Causes, signs and treatments of anxiety RESEARCH

DEPRESSION AND ANXIETY 33:895–906 (2016)

2015 ADAA Scientific Research Symposium KAPPA-OPIOID ANTAGONISTS FOR PSYCHIATRIC DISORDERS: FROM BENCH TO CLINICAL TRIALS

William A. Carlezon Jr., Ph.D.1∗ and Andrew D. Krystal, M.D., M.S.2

Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anx- iety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their pu- tative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to char- acterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs—the endogenous receptors for dynorphin—produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans. Depression and Anxiety 33:895–906, 2016. C© 2016 Wiley Periodicals, Inc.

Key words: anxiety; anxiety disorders; mood disorders; substance use disorders; pharmacotherapy; treatment

1Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 2Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina

Grant numbers: MH063266 and HHS-N271-2012-000006-I.

∗Correspondence to: William A. Carlezon Jr., Department of Psy- chiatry, McLean Hospital, 115 Mill Street, Belmont MA, 02478. E-mail: [email protected]

THE PAST: A BRIEF HISTORY OF PRECLINICAL STUDIES OF KOR

ANTAGONISTS OVERVIEW Kappa-opioid receptor (KOR) antagonists are currently being considered for treating a variety of neuropsy- chiatric conditions, including depressive, anxiety, and

Received for publication 6 January 2016; Revised 9 March 2016; Accepted 9 March 2016

DOI 10.1002/da.22500 Published online in Wiley Online Library (wileyonlinelibrary.com).

C© 2016 Wiley Periodicals, Inc.

896 Carlezon and Krystal

substance abuse disorders. An ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The hypothesis that KOR antagonists might be useful for these conditions evolved from molecular and behavioral studies in lab- oratory animals demonstrating that stress or repeated exposure to drugs of abuse triggers a complex sequence of intracellular events involving the transcription fac- tor CREB (cAMP response element binding protein) in the nucleus accumbens (NAc). The NAc is an element of the mesolimbic system, which plays a role in moti- vation and the pathophysiology of psychiatric illness.[1] Although elevated CREB activity leads to alterations in the function of scores of target genes,[2] it has been estab- lished that CREB-mediated increases in the expression of the endogenous opioid peptide dynorphin (DYN)— which acts at KORs[3]—produces depressive-like signs in rodents. KOR antagonists mitigate these signs, and pro- duce antidepressant- and anxiolytic-like effects in pre- clinical screening procedures known to identify standard drugs of these classes.[4–7]

IMPLICATING CREB CREB plays a well-characterized role in translating

events that occur at the cell surface into alterations in gene expression.[2] At the time that our research on CREB began, it was under intense investigation as a potential regulator of the effects of standard antide- pressant medications and electroconvulsive shock ther- apy (ECT).[8, 9] Evidence suggested that CREB in the hippocampus (HIP) plays a critical role in neuroplastic events that produce antidepressant-like effects in pre- clinical models, and served as a foundation for influ- ential theories such as the neurogenesis hypothesis of antidepressant action.[10] Discovery of beneficial effects of CREB in the HIP laid the groundwork for a way of thinking that persists today: that more CREB function leads to enhanced responsiveness to stimuli such as ther- apeutic agents or, by extension, drugs of abuse. As such, when it was reported that repeated administration of amphetamine produces enhancements in the activated (phosphorylated at the SER-133 residue) form of CREB in the NAc,[11] it was easy to assume that this neuroad- aptation must play a key role in the development of en- hanced responsiveness (sensitization) to the locomotor- stimulating[12] and rewarding[13] effects of the drug (and related drugs). In fact, experiments utilizing viral vectors to enhance or block CREB function in the NAc showed almost exactly the opposite effect: elevations in CREB produced reductions in sensitivity to the rewarding ef- fects of high doses of cocaine, and conditioned place aversions to intermediate doses of the drug.[14] These ef- fects are putative indicators of anhedonia and dysphoria, which are key signs of depression. In contrast, disrup- tion of CREB function enhanced cocaine reward. Sub- sequent work[15] demonstrated that forced swimming (a stressor) also activates CREB in the NAc, and that

viral vector-induced elevations in CREB intended to mimic this effect produced increases in immobility be- havior in the forced swim test (FST), a prodepressant- like effect. Importantly, disruption of CREB function in the NAc produced effects in the FST that were in- distinguishable from those of standard antidepressant drugs. Together, these data demonstrated that elevation of CREB function in the NAc can produce homeostatic- like—and arguably detrimental, since they resemble key signs of depression—effects, which had two important implications:[2] first, that it is critical to include the brain region under study when describing the consequences of altering CREB function, since a given CREB manip- ulation can produce beneficial effects in some regions and detrimental effects in other regions; and second, that treatments intended to broadly “boost” CREB function throughout the brain would be unlikely to produce un- equivocally beneficial (therapeutic) effects.

