Showing posts with label D-Cycloserine. Show all posts
Showing posts with label D-Cycloserine. Show all posts

Monday, July 30, 2012

OCD and D-cycloserine: A Promising Medication for OCD Treatment


by Steven J. Seay, Ph.D., August 25, 2011




OCD D-cycloserine 


"OCD, I'd like you to meet my friend, D-cycloserine. D-cycloserine, this is OCD. I think you two should get to know each other a little better. You just might have a future together..."


As someone who has long been enamored with basic science, I find it fascinating when classic medications are re-purposed in surprising ways.  One of the newest examples of this is the use of D-cycloserine (also known as Seromycin) in the treatment of obsessive-compulsive disorder (OCD). What’s interesting about D-cycloserine is not so much what it is…but what it isn’t:
  • D-cycloserine is neither an SRRI nor any other type of antidepressant (e.g., Prozac).
  • It’s not an anti-anxiety medication (e.g., Xanax, Klonopin).
  • It’s not even an atypical antipsychotic (e.g., Abilify, Risperdal).
If it’s not one of the above, then what is it?

The answer might surprise you.  Seromycin is actually an antibiotic that was originally developed to help fight off tuberculosis.  What’s exciting about using an antibiotic to treat OCD is that it’s not subject to the same side effects as other medications (i.e., the SSRIs, anxiolytics, or antipsychotics).  In fact, most clinical studies have found few, if any, significant side effects when using D-cycloserine in OCD treatment.

Before I go further, there’s an important caveat to keep in mind:

Research on D-cycloserine in OCD treatment is still a work-in-progress, so it’s important to maintain some healthy skepticism on this issue.

Research studies looking at using D-cycloserine to treat OCD have been fairly limited, and the results of these studies have been mixed.  Some studies have suggested that the medication has small or non-significant effects, whereas other studies have found the medication to be beneficial.  Several recent, placebo-controlled studies have been quite promising and have indicated that taking seromycin can initially “speed up” the therapeutic response to exposure and response prevention therapy (ERP), a form of cognitive behavioral therapy (CBT) developed to treat OCD.  In essence, you benefit more from initial ERP therapy sessions.  D-cycloserine doesn’t appear to have any effects on OCD when taken on its own (i.e., when not combined with exposure and response prevention).  Read more about how ERP is thought to work.


It’s important to note that D-cycloserine doesn’t appear to offer any long-term benefits above and beyond what you would get from ERP alone.  In the end, you’re likely to achieve the same amount of symptomatic improvement whether or not you take the medication.  However, the research indicates that you’re likely to get more “bang for your buck” if you’re taking Seromycin during early exposure sessions.  This is important, because it reduces early treatment frustration and drop out.

How does D-cycloserine work?  Does the fact that it is an antibiotic mean that OCD is caused by bacteria?


No.  Like most medications, D-cycloserine is a complicated chemical that has many different biological effects.  It is not D-cycloserine’s antibiotic properties that are thought to make it useful in OCD treatment, but rather how this medication works on certain neurotransmitter receptors in the amygdala (a part of your brain that is associated with emotions like fear).

Without getting too technical, D-cycloserine is thought to affect certain amygdala receptors (i.e., NMDA receptors) that are associated with learning and memory.  Researchers theorize that action at these receptors facilitates learning/fear extinction, which is why the medication can apparently augment learning-based treatments like ERP. On a related note, feel free to read my short blog post on whether or not ERP works via learning or unlearning.
Can D-cycloserine be used to treat other anxiety disorders? 

Yes.  Research indicates that behavioral treatment of other anxiety disorders (panic, phobias, and the like) may also be enhanced by the addition of D-cycloserine.  Again, overall symptom reduction may be the same whether or not the medication is used; however, the addition of seromycin may help individuals benefit more from early exposure sessions.


