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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 original 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 original 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 presented 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. Current 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 original 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.

Treatments for anxiety disorder subtypes
Generalized anxiety disorder
Treatments for Generalized anxiety disorder (GAD) overlap greatly with those for other
anxiety dosorders and depression (Figure 9-33). First line treatments include SSRIs and SNRIs,
benzodiazepines, buspirone, and

ligands such as pregabalin and gabapentin. Some
pescribers are relucrant to give benzodiazepines for anxiety disorders in general and for GAD in
particular, because of the long-term nature of GAD and the possibility of dependence, abuse and
withdrawal reactions with benzodiazepines.
While it is not a good idea to give benzodiazepines to a GAD patient who is abusing
other substances, particularly alcohol, benzodiazepines can be useful when intiating an SSRI or
SNRI, since these serotonergic agents are often activating, difficult to tolerate early in dosing,
and have a delayed onset of action.

ligands can have a role in some patients as augmenting
agents, especially when intiating treatment with another agent that may be slower-acting or even
activating. In other patients, benzodiazepines can be usefulto “top up” an SSRI or SNRI for
patients who have experienced only partial relief of symptoms.

can also be useful for
occasional intermittent use when symptoms surge and sudden relief is needed.
It should be noted that remission from all symptoms in patients with GAD who are taking
an SSRI or SNRI may be slower in onset than it is in depression, and be delayed for 6 months or
longer. If a GAD patient is not doing well after several weeks to months of treatment, switching
to another SSRI/SNRI or buspirone or augmenting with a benzodiazepine or an

ligand can
be considered. Failure to respond to first-line treatments can lead to trials of sedating
antidepressants, or even sedating antihista mines such as hudroxyzine. Althought not well
studied, the SPARI vilazodone should theoretically have efficacy for GAD and can be
considered as a second line adent as well. Adjunctive treatment that can be added to first or
second line therapies for GAD include hypnotics for continuing insomnia, atypical
antipsychotics for severe, refractory, and disabling symtoms unresponsive to aggressive
treatment and cognitive behavioral psychotherapy. Old-fashioned treatments for anxiety such as
barbiturates and meprobamate are not considered appropriate todau, given the other choices
shown in Fifure 9-33.

Panic disorder
Panic attacks occur in many conditions, not just panic disorder, and panic disorder is
frequently comorbid with the other anxiety disorders and with major depression. It is thus not
suprising that contemporary treatments for panic disorder overlap significantly with those for
major depression (Figure 9-34). First line treatments include SSRIs and SNRIs, as well as
benzodiazepines and

ligands, although benzodiazepines are often used second line, during
treatment intiation with an SSRI/SNRI, for emergent use during a panic attact, or for incomplete
response to an SSRI/SNRI.

ligands are approved for the treatment of anxiety in Europe and
other countries but not in the US.
Second line treatments include older antidepressants such as tricyclic antidepressants.
Mirtazapine and trazodone are sedating antidepressants that can be helpful in some cases, and are
occasionally used as augmenting agents to SSRI/SNRIs when these first line agents have only a
partial treatment response. The MAO inhibitors, discussed in Chapter 7, are much neglected in
psychopharmacology in general and for the treatment of panic disorder in particular. However,
these agents can have powerful efficacy in panic disorder and should be considered when first
line agents and varios augmenting strategies fail.
Cognitive behavioral psychotheraphy can be an alternative or an augmentation to
psychoparmacologic approaches, and can help modify cognitive distortions and throught
exposure, diminish phobic avoidance behaviors.

Social anxiety disorder
The treatment options for this anxiety disorder (Figure 9-35) are very similar to those for
panic disorder, with a few noteworthy differences. The SSRIs and SNRIs and

ligands are
certainly first line therapies, but the butility of benzodiazepine monotherapy for forst line
treatment is not generally as widely accepted as it might be for GAD and panic disorder. There is
also less evidence for the utility of older antidepressants such as mirtazapine and trazodone. Beta
blockers, sometimes with benzodiazepine , can be useful for some pateients with very discrete
types of social anxiety, such as performance anxiety. Listed as adjunctive treatments are agents
for alcohol dependence/abuse, such as naltrexone and acamprosate, since many patients may
discover the utility if alcohol in relieving their social anxiety symptoms and develop alcohol
depencence/abuse. Cognitive behavioral psychotheraphy can be a powerful intervention,
sometimes better than drugs for certain patients, and often helpful in combination with drugs.


Posttraumatic stress disorder
Although many treatments are shown in Figure 9-36, psychopharmacologic treatmens
for PTSD in general may not be as sffective as these same treatments are in other anxiety
disorders. Also PTSD is so highly comorbid that many of the psychopharmacologic treatments
are more effectively aimed at comorbidities such as depression, insomnia, substance abuse, and
pain than at core symtomps of PTSD. SSRIs andSNRIs are proven effective and are considered
first line treatments, but often leave the patient with residual symptoms, including sleep
problems. Thus, most patients with PTSD do not take monotherapy. Benzodiazepines are to be
used with caution, not only because of limited evidence from clinical trials for efficacy in PTSD,
but also because many PTSD patients abuse alcohol and other substances. A unique treatment for
PTSD is the administration of

antagoonists at night to prevent nightmares. Pre-emptive
treatment with blockers or opioids is discussed above, but is not a proven or practical treatment
option at this point. Much more effective treatments for PTSD are greatly needed.
Much of the advance in treatment of PTSD has been in using drugs to treat comorbidities
and psychotherapies to treat core symptoms. Exposure therapy is perhaps most effective among
psychotherapies, but many forms of CBT are being investigated and used in clinical practice,
depending upon the training of the therapist and the bspecific needs of the individual.
Summary
Anxiety disorders have core features of fear and worry that cut across the entire spectrum
of anxiety disorder subtypes, from geralized anxiety disorder to panic disorder, social anxiety
disorder and posttraumatic stress disorder. The amygdala plays a central role in the fear response
and cortico striato thalamo cortical (CSTC) circuits are thought to play a key role in mediating
the symptom of worry. Numerous neurotransmitters are involved in regulating the circuits that
underlie the anxiety disorders. GABA (-aminobutyric acid) is a key neurotransmitter in anxiety
and the benzodiazepine anxiolytics upon this neurotransmitter system. Serotonin norepinephrine,

ligands for voltage-gated calcium channels, and other regulators of anxiety disorders. The
concept of opposing actions of fear conditioning versus fear extinction within amygdala circuits
hypothetically is linked to the production and maintenance of symptoms in anxiety disorder and
provides a subsrate for potential novel therapeutics combining psychotheraphy and drugs.
Numerous treatments are available for anxiety disorders, most of which are similar for the entire
anxiety disorder spectrum and are also used for the treatment of depression.