IMPLICATING DYNORPHIN, A CREB TARGET Because these early studies raised the possibility that

reducing CREB function in the NAc might produce therapeutic effects, while at the same time suggesting that CREB is not a tenable drug target, it became critical to determine if the behavioral endpoints could be linked to specific CREB-regulated target genes. Although nu- merous target genes were explored, including those en- coding glutamate receptor subunits,[16] none provided a stronger signal than the gene encoding DYN, an en- dogenous agonist at KORs.[3] Several lines of evidence pointed to the possibility that elevated DYN plays a key role in the depressive-like effects of elevated CREB func- tion in the NAc. First, administration of KOR agonists to people produces dysphoric and depressive effects.[17, 18] Second, microinjections of KOR agonists into the NAc produce conditioned place aversions resembling those seen with intermediate doses of cocaine in rats overex- pressing CREB in the NAc.[19] Third, DYN expression levels are elevated in the NAc after viral vector-induced elevations of CREB and reduced by disruption of CREB function,[14] and also elevated by exposure to forced swim stress.[20] And fourth, the prototypical KOR antagonist norBNI blocked the prodepressive-like effects of ele- vated CREB function, but perhaps more importantly, produced antidepressant-like effects of its own, thereby mimicking the effects of CREB disruption.[15] This gen- eral finding has been widely replicated[21–23] and strongly implicates DYN and KORs in the cascade of events that produces depressive-like behaviors, and was impactful because it showed that a pharmacological intervention at a well-characterized receptor (and eminently drug- gable target) can mitigate the behavioral consequences of an experience-dependent molecular adaptation. More recent work indicates that other stressors, such as immo- bilization, footshock, and social defeat all alter CREB and KOR function in the NAc, and that selectively mimicking these effects can produce other key signs of stress-related illness.[24–26] Thus this line of work iden-

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tified an intracellular cascade that produces key signs of depressive behavior as modeled in preclinical studies, and offered a pharmacological intervention to mitigate these effects, setting the stage for elevated interest in developing KOR antagonists for the treatment of de- pressive illness in humans.[5, 27, 28]

FIRST IN CLASS, BEST IN CLASS? Considering that the antidepressant-like effects of

KOR antagonists were discovered in the context of stress, we next explored the possibility that KOR an- tagonists would also produce a signal in anxiety-related preclinical assays. Indeed, acute administration of the prototypical KOR antagonists norBNI and JDTic each produced anxiolytic-like effects in the elevated plus maze (EPM) and open-field tests.[29] Subsequent work demonstrated that KOR antagonist actions in the amyg- dala (AMG) play a key role in these effects.[30] The discovery that KOR antagonists have acute anxiolytic- like actions raises two critical points relevant to their de- velopment as therapeutics. First, it is important to note that although standard antidepressants can ultimately produce anxiolytic effects in people, a period of sustained treatment is generally required before these effects be- come evident. In fact, humans often report that stan- dard antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs]) initially produce anxiogenic effects, which can adversely affect adherence; evidence of these same anxiogenic-like effects has been reported in pre- clinical rodent assays after acute treatment.[29, 31, 32] As such, the presence of acute anxiolytic-like effects dis- tinguishes KOR antagonists from standard antidepres- sants. Second, although the preclinical assays used most frequently to identify in rodents standard treatments with antidepressant effects in people (e.g., the FST, tail suspension test) are sensitive to the therapeutic effects standard antidepressants after acute/subacute treatment regimens, KOR antagonists currently represent the only class of agents where acute treatment produces both antidepressant- and anxiolytic-like effects together. As such, it is conceivable that KOR antagonists would rep- resent an improvement over existing treatments, since it would be predicted that they would lack a side effect (anxiogenesis) that leads many patients to discontinue their medication regimens.

One theme that has emerged from preclinical stud- ies is that KOR antagonists seem particularly effective in mitigating the effects of stress. Owing to the persis- tent effects of the prototypical KOR antagonists,[33, 34] it is possible to determine if KOR antagonists have pro- tective (prophylactic) effects. The original studies with KOR antagonists in the FST involved pretreatment: norBNI was delivered intracerebroventricularly (ICV) at the same time as the viral vectors were microinfused into the NAc.[15] Other studies showed that norBNI or JDTic pretreatment reduce fear conditioning.[29] which is often used to study stress-related conditions such as post-traumatic stress disorder (PTSD) in both labo-

ratory animals and humans.[35] In addiction research, KOR antagonists prevent stress-induced drug seeking like behaviors.[23] They also prevent the development of cocaine withdrawal-related anhedonia as measured in the intracranial self-stimulation (ICSS) test, although they do not reverse such changes once established.[36] The prototypical KOR antagonist JDTic does, however, attenuate anxiety-like behaviors associated with alco- hol withdrawal,[37] raising the possibility of drug-specific interactions. Interestingly, pretreatment with KOR an- tagonists do not prevent the development of anhedonia- like behaviors in response to chronic social defeat stress (CSDS) in mice, perhaps owing to some of the unique characteristics of this procedure, although ablation of KORs from dopaminergic neurons significantly delays their onset.[26] Pretreatment with KOR antagonists also reduces the disruptive effects of moderate (but not high) doses of corticotropin-releasing factor [CRF]), which produces stress-like effects in rodents and humans, on attention[38] and error processing.[39] Collectively, these studies suggest that KOR antagonists may be effective in mitigating the effects of weak-to-moderate stressors, thereby preventing their long-term consequences, but less effective against strong stressors or when stress- induced neuroadaptations are already established. To the extent that stress can trigger new cases of psychi- atric illness and exacerbate existing cases, the idea that KOR antagonists can block stress effects may offer an un- precedented opportunity: prevention of psychiatric ill- ness. Although exposure to stress is often unpredictable, there are instances when it can be predicted at least a few minutes in advance: examples include combat and responding to major accidents or natural disasters. What remains to be demonstrated is whether the prophylactic effects of the prototypical KOR antagonists are inextri- cably linked to their long-lasting effects, or if they can be achieved with shorter-acting agents, which are currently under development.