You can also access some of the original research about D-cycloserine at the links below:
Some Effects Found:
  • D-Cycloserine Augmented Exposure Therapy for Obsessive-Compulsive Disorder (abstract only)
  • A Meta-Analysis of D-Cycloserine and the Facilitation of Fear Extinction and Exposure Therapy (full-text)
  • Augmentation of Behavior Therapy With D-Cycloserine for Obsessive-Compulsive Disorder (full-text)
No Effects Found:
  • D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder (abstract only)

Anxiety: Face Your Fears: Extinction through CBT




Some of the best ways to treat anxiety disorders are through the processes of desensitization, exposure response prevention (ERP), and fear extinction. It seems that those with high levels of anxiety may suffer a super-sensitive "fear circuit," that stores and recalls emotionally-charged learned memories much more quickly and strongly than neurotypicals.

Cognitive Behavioral Therapy (or CBT) retrains the arousal system and "overwrites" the phobias or triggers until at last the mind relents, and accepts that the feared situations are not so threatening. The mind is basically sending out a "Chicken Little"-styled false alarm. However, although desensitized, the fearful memories remain encoded in the brain, and under stress and certain conditions, a person may experience a relapse or resurgance. Then it's time to pick yourself up, dust yourself off, and go back to the same technique.

Avoidance is the worst response, because the fears can grow, and become debilitating.


From yee Wiki:

Extinction is the conditioning phenomenon in which a previously learned response to a cue is eliminated when the cue is presented in the absence of the previously paired aversive (unpleasant) or appetitive (pleasant) stimulus.

Fear conditioning

Extinction is typically studied within the Pavlovian fear conditioning framework in which extinction refers to the reduction in a conditioned response (CR; e.g., fear response/freezing) when a conditioned stimulus (CS; e.g., neutral stimulus/light or tone) is repeatedly presented in the absence of the unconditioned stimulus (US; e.g., foot shock/loud noise) with which it has been previously paired.

The simplest explanation of extinction is that as the CS is presented without the aversive US, the animal gradually "unlearns" the CS–US association which is known as the associative loss theory. However, this explanation is complicated by observations where there is some fear restoration, such as reinstatement (restoration of CR in the context where extinction training occurred but not a different context after aversive US is presented again), renewal (restoration of CR in context A but not in B when learning occurred in context A and extinction in context B), and spontaneous recovery (restoration of CR when the retention test occurs after a long but not a short delay after extinction training) and alternative explanations have been offered.

Research on fear extinction in animal models (typically rats) has clinical implications such as exposure-based therapies for the treatment of phobias and anxiety conditions.


Theories

The dominant account of extinction involves associative models. However, there is debate over whether extinction involves simply "unlearning" the US–CS association (e.g., the Rescorla–Wagner account) or, alternatively, a "new learning" of an inhibitory association that masks the original excitatory association (e.g., Konorski, Pearce and Hall account). A third account concerns non-associative mechanisms such as habituation, modulation and response fatigue. Myers and Davis laboratory work with fear extinction in rodents has suggested that multiple mechanisms may be at work depending on the timing and circumstances in which the extinction occurs.

Given the ompeting views and difficult observations for the various accounts researchers have turned to investigations at the cellular level (most often in rodents) to tease apart the specific brain mechanisms of extinction, in particular the role of the brain structures (amygdala, hippocampus, the prefontal cortex), and specific neurotransmitter systems (e.g., GABA, NMDA). A recent study in rodents by Amano, Unal and Paré published in Nature Neuroscience found that extinction is correlated with synaptic inhibition in the fear output neurons of the central amygdala that project to the periaqueductal gray that controls freezing behavior. They infer that inhibition derives from the prefrontal cortex and suggest promising targets at the cellular level for new treatments of anxiety.

Operant conditioning

In the operant conditioning paradigm, extinction refers to the decline of an operant response when it is no longer reinforced in the presence of its discriminative stimulus. Extinction is observed after withholding of reinforcement for a previously reinforced behavior which decreases the future probability of that behavior. For example, a child who climbs under his desk, a response which has been reinforced by attention, is subsequently ignored until the attention-seeking behavior no longer occurs. In his autobiography, B.F. Skinner noted how he accidentally discovered the extinction of an operant response due to the malfunction of his laboratory equipment:

