposed Study

Research Question: whether D-Cycloserine with different doses would enhance exposure-based therapy treatment effects in animal typed specific phobia (the present research will deal with patients will snake phobia).

Hypothesis: enhancement of  ET for animal phobia with DCS, regardless of dose, would lead to significantly better outcome than enhancement with placebo at both post-treatment and follow-up assessment, but there would be no difference between 50 and 500 mg DCS.

Why is the research question important?

The traditional dosing of DCS typical for modern experiments is 50 mg; this dosing was accepted due to the effect it showed in the prevailing number of clinical research cases. However, taking into consideration much controversy and disagreement on potential effects from various dosing of DCS and experiments that did not show effect of DCS in anxiety disorder treatment, it becomes necessary to advance in the field of determining proper dosage of DCS as well as identifying the existence of its positive effect on fear extinction. In case the hypothesis is confirmed, further research on the proper dosing will become more relevant because of the proven effect of DCS. More firm assumptions on the acceptance of the conventional 50-mg dose of DCS combined with exposure therapy will become possible.

Method

Sample

The sample for experiment will consist of 90 individuals who meet DSM-IV criteria for animal typed specific phobia. The participants will have to complete the Snake Anxiety Questionnaire, and only those who score 25+ (meaning definite presence of snake phobia) will be accepted to participate in the experiment. Afterwards the participants will be randomly assigned to 3 groups (by mans of double-blind design):  the first group will take a 50-mg dose of DCS and will be exposed to exposure therapy; the second group will take a 500-mg dose of DCS and will receive the exposure therapy session; the third group will take a Placebo with the same exposure therapy session.

Compliance with ethical standards of conducting an experiment is also important. For this reason provision of full and proper information about the study will be provided for all participants, each of which will sign the informed consent certifying his or her voluntary participation in the experiment. Each person will have an ability to quit the experiment at any stage of its completion.

Procedures and Treatment

Before the beginning of exposure therapy the respondents will be asked to complete the BAT task to assess two ophidiophobia-related characteristics that will vary independently across respondents. BATs possess a powerful potential for fear assessment, so the 100-point scale will be offered to respondents to show how close they are able to approach snakes as well as their own confidence of the BAT completion. The assessment will take place in a chamber with isolated snakes of several types (it will be better to choose small and large snakes to ensure variability of conditions without any bias and unequal conditions for various respondents). Respondents’ heart rate will be measured at all stages of the experiment. At the level of exposure therapy itself participants will be instructed to take a single pill of study medication (placebo, 50mg of DCS, 500mg of DCS) 2 to 4 hours before the therapy session to get the peak of DCS effect comply with therapeutic exercises. Before the beginning of the experiment placebo and DCS drugs will be brought to the identical form to ensure accuracy of results for both DCS and placebo groups.

Treatment will involve two sessions of gradual exposure that will include 1 hour of education about cognitive, behavioral, and physical aspects of ET. The goal is to have the participant complete each treatment step (7–8 specific skills or types of interactions with the animal) independently. The 8-step exposure session is set for a maximum time of 2 hours. The final step will involve placing a hand in the cage and moving the snake over a hand. Treatment will be terminated earlier if a participant experiences an extreme emotional reaction (based on the therapist’s clinical judgment) or ask to finish treatment after modest encouragement to continue has no effect. The two treatment sessions will occur with the interval of 1-2 weeks.

Assessment

Assessment of results of the present experiment will occur with the application of a set of questionnaires and scoring scales to assess various behavioral, cognitive and psychological measures as well as individual characteristics of the respondents concerning the graveness of ophidiophobia they have. Assessment will be conducted at four evaluation points (pre-treatment, post-treatment, 3-, 6-month follow-ups) according to the following set of tools.

DSM-IV criteria for specific phobia according to the Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV) – this initial schedule will serve as a margin for participation in the experiment. It turns out that many people exaggerate their fears or represent their disgust to snakes as a phobia, which will alter the results of the experiment. Thus, the ADIS-IV schedule will establish firm criteria for disorders in which exposure therapy combined with DCS is applicable.