MECHANISMS OF PUTATIVE THERAPEUTIC EFFECTS

Psychiatry is replete with examples of medications that were discovered by serendipity and thus the mech- anisms of their therapeutic action are, at minimum, still open to debate.[1, 40] In contrast, the mechanisms by KOR antagonists produce therapeutic-like actions are well understood because their discovery evolved directly from an appreciation for how stress affects the brain; indeed, KOR antagonists were selected for study pre- cisely because they block a prominent stress-induced neuroadaptation (elevated expression of dynorphin in the NAc[20, 26]). This “brain-centric” approach[41] elim- inates the need to reverse-engineer an understanding of the pathophysiology of stress-related psychiatric ill- ness by sorting through the myriad biological actions of therapeutics discovered by serendipity. Our model (Fig. 1) provides an overarching hypothesis for how CREB in the NAc triggers depressive- and

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Figure 1. Simplified model by which interactions of CREB, DYN, and KORs regulate mood. Stress induces CREB-mediated increases in DYN actions at KORs on VTA neurons, which decreases their activity (Red X) and causes depressive- and anxiety-like behaviors. KOR antagonists would block dynorphin actions, restoring VTA cell function. Note that VTA projections to the NAc, prefrontal cortex (PFC), and amygdala (AMG) are separate cell populations. Based on Muschamp and Carlezon, 2013, with extensive modifications to artwork originally drawn by John Muschamp.

anxiety-like behaviors and why KOR antagonists have antidepressant- and anxiolytic-like effects.[5–7, 42] KORs are expressed on the cell bodies and terminals of meso- corticolimbic (VTA) dopamine (DA) neurons.[43, 44] Activation of these KORs, which are Gi-coupled, in- hibits DA release.[45, 46] In our model, stress activates CREB[15, 25] in the NAc, which leads to increases in DYN expression.[14, 20, 24] In turn, increased DYN tone pro- motes activation of KORs,[3] which dampens DA func- tion and triggers depressive- and anxiety-like behaviors, the latter being consistent with evidence that DA mod- ulates anxiety in animal models.[25, 47, 48] KOR antago- nists block DYN actions, restoring DA function.[7, 28] A related possibility is that KOR antagonists and standard antidepressants disrupt CREB function in the NAc,[20, 49] preventing stress-induced neuroadaptations. Regions in- cluding the AMG and prefrontal cortex (PFC) may also be substrates for the antidepressant-like effects of KOR antagonists.[27, 30, 50]

If the therapeutic effects KOR antagonists are derived from their ability to re-enable the function of a mesolim- bic system that is dysregulated by experience, then an ob- vious concern is that KOR antagonists may have abuse liability.[51] Current evidence suggests that this is not the case: there is nothing in the literature to indicate that KOR antagonists are self-administered, and on their own they do not affect ICSS thresholds,[52] which are de- creased by drugs with abuse liability.[53, 54] These find- ings are consistent with previous data indicating that

while KOR antagonists enable DA function, their effects are modest compared to classic drugs of abuse: infusion of KOR antagonists into the NAc increases local concen- trations of DA to �175% of baseline,[55] whereas psy- chostimulants such as cocaine and amphetamine cause increase approaching 1000% of baseline.[55, 56] Modest increases in DA function within the NAc may be suf- ficient to produce antidepressant and anxiogenic effects without rewarding effects.

NEEDS Pharmacodynamic effects can complicate drug devel-

opment and clinical trials. A single injection of the proto- typical KOR antagonist norBNI can block the effects of KOR agonists for months.[57, 58] Although the effects of JDTic are also persistent (>11 days in rats[38]), they are much more brief than those of norBNI.[34] The reasons for these extraordinarily long time courses are not un- derstood and are beyond the scope of the present review; explanations such as “drug depot” effects and biased lig- and actions have been proposed.[6, 34, 59] Regardless, such a long-time course can make many types of preclinical studies—including those designed to assess abuse lia- bility (e.g., intravenous drug self-administration, place conditioning)—difficult. It is also less than optimal for studies in humans, at least at the early stages of drug development, when a short duration of action or the abil- ity to reverse unanticipated side effects would be prefer-

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2015 ADAA Scientific Research Symposium: KORs in Psychiatric Illness 899

able until safety is established. Although long actions are common with the prototypical KOR antagonists, they are not an inevitable consequence of KOR blockade: per- sistent effects are not seen with nonselective opioid re- ceptor antagonists (e.g., naloxone) or LY2456302,[34, 60] a novel and selective KOR antagonist recently licensed to Cerecor (as CERC-501). Broad availability of selec- tive, short-acting KOR antagonists are needed to answer critical questions about the degree to which the same antistress effects are seen with agents devoid of persis- tent effects, or whether short-acting agents would have enhanced abuse liability, considering the importance of pharmacokinetics in drug self-administration.[61] Re- gardless, the preclinical portfolio for KOR antagonists has led to interest in developing this class of drugs[6] and moving them into clinical studies.