My first extinction curve showed up by accident. A rat was pressing the lever in an experiment on satiation when the pellet dispenser jammed. I was not there at the time, and when I returned I found a beautiful curve. The rat had gone on pressing although no pellets were received. ... The change was more orderly than the extinction of a salivary reflex in Pavlov's setting, and I was terribly excited. It was a Friday afternoon and there was no one in the laboratory who I could tell. All that weekend I crossed streets with particular care and avoided all unnecessary risks to protect my discovery from loss through my accidental death.
When the extinction of a response has occurred, the discriminative stimulus is then known as an extinction stimulus (SΔ or S-delta). When an S-delta is present, the reinforcing consequence which characteristically follows a behavior does not occur. This is the opposite of a discriminative stimulus which is a signal that reinforcement will occur. For instance, in an operant chamber, if food pellets are only delivered when a response is emitted in the presence of a green light, the green light is a discriminative stimulus. If when a red light is present food will not be delivered, then the red light is an extinction stimulus (food here is used as an example of a reinforcer).

Successful extinction procedures

In order for extinction to work effectively, it must be done consistently. Extinction is considered successful when responding in the presence of an extinction stimulus (a red light or a teacher not giving a bad student attention, for instance) is zero. When a behavior reappears again after it has gone through extinction, it is called resurgence.

Extinction burst

While extinction, when implemented consistently over time, results in the eventual decrease of the undesired behavior, in the short-term the subject might exhibit what is called an extinction burst. An extinction burst will often occur when the extinction procedure has just begun. This consists of a sudden and temporary increase in the response's frequency, followed by the eventual decline and extinction of the behavior targeted for elimination.

Take, as an example, a pigeon that has been reinforced to peck an electronic button. During its training history, every time the pigeon pecked the button, it will have received a small amount of bird seed as a reinforcer. So, whenever the bird is hungry, it will peck the button to receive food. However, if the button were to be turned off, the hungry pigeon will first try pecking the button just as it has in the past. When no food is forthcoming, the bird will likely try again ... and again, and again. After a period of frantic activity, in which their pecking behavior yields no result, the pigeon's pecking will decrease in frequency.

Although not explained by reinforcement theory, the extinction burst can be understood using control theory. In perceptual control theory, the degree of output involved in any action is proportional to the discrepancy between the reference value (desired rate of reward in the operant paradigm) and the current input. Thus, when reward is removed, the discrepancy increases, and the output is increased. In the long term, 'reorganisation', the learning algorithm of control theory, would adapt the control system such that output is reduced.

The evolutionary advantage of this extinction burst is clear. In a natural environment, an animal that persists in a learned behavior, despite not resulting in immediate reinforcement, might still have a chance of producing reinforcing consequences if the animal tries again. This animal would be at an advantage over another animal that gives up too easily.

Despite the name, however, not every explosive reaction to adverse stimuli subsides to extinction. Indeed a small minority of individuals persist in their reaction indefinitely.

Extinction-induced variability

Extinction-induced variability serves an adaptive role similar to the extinction burst. When extinction begins, subjects can exhibit variations in response topography (the movements involved in the response). Response topography is always somewhat variable due to differences in environment or idiosyncratic causes but normally a subject's history of reinforcement keeps slight variations stable by maintaining successful variations over less successful variations. Extinction can increase these variations significantly as the subject attempts to acquire the reinforcement that previous behaviors produced. If a person attempts to open a door by turning the knob, but is unsuccessful, they may next try jiggling the knob, pushing on the frame, knocking on the door or other behaviors to get the door to open. Extinction-induced variability can be used in shaping to reduce problematic behaviors by reinforcing desirable behaviors produced by extinction-induced variability.

D-Cycloserine

D-Cycloserine (DCS) is being trialed as an adjuvant to conventional exposure-based treatments for anxiety disorders. The psychotropic responses are related to D-Cycloserine's action as a partial agonist of the neuronal NMDA receptor for glutamate and have been examined in implications with sensory-related fear extinction in the amygdala.

Here's a video link on exposure therapy, that Dr. R. shared with me when I started my CBT with him:

http://www.medicanalife.com/Treatment-of-Snake-Phobia-Part-1-of-3_v5606