Benzodiazepine treatment can impair or spare extinction, depending on when it is given

Hart, Genevra; Panayi, Marios C.; Harris, Justin A.; Westbrook, R. Frederick

doi:10.1016/j.brat.2014.02.004

Cited by 24 publications

(12 citation statements)

References 24 publications

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“…Indeed, there have been various attempts to combine exposure therapy with fast-acting anxiolytics such as diazepam in order to increase its tolerability. This approach, however, has revealed disappointing outcomes as benzodiazepines seem to interfere with extinction learning processes, probably involving state-dependent mechanisms ( Goldman, 1977 ; Pereira et al, 1989 ; Bouton et al, 1990 ; Bustos et al, 2009 ; Hart et al, 2014 ). In line with previous observations in animals ( Pereira et al, 1989 ; Bouton et al, 1990 ) and humans ( Spiegel and Bruce, 1997 ; Birk, 2004 ), diazepam also impaired fear extinction in LAB rats and decelerated extinction acquisition in HAB rats ( supplementary Figure 1 ), further supporting the value of the HAB/LAB model in translational research for investigating extinction-facilitating drugs.…”

Section: Discussionmentioning

confidence: 99%

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

Sartori

Maurer

Murphy

et al. 2015

IJNPPY

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Background:Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear.Methods:The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse.Results:Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice.Conclusions:By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term.

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Section: Discussionmentioning

confidence: 99%

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

Sartori

Maurer

Murphy

et al. 2015

IJNPPY

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“…BZDs may also render extinction memories dependent on the drug-induced internal anxiolytic-state (state dependent learning), which upon BZD discontinuation may no longer be accessible. These concerns are borne out by preclinical data showing that systemic ( Bouton et al, 1990 ; Bustos et al, 2009 ; Goldman, 1977 ; Hart et al, 2009 , 2010 , 2014 ; Pereira et al, 1989 ) or intra-BLA ( Hart et al, 2009 , 2010 ) BZD administration impairs extinction ( Table 5 ), presumably also through state-dependent mechanisms. Systemic treatment with a BZD inverse agonist ( Harris & Westbrook, 1998 ; Kim & Richardson, 2007 , 2009 ) has similar effects (see Table 5 for a summary].…”

Section: Pharmacologically Enhancing Extinctionmentioning

confidence: 99%

“… 1 Drug administration following extinction training; 2 only cued memory, contextual intact, 3 trace conditioning, 4 reconsolidation (injection prior reactivation of memory), 5 conditioned taste aversion, 6 midazolam may not impair fear extinction if initial extinction occurs drug-free [see ( Hart et al, 2014 )], 7 short extinction training (5 CS presentations), 8 injection prior renewal-testing. # Reduced fear expression at start of extinction training; ## enhanced immobility at start of extinction training; +, Improved; -, impaired; (+) or (−), only minor effects; ip, intraperitoneal injection; po, peroral administration; ns, not studied; HPC, intra-hippocampal administration; BLA, intra-basolateral amygdala administration; IL, infralimbic cortex; PL, prelimbic cortex; Ren-A, Fear renewal in conditioning context; ag, agonist; ant, antagonist, KO, knock-out; …”

Section: Figmentioning

confidence: 99%

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Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders

Singewald

Schmuckermair

Whittle

et al. 2015

Pharmacology & Therapeutics

357

271

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Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.

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“…Similar findings exist for anxiety disorders (Otto, McHugh, & Kantak, 2010) where the combination of medications and psychotherapy do not yield greater improvements relative to either treatment alone. While medications might be useful for brief periods to help control anxiety, it is important to note that their use often undermines the effectiveness of psychotherapy, particularly CBT and BT approaches that rely on exposure and new learning or extinction (Hart, Panayi, Harris, & Westbrook, 2014;Otto, McHugh, & Kantak, 2010).…”

Section: Common Misconceptions About Psychotherapy and Medicationmentioning

confidence: 99%

The Efficacy of Psychotherapy: Focus on Psychodynamic Psychotherapy as an Example

Levy¹,

Ehrenthal

Yeomans³

et al. 2014

Psychodynamic Psychiatry

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The growing number of individuals seeking treatment for mental disorders calls for intelligent and responsible decisions in health care politics. However, the current relative decrease in reimbursement of effective psychotherapy approaches occurring in the context of an increase in prescription of psychotropic medication lacks a scientific base. Using psychodynamic psychotherapy as an example, we review the literature on meta-analyses and recent outcome studies of effective treatment approaches. Psychodynamic psychotherapy is an effective treatment for a wide variety of mental disorders. Adding to the known effectiveness of other shorter treatments, the results indicate lasting change in many cases, especially for complex and difficult to treat patients, ultimately reducing health-care utilization. Research-informed health care decisions that take into account the solid evidence for the effectiveness of psychotherapy, including psychodynamic psychotherapy, have the potential to promote choice, increase mental health, and reduce society's burden of disease in the long run.

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Benzodiazepine treatment can impair or spare extinction, depending on when it is given

Cited by 24 publications

References 24 publications

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders

The Efficacy of Psychotherapy: Focus on Psychodynamic Psychotherapy as an Example

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