THE FUTURE: TRANSLATING PRECLINICAL DISCOVERIES TO HUMAN DRUG DEVELOPMENT

POTENTIAL THERAPEUTIC TARGETS IN HUMANS

The evidence reviewed above provides a strong pre- clinical basis for suggesting that KOR antagonists would have therapeutic effects in humans suffering from a num- ber of different disorders as defined in the DSM. This includes studies suggesting that KOR antagonists have effects in preclinical models often used to study mood disorders, anxiety disorders, and substance use disor- ders. However, categorical diagnostic systems such as the DSM have a series of inherent limitations. Among these are that they fail to characterize all individuals, and are less likely to be useful for the identification of biomarkers and mechanisms of pathology which are gen- erally dimensional phenomena.[62] The DSM categori- cal system has such limitations and has been noted to suffer from limited interrater reliability, and a lack of robust animal models for many conditions.[62] As a re- sult, the NIMH developed a dimensional framework for classifying psychophathology referred to as the Research Domain Criteria (RDoC) project, which is intended to serve as a framework for organizing research findings and a means of classifying psychopathology based on dimensions of observable behavior and neurobiological dimensions. The RDoC framework aligns particularly well with the effects of KOR antagonists as characterized by preclinical research. These agents have promise for having therapeutic effects on two types of RDoC-defined domains: those related to reward and those related to the adverse effects of stress.

The domain related to reward, referred to as “Posi- tive Valence Systems”, includes several key dimensions of reward function: Reward valuation, Expending Ef- fort for Reward, Reward prediction/expectancy, Reward Responsivity, and Effect of Reward on Learning. Impair- ments in these dimensions are broadly referred to as an- hedonia. Numerous preclinical studies reviewed above

suggest that KOR antagonists might have therapeutic effects on anhedonia.[25, 36, 46, 55, 63–66]

The other RDoC domain relevant to effects of KOR antagonists is related to stress and referred to as “Neg- ative Valence Systems.” Within this domain are sub- sumed Threat, Potential Harm, and Sustained Threat, all of which are endpoints that are potentially sensitive to KOR antagonists, based on the studies reviewed above indicating their potential to block the adverse effects of stress.[5, 7, 27, 67–69]

KOR ANTAGONIST AND KOR ANTAGONIST-LIKE DRUGS AND THEIR CHARACTERISTICS

There are numerous agents that are relatively potent and selective KOR antagonists. These include irreversible KOR antagonists, long-acting KOR antag- onists, and relatively short-acting KOR antagonists (see Table 1). Several agents have been developed which bind irreversibly to KOR receptors. For reasons described above, these agents are unlikely to be developed for clin- ical application. Two such agents, UPHIT and DIPPA block the effects of KOR agonists and DIPPA was found to have anxiolytic-like effects in rats.[6, 70]

Another group of agents, including JDTic, norBNI, and GNTI are relatively potent and selective KOR antagonist which have (1) a substantial delay in on- set of effects, (2) a duration of effect of up to weeks even at minimally effective doses, (3) limited brain penetration, and (4) problematic side effects.[59] JDTic has therapeutic effects in preclinical models used to study depression, anxiety, opiate withdrawal, as well as the stress-induced cocaine relapse and nicotine with- drawal models.[22, 23, 29, 59, 71] NorBNI has been found to have antidepressant-like effects in the FST and anxi- olytic effects in the EPM and fear-potentiated startle tests.[15, 22, 29] Finally, GNTI has antidepressant-like ef- fects in the FST, although one factor limiting its utility is very poor bioavailability.[22, 72, 73]

The group of KOR antagonists with the most promise for clinical use is agents with a relatively shorter duration of action and relatively rapid absorption. These agents include CERC-501 (previously called LY2456302), PF-4455242, AZ-MTAB, and peptides derived from dynorphin A. CERC-501 has a half-life of 38.5 hr and reversed the analgesic effects induced by a po- tent KOR agonist for less than a week.[59] This agent shows therapeutic-like effects in a preclinical model of alcoholism and appears not to have a risk of abuse based on evidence that it does not increase extracel- lular levels of DA in the NAc, an effect common to all reinforcing substances.[51, 59, 60, 74] CERC-501 also has antidepressant-like effects in the FST and there is some evidence that this agent may have synergistic ef- fects with imipramine indicating that it may have po- tential to be used as an antidepressant augmentation agent.[59] Similarly, PF-4455242 has been found to have antidepressant-like effects in the FST and social-defeat

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TABLE 1. Agents that block KORs

Agent Chemical name Key characteristics Selectivity

UPHIT (1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N- methyl-N-[2-(1- pyrrolidinyl)cyclohexyl] benzeneacetamide

Binds irreversibly to KOR Not available

DIPPA 2-(3,4-Dichlorophenyl)- N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2- (1-pyrrolidinyl)ethyl]acetamide

Binds irreversibly to KOR 814-Fold selectivity for KORs over MORs and greater than 450-fold selectivity over DORs

JDTic (3R)-7-Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3- methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide

Very long-lasting effects even at minimally effective doses; Slow Onset of Effects; Poor Bioavailability

341-Fold selectivity for KORs over MORs and 7930-fold selectivity over DORs

norBNI Norbinaltorphimine Very long-lasting effects even at minimally effective doses; Slow Onset of Effects; Poor Bioavailability

484-Fold selectivity for KORs relative to MORs and 113-fold selectivity for KORs vs DORs

GNTI 5′-Guanidinonaltrindole Very long-lasting effects even at minimally effective doses; Slow Onset of Effects; Poor Bioavailability

193-Fold selectivity for KORs relative to MORs and 366-fold selectivity for KORs vs DORs

CERC-501 (Previously known as LY2456302)

4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide

Relatively shorter duration of action and relatively rapid absorption

21- to 43-Fold selectivity for KORs over MORs

PF-4455242 2-Methyl-N-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl- 4-yl)methyl)propan-1-amine

