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KETIKAN DARI HAL 411-419.docx

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NOVEL approaches to the treatment of anxiety disorders Once fear conditioning is in place, it can be very difficult to reserve. Nevertheless, there may be two ways to neutralize fear conditioning: either by facilitating a process called extinction or by blocking a process called reconsolidation. Fear extinction Fear extinction is the progressive reduction of the response to a feared stimulus, and occurs when the stimulus is repeatedly presented without any adverse c
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  NOVEL approaches to the treatment of anxiety disorders Once fear conditioning is in place, it can be very difficult to reserve. Nevertheless, there may be two ways to neutralize fear conditioning: either by facilitating a process called extinction or by blocking a process called reconsolidation. Fear extinction Fear extinction is the progressive reduction of the response to a feared stimulus, and occurs when the stimulus is repeatedly presented without any adverse consequence. When fear extinction occurs , it appears that the srcinal fear conditioning is not really “for gotten” even though the fear response can be profoundly reduced over time by the active process of fear extinction. Rather than revershing the synaptic changes described above for fear conditioning, it appears that a new form of learning with additional synaptic changes in the amygdala occurs during fear extinction. These changes can suppress symptoms of anxiety and fear by inhibiting the srcinal learning but not by removing it (Figure 9-30). Specifically, activation of the amygdala by the VMPFC uccurs while the hippocampus remembers” the context in which the feared stimulus did not have any adverse consequences and fear is no longer activated (Figure 9-30). Fear extinction hypothetically occurs when inputs from the VMPFC and hippocampus activate glutamatergic neurons in the lateral amygdala that synapse upon an inhibitory GABAergic interneuron located within the intercalated cell mass of the amygdala (Figure 9-30). This sets up a gate within the central amygdala, with fear outputoccurring if the fear conditioning circuit predominates, and no fear output occurring if the fear extinction circuit predominates.   Fear extinction theoretically predominates over fear conditioning when synaptic strengthening and long term potentiation in the new circuit are able to produce inhibitory GABAergic drive that can overcome the excitatory glutamatergic drive produced by the pre-existing fear conditioning circuitry (Figure 9-30). When fear extinction exist simultaneously with fear conditioning, memory for both are present, but the output depends upon which system is “stronger, better remembered, and has the most robust synaptic efficiency. These factors will determine which gate will open, the one with the fear response or the one that keeps the fear response in check. Unfortunately, over time, fear conditioning may have the upper hand over fear extinction. Fear extinction appears to be more labile than fear conditioning can return if the old fear is pres ented in a context different than the one “learned” to suppress the fear during fear extinction, a process termed renewal.  Novel treatment approaches to anxiety disordes seek to facilitate fear extinction rather than just suppress the fear response triggered by fear conditioning, which is how current anxiolytic drugs work (Figures 9-25 through 9-30). Among currently effective treatments for anxiety, cognitive behavioral therapies that use exposure techniques and that require the patient to confront the fear-inducing stimuli in a safe environment may come closest to facilitating fear extinction, hypothetically because when these therapies are effective, they are able to trigger the learning of fear extinction in the amygdala (Figure 9-30). Unfortunately, because the hippocampus “remembers” the context of this extinction, such therapies are often context -  specific and do not always generalize once the patient is outside the safe therapeutic environment; thus fear and worry may be “renewed” in the real world. Cur  rent psychotheraphy research in investigating how contextual cues can be used to strengthen extinction learning so that the therapeutic learning generalizes to other environments. Current psycho pharmacology research is in investigating how specific drugs might also streghthen extinction learning by  pharmacologycallly strengthening the synapses on the fear  –   extinction side of the amygdala gate disproportionately to the synapses on the fear-conditioned side of the amygdala gate. How could this be done? Based on successful animal experiments of extinction learning, one idea, shown in Figure 9-31, is to boost NMDA receptor activation at the very time when a patient receives systematic exposure to feared stimuli during cognitive behavioral therapy sessions. This can be done either with direct-acting agonists such as D-cycloserine or with inindirect glycine enhancing agents such as selective glycine reuptake inhibitors (SGRIs). This approach to boosting activity at  NMDA synapses is discussed in Chapter 5 in relation to schizophrenia and is illustrated and is illustrated in Figure 5-90. As applied to novel anxiolytic therapy, the idea is that as therapy  progresses, learning occurs, because glutamate release is provoked in the lateral amygdala and in the intercalated cell mass at inhibitory GABA neurons by the psychotheraphy. If NMDA receptors at these two glutamate synapses could be pharmacologically boosted to trigger disproportionately robust long-term pontiation and synaptic palasticity, timed to occir at the exact time this learning ang theraphy is taking place and thus exactly when these synapses are  selectively activated, it could theoretically result in the predominance of the extinction pathway over the conditioned pathway. Animal studies support this possibility, and early clinical studies are encouraging but not always robust or consistent to date. In the meantime, prudent  psychopharmacologists are ancreasingly leveraging their current anxiolytic drug portfolio with coccomitant psychotheraphy, since many patients have already received enhanced therapeutic  benefit from this combination. Reconsolidation Blocking Reconsolidation of fear memories is a second mechanism that could theoretically be therapeutic for patients with anxiety disorders. Althought classically, emotional memories that have been fear-conditioned were thought to last forever, recent animal experiments show that emotional memories can in fact be weakened or even erasedat the time they are re- experienced. When fear is first conditioned, that memory is sad to be “consolidated” via a nolecular process that some have thought was essentially permanent. Hints aat the mechanism of the intial consolidation of fear conditioning come from observations that both    blocker and opioids can potentiallymitigate the conditioning of the srcinal traumatic memory, even in humans, and some studies show that these agents can potentially reduce the chances of getting PTSD after a traumatic injury (Figure 9-32). Furthermore, once emotional memories have been consolidated as fear conditioning, animal experiments now show that they are not necessarily permanent, but can chance when they are retrieved. Reconsolidation is the state in which reactivation of a consolidated fear memory makes it labile, and requires protein synthesis to keep the memory intact. Beta blockers disrupt reconsolidation of fear memories as well as formation of fear conditioning (Figure 9-32). Future research is trying to determine how to use  psychotheraphy to provoke emotional memories and reactivate them by producing a state where a pharmacological agent could be administered to disrupt reconsolidation of these emotional memories and thereby relieve symptoms of anxiety. These are early days in terms of applying this concept in clinical settings, but this notion supports the growing idea that psychotherapy and  psychopharmacology can be synergistic. Much more needs to be learned as to how to exploit this theoretical synergy.

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Jul 23, 2017

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Jul 23, 2017
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