The Fear Survey Schedule-III (FSS-III) and the Snake Anxiety Questionnaire are used to measure small animal fear. These schedules are also important for the comprehensive assessment of experiment’s results because these assessment tools are more flexible towards effects of treatment.

Cognitive-Somatic Anxiety Questionnaire (CSAQ) is also used to assess animal fear. This tool is used for efficient assessment of somatic and cognitive elements of anxiety, which is highly helpful afterwards in the choice of intervention means and understanding the impact of treatment on each of anxiety aspects.

Behavioral Approach Test (BAT) tasks help measure the closest distance at which participants are able to approach snakes at each phase in treatment and assessment. Special attention should be paid to their appropriate construction to eliminate contamination by demand, participant misunderstanding and experimenter effects, as these pitfalls are likely to cause distortion of results.

Subjective Units of Distress Scale (SUDS) are participant and therapist ratings of phobia severity during BAT. These simple tools possess a clear advantage in the affluent assessment of subjective feelings the participant has towards the fear stimuli, which can assist in reviewing the procedure of the experiment and find out the peak of DCS effect.

Potential threats (internal and external validity)

The present experiment surely has some potential threats and limitations that should be identified before it is conducted. The first threat is the increased self-exposures between the first and second session. Participants in DCS groups may increase the amount of self- exposure in the days after the first treatment and it makes a positive feedback for participants to reduce their fears. So, the extra amount of self-exposures may account for the effective outcome. The cases of self-exposures thus should be carefully recorded and reported to the researcher not to impede on the validity of experiment’s results.

Secondly, individual peculiarities of the human body’s reaction to DCS should be considered as an unpredictable variable that nonetheless can seriously affect the outcomes of research. This fact especially concerns the individual peak of DCS activity that is calculated on average and can occur in some participants before the treatment session or already after it. Participants take a DCS pill individually about 2 hours before the treatment. Even though previous research has proven that DCS reaches its peak effect approximately 2-3 hours post-administration, but due to individual biological mechanisms differences and different taking time prior to ET, it’s difficult to see if these differences could potentially impact upon DCS treatment effects.

Plan for data analysis

Analysis of DCS effect as an adjunct to exposure therapy will be conducted with the help of the ANOVA scale. Factors included will be the type of drug taken (DCS or placebo) and time of examination (pre-, post- and two follow-ups). This data analysis tool will aid in determining treatment advancement as well as potential return of fear in follow-up examinations. Further data analysis will depend on initial SNAQ and BAT scores of respondents, with particular attention to comparative progress of the most snake-fearful respondents. Initial conditions of participants who will reveal the least amount of fear extinction will be examined separately in an attempt to find individual determinants for success and failure allowing ultimate conclusions, generalizations and implications for further research.

Anticipated results

The present study aims at achieving a set of results. First of all, the initial hypothesis about the indiscriminate usage of the 50-mg and 500-mg DCS dosage is likely to be supported (as previously discussed in numerous studies, resulting in conventional choice of the 50-mg dosage as the most effective and reasonable one). Positive effect of both doses is also likely to be present in the result, again giving additional clues to identification of DCS proper dosage. However, the choice of different DCS doses is not done in vane: the effect of different doses will be explored in the second follow-up procedure. Since the effect of the properly dosed DCS in combination with ET is reported to last about 3 months, the 6-month follow-up is likely (though not for sure) to reveal particular differences in DCS dosage effect in the long-run. The results will be compared to the placebo-group responses at every measurement stage, so they are likely to show the advantage of combined exposure therapy and DCS usage as contrasted to unimodal ET treatment even under the conditions of post-treatment results being not significantly different. However, this hypothesis finds no theoretical grounding yet, so the results of the 6-month follow-up in all three groups can hardly be assessed before the experiment is accomplished.

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