Relatively shorter duration of action and relatively rapid absorption

21-Fold selectivity for KORs over MORs

AZ-MTAB 3- [[(3-Endo)-8-[(5-methyl-2-thienyl)methyl]-8- azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide

Relatively shorter duration of action and relatively rapid absorption

37-Fold selectivity for KORs relative to MORs and 440-fold selectivity for KORs relative to DORs

Arodyn Ac[Phe1,2,3,Arg4,D-Ala8]dynorphin A-(1–11) amide Dynorphin A derivative 174-Fold selectivity for KOR over MOR and 583-fold selectivity over DOR

Zyklophin N-Benzyl-L-tyrosylglycylglycyl-N-[(3S,6S,9S,12S)- 6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido- 1-[(2S)-2-{[(2S)-1,6-diamino-1-oxo-2- hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2- pentanyl}carbamoyl)-9-(3- carbamimidamidopropyl)-5,8,11,14-tetraoxo- 1,4,7,10-tetraazacyclotetradecan-12-yl]-L- phenylalaninamide

Dynorphin A derivative 194-Fold selectivity for KOR over MOR and 330-fold selectivity over DOR

Buprenorphine (2S)-2-[(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5- epoxy-6,14-ethano-3-hydroxy-6- methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol

Weak partial MOR agonist, KOR antagonist, DOR antagonist, weak partial agonist at nociception receptors

Receptor-binding affinities are: MOR Ki = 1.5 nM; KOR Ki = 2.5 nM; DOR Ki = 6.1 nM; and nociception receptors Ki = 77.4 nM

Sources: [6, 22, 59, 68, 76–79, 102, 103]

test.[75] It also has demonstrated promise as a treat- ment for substance use related disorders in preclinical models.[59, 75] A key factor impeding the development of this compound is evidence of toxicity in animal studies when taken for over 90 days.[59] Finally, AZ-MTAB has been found to block the effects of KOR agonists and have antidepressant and anxiolytic-like effects in animal models.[68]

Peptide-selective KOR antagonists derived from dynorphin A represent an interesting alternative to these more classical agents. These include arodyn and zyklophin, which have been found to block the effects

of KOR agonists.[76, 77] In preclinical models, zyklophin has been found to prevent stress-induced resumption of cocaine seeking.[77]

Some agents that have clinically significant pharma- cologic effects in addition to KOR antagonism have been evaluated for the treatment of psychiatric condi- tions. The most important of these is buprenorphine, which is a weak partial MOR agonist, KOR antago- nist (or weak partial agonist), DOR antagonist, as well as a weak partial agonist at nociceptin receptors.[78, 79] The use of buprenorphine for opiate dependence is well established.[80, 81] In addition, buprenorphine has

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been found to have antidepressant-like and anxiolytic- like effects in mice based on the FST and the novelty- induced hyperphagia test that were sustained over 6 days of daily treatment.[82] However, there is some evi- dence that in rats the antidepressant-like effects are strain dependent.[83]

There has been interest in combining buprenor- phine with other agents in order to achieve greater pharmacologic selectivity.[84–86] It has been combined with naltrexone, a nonselective antagonist at all types of opioid receptors, to create a relatively selective KOR antagonist. This combination has been found to have antidepressant-like effects in the FST and novelty- induced hypophagia tests,[86] as well as tests for potential as a therapy for cocaine abuse and prevention of relapse in prior cocaine and opiate-dependent individuals.[84, 85]

CLINICAL TRIALS COMPLETED WITH KOR ANTAGONISTS AND KOR ANTAGONIST-LIKE AGENTS

JDTic was evaluated in phase I trials with the intent to develop this agent for the treatment of cocaine abuse. However, this effort was halted due to prohibitive ad- verse events including ventricular tachycardia.[59, 87] PF- 4455242 was evaluated in a human phase 1 trial with the intent to develop this agent for the treatment of mood disorders and substance use disorders. However, as de- scribed above, these efforts were discontinued due to evidence of toxicity in animal studies when administered for over 90 days.[59] Buprenorphine has been studied in a number of clinical trials of its utility in the treatment of psychiatric conditions. By far the best-studied condi- tion has been the treatment of opioid dependence.[81] Thirty-one trials including 5430 patients have es- tablished the utility of buprenorphine maintenance therapy for the treatment of this condition. Some evidence also suggests that buprenorphine has efficacy for the treatment of concurrent opiate and cocaine dependence.[88–90] There is also preliminary evidence that buprenorphine may have antidepressant effects. This includes reports of improvement in depression in depressed opiate-dependent individuals treated with buprenorphine,[88] antidepressant effects in a double- blind, placebo-controlled, cross-over study involving 10 depressed patients,[78] and improvement in depression in open label-studies including 10 patients with treatment- refractory depression,[91] six patients who failed antide- pressant medications and ECT,[92] as well as 15 older adults with treatment resistant depression.[93] Lastly, one double-blind, placebo-controlled study including 48 healthy controls found evidence that buprenor- phine diminishes the response to social stress that was elicited with the Trier Social Stress Test.[94] There is also one preliminary study indicating that ultra-low dose buprenorphine may have a therapeutic effect on suicidality.[95] Buprenorphine has well-established ef- fects as a treatment for opioid dependence. In addition, the available studies provide preliminary evidence that

buprenorphine may have therapeutic effects in patients with mood disorders and in mitigating the effects of stress. However, because buprenorphine is not a selec- tive KOR antagonist, it cannot be concluded that this promise is linked specifically to KOR antagonism.

Two open-label studies have been carried out evaluat- ing the effects of the combination of buprenorphine and naltrexone in patients with substance use disorders.[96] Evidence for a therapeutic effect was found in open- label studies including 15 and 60 heroin-dependent individuals.[97, 98] These studies provide preliminary evi- dence that therapeutic effects of buprenorphine on opi- oid dependence may be due, at least in part, to KOR antagonism.

Based on the same logic that supports the use of the combination of buprenorphine and naltrexone as a relatively selective KOR antagonist, there have been studies of buprenorphine combined with the MOR an- tagonist samidorphan.[99] One study was intended to es- tablish the relationship between dose of samidorphan and opioid antagonism when added to a fixed dose of buprenorphine.[99] This parallel-group study was car- ried out in “opioid-experienced adults” and utilized as outcome measures of opioid antagonism, pupillome- try, and self-ratings of euphoria and drug-liking. The doses of samidorphan that led to clinically significant opioid antagonism were then administered along with a fixed dose of buprenorphine in a double-blind, placebo- controlled, cross-over trial in 32 patients with treatment- resistant depression.[99] A rapid antidepressant response was noted (observed after 7 days of treatment) with a 1:1 ratio of dosage of samidorphan and buprenorphine; a regimen that was associated with maximal blockade of opioid clinical effects.[99] Given that this treatment was well tolerated, this study indicates the promise of the combination of samidorphan and buprenorphine and more generally KOR antagonism as a rapidly acting an- tidepressant therapy.

CURRENTLY ONGOING NIMH-SUPPORTED CLINICAL TRIALS OF KOR ANTAGONISTS

The National Institute of Mental Health (NIMH) is currently supporting two clinical trials evaluating CERC-501. One is being carried out under the Rapidly- Acting Treatments for Treatment-Resistant Depression (RAPID) program and the other in New Experimental Medicine Studies: Fast-Fail Trials in Mood and Anxiety Spectrum Disorders (FAST-MAS) Program.

The goal of the RAPID NIMH contract initiative is to develop treatments for severe treatment-resistant major depression that have a more rapid onset of antidepressant effects than currently available therapies. The RAPID initiative is based on increasing evidence that it is possible to achieve a significantly more rapid therapeutic antide- pressant effect with some therapies such as electroncon- vulsive therapy (ECT), sleep deprivation, and ketamine infusion. The RAPID program is carrying out studies of other antidepressant interventions that have promise

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for having onset of effects within several days and hav- ing fewer limitations than the existing rapid-onset op- tions. Among the promising therapies being studied is CERC-501. The RAPID study is assessing outcome 3 days after initiating treatment with CERC-501 and placebo. As such, it will provide a definitive indication of whether KOR antagonism is associated with a rapid on- set of antidepressant effects. A secondary objective is to also assess the degree to which benefit is sustained after the initial 3-day period. If CERC-501 is found to have significant and sustained therapeutic effects within 3 days of initiating treatment and is well tolerated, it will be po- sitioned to serve as rapidly acting antidepressant therapy suitable for widespread use and will make a significant and needed contribution to the clinical management of major depression.

The NIMH FAST-MAS contract program is in- tended to address the need for new medications that better treat patients with mood and anxiety spectrum disorders. It seeks to do so by (1) identifying promising new targets in the brain that could be the basis for devel- opment of new drugs, and (2) employing methodology for rapidly assessing the promise of those targets.[100, 101] KOR antagonism was identified as among the most promising new targets and CERC-501 is being evaluated in an ongoing FAST-MAS trial. Among the method- ologic innovations being implemented in FAST-MAS is the use of the RDoC dimensional approach to clas- sifying psychiatric pathology and the use of biomark- ers to assess the promise of a target more robustly with a smaller number of subjects than current methods by testing the hypothesis that engaging the target has the intended effect on brain circuitry. The FAST-MAS trial is evaluating the effects of CERC-501 on anhedonia. The associated reward-related biomarker that is being used to test the hypothesis that engaging the target (blocking KOR) has the hypothesized effect on brain function is task-related fMRI activation in the ventral striatum (NAc) during anticipation of rewards in the Monetary Incentive Delay Task. If this is found to be the case, the FAST-MAS trial will indicate that KOR antagonism is promising as a means of treating anhe- donia, which is one of the most prominent hypothe- sized effects of KOR antagonism based on preclinical research.

SUMMARY AND FUTURE DIRECTIONS The available studies support the utility of KOR

antagonism for treating substance use related disor- ders and suggest their potential as treatments for ma- jor depression. Trials are underway testing whether they are indeed useful as antidepressant therapies and whether they may have particular utility as rapidly acting treatments.

The preclinical studies and some preliminary human trial data also suggest that KOR antagonists may be particularly useful for the treatment of stress-mediated symptoms. Currently, there is no precedent for a treat-

ment directed at mitigating the adverse effects of stress. Social anxiety disorder and phobias should be consid- ered as potential conditions to treat with KOR antag- onists. The lack of precedent presents a challenge to pursuing development of KOR antagonists for the mit- igation of stress-related symptoms, in part because of challenges with respect to study design. The existing data would suggest that KOR antagonists might be use- ful as prophylactic therapy to prevent adverse sequelae arising from stress. In this regard, it is reasonable to consider whether KOR antagonism might be a much- needed means to prevent the development of PTSD in individuals at great risk to experience trauma. Clearly, further work is needed to better delineate the nature of the effects of KOR antagonists in humans with respect to mitigation of stress-related symptoms. However, the preclinical work suggests that this is another avenue to pursue.

Yet another promising therapeutic application of KOR antagonism suggested by the preclinical research is the treatment of impairment in reward-related function as it frequently occurs in patients with mood and anxiety spectrum disorders, but may occur in those with other types of conditions such as schizophrenia. This is another potential use of KOR antagonists for which there is no precedent in terms of approved therapies or attempts at treatment development. The potential of KOR an- tagonism as a means of treating anhedonia is currently being evaluated in the FAST-MAS trial. This trial also has the potential to help address some of the challenges facing developing a treatment for anhedonia by evalu- ating potential outcome measures that could be used in subsequent trials.

Overall, KOR antagonism is a highly promising tar- get for the treatment of psychiatric conditions. There are molecules available and in development that are highly selective and potent and thus are of interest as potential treatments for the key psychopathologic entities of inter- est including substance use disorders, major depression, anhedonia, and stress-related symptoms. Importantly, the mechanism of action by which these drugs would produce therapeutic actions is already well established (Fig. 1), as opposed to the case for the vast majority of psychiatric medications,[40] Developing these molecules as treatments for these conditions might not only provide some improved therapeutics for psychiatric pathological conditions, but also help us to better define our psy- chopathological entities and, in so doing, may provide us with means to better help patients who suffer from psychiatric disorders.

FUNDING AND DISCLOURES. Supported by MH063266 (to W.A.C.) and HHS-N271-2012-000006- I (to A.D.K.). Dr. Carlezon discloses that he is an inventor on several patents that claim the use of se- lective kappa-opioid ligands to treat psychiatric illness (Assignee: McLean Hospital) and during the past 2 years has received compensation as a consultant for Cerecor.

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REFERENCES

1. Nestler EJ, Carlzon WA. The mesolimbic dopamine reward cir- cuit in depression. Biol Psychiatry 2006;59:1151–1159.

2. Carlezon WA, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci 2005;28:436–445.

3. Chavkin C, James IF, Goldstein A. Dynorphin is a specific en- dogenous ligand of the κ opioid receptor. Science 1982;215:413– 415. doi:10.1016/0304-3959(82)90120-8.

4. Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 2010;1314:44–55. doi:10.1016/j.brainres.2009.08.062.

5. Knoll AT, Carlezon WA. Dynorphin, stress, and depression. Brain Res 2010;1314:56–73. doi:10.1016/j.brainres.2009.09.074.

6. Carroll FI, Carlezon William AJ. Development of κ opi- oid receptor antagonists. J Med Chem 2013;56:2178–2195. doi:10.1021/jm301783x.

7. Van’t Veer A, Carlezon WA. Role of kappa-opioid receptors in stress and anxiety-related behavior. Psychopharmacology (Berl) 2013;229:435–452. doi:10.1007/s00213-013-3195-5.

8. Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant ad- ministration increases the expression of cAMP response ele- ment binding protein (CREB) in rat hippocampus. J Neurosci 1996;16:2365–2372.

9. Chen ACH, Shirayama Y, Shin KH, et al. Expression of the cAMP response element binding protein (CREB) in hip- pocampus produces an antidepressant effect. Biol Psychiatry 2001;49:753–762. doi:10.1016/S0006-3223(00)01114-8.

10. Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 2006;59:1136–1143. doi:10.1016/j.biopsych.2006.03.082.

11. Turgeon SM, Pollack AE, Fink JS. Enhanced CREB phospho- rylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization. Brain Res 1997;749:120– 126. doi:10.1016/S0006-8993(96)01316-9.

12. Kalivas PW, Stewart J. Dopamine transmission in the ini- tiation and expression of drug-induced and stress-induced sensitization of motor-activity. Brain Res Rev 1991;16:223–244. doi:10.1016/0165-0173(91)90007-U.

13. Lett BT. Repeated exposures intensify rather than di- minish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology (Berl) 1989;98:357–362. doi:10.1007/BF00451687.

14. Carlezon WA, Thome J, Olson VG, et al. Regulation of co- caine reward by CREB. Science (80-) 1998;282:2272–2275. doi:10.1126/science.282.5397.2272.

15. Pliakas AM, Carlson RR, Neve RL, et al. Altered responsiveness to cocaine and increased immobility in the forced swim test asso- ciated with elevated cAMP response element-binding protein ex- pression in nucleus accumbens. J Neurosci 2001;21:7397–7403. doi:21/18/7397 [pii].

16. Kelz MB, Chen J, Carlezon WA, Jr., et al. Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature 1999;401:272–276. doi:10.1038/45790.

17. Pfeiffer A, Brantl V, Herz A, et al. Psychotomimesis medi- ated by kappa opiate receptors. Science (80-) 1986;233:774–776. doi:10.1126/science.3016896.

18. Walsh SL, Strain EC, Abreu ME, et al. Enadoline, a se- lective kappa opioid agonist: Comparison with butorphanol and hydromorphone in humans. Psychopharmacology (Berl) 2001;157:151–162. doi:10.1007/s002130100788.

19. Bals-Kubik R, Ableitner A, Herz A, et al. Neuroanatomical sites mediating the motivational effects of opioids as mapped by the

conditioned place preference paradigm in rats. J Pharmacol Exp Ther 1993;264:489–495.

20. Chartoff EH, Papadopoulou M, MacDonald ML, et al. Desipramine reduces stress-activated dynorphin expression and CREB phosphorylation in NAc tissue. Mol Pharmacol 2009;75:704–712. doi:10.1124/mol.108.051417.

21. Newton SS, Thome J, Wallace TL, et al. Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. J Neurosci 2002;22:10883–10890. doi: 22/24/10883 [pii].

22. Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant- like effects of κ-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther 2003;305:323–330.

23. Beardsley PM, Howard JL, Shelton KL, et al. Differen- tial effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by foot- shock stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl) 2005;183:118–126. doi:10.1007/s00213-005-0167-4.

24. Shirayama Y, Ishida H, Iwata M, et al. Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like ef- fects. J Neurochem 2004;90:1258–1268. doi:10.1111/j.1471- 4159.2004.02589.x.

25. Muschamp JW, Van’t Veer A, Parsegian A, et al. Activation of CREB in the nucleus accumbens shell produces anhedonia and resistance to extinction of fear in rats. J Neurosci 2011;31:3095– 3103. doi:10.1523/JNEUROSCI.5973-10.2011.

26. Donahue RJ, Landino SM, Golden SA, et al. Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system. Behav Pharmacol 2015;26:654–663. doi:10.1097/FBP.0000000000000155.

27. Bruchas MR, Land BB, Lemos JC, et al. CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amyg- dala mediates anxiety-like behavior. PLoS One 2009;4:e8528. doi:10.1371/journal.pone.0008528.

28. Carlezon WA. Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther 2009;123:334–343.

29. Knoll AT, Meloni EG, Thomas JB, et al. Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 2007;323:838–845. doi:10.1124/jpet.107.127415.

30. Knoll AT, Muschamp JW, Sillivan SE, et al. Kappa opioid re- ceptor signaling in the basolateral amygdala regulates condi- tioned fear and anxiety in rats. Biol Psychiatry 2011;70:425–433. doi:10.1016/j.biopsych.2011.03.017.

31. Bagdy G, Graf M, Anheuer ZE, et al. Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor an- tagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635. Int J Neuropsychopharmacol 2001;4:399–408. doi:10.1017/S1461145701002632.

32. Drapier D, Bentué-Ferrer D, Laviolle B, et al. Effects of acute fluoxetine, paroxetine and desipramine on rats tested on the elevated plus-maze. Behav Brain Res 2007;176:202–209. doi:10.1016/j.bbr.2006.10.002.

33. Endoh T, Matsuura H, Tanaka C, et al. Nor-binaltorphimine: a potent and selective k-opioid receptor antagonist with long-lasting activity in vivo. Arch Int Pharmacodyn Thér 1992;316:30–42.

34. Melief EJ, Miyatake M, Carroll FI, et al. Duration of action of a broad range of selective κ-opioid receptor antagonists is positively correlated with c-Jun N-terminal kinase-1 activation. Mol Pharmacol 2011;80:920–929. doi:10.1124/mol.111.074195.

Depression and Anxiety

904 Carlezon and Krystal

35. Mahan AL, Ressler KJ. Fear conditioning, synpatic plasticity, and the amygdala: implications for posttrau- matic stress disorder. Trends Neurosci 2013;35:24–35. doi:10.1016/j.tins.2011.06.007.Fear.

36. Chartoff E, Sawyer A, Rachlin A, et al. Blockade of kappa opioid receptors attenuates the development of depressive-like behav- iors induced by cocaine withdrawal in rats. Neuropharmacology 2012;62:167–176. doi:10.1016/j.neuropharm.2011.06.014.

37. Schank JR, Goldstein AL, Rowe KE, et al. The kappa opioid receptor antagonist JDTic attenuates alcohol seek- ing and withdrawal anxiety. Addict Biol 2012;17:634–647. doi:10.1111/j.1369-1600.2012.00455.x.

38. Van’t Veer A, Yano JM, Carroll FI, et al. Corticotropin-releasing factor (CRF)-induced disruption of attention in rats is blocked by the κ-opioid receptor antagonist JDTic. Neuropsychophar- macology 2012;2809–2816. doi:10.1038/npp.2012.151.

39. Beard C, Donahue RJ, Dillon DG, et al. Abnormal error pro- cessing in depressive states: a translational examination in hu- mans and rats. Transl Psychiatry 2015;5:e564. doi:10.1038/ tp.2015.54.

40. Carlezon WA, George TP. Circumspectives: the promise of ke- tamine. Neuropsychopharmacology 2015;40:257–258.

41. Carlezon WA, Chartoff E. Perspective: Progress on the study and treatment of depressive illness. Neuropsychopharmacology 2009;34:1361–1362. doi:10.1038/npp.2009.16.

42. Muschamp JW, Carlezon WA. Roles of nucleus accum- bens CREB and dynorphin in dysregulation of motiva- tion. Cold Spring Harb Perspect Med 2013;3:a012005. doi:10.1101/cshperspect.a012005.

43. Svingos AL, Colago EE, Pickel VM. Cellular sites for dynorphin activation of κ-opioid receptors in the rat nucleus accumbens shell. J Neurosci 1999;19:1804–1813.

44. Svingos AL, Chavkin C, Colago EEO, et al. Major coexpres- sion of κ-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles. Synapse 2001;42:185–192. doi:10.1002/syn.10005.

45. Donzanti BA, Althaus JS, Payson MM, et al. Kappa agonist- induced reduction in dopamine release: site of action and toler- ance. Res Commun Chem Pathol Pharmacol 1992;78:193–210.

46. Carlezon WA, Béguin C, DiNieri JA, et al. Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther 2006;316:440–447. doi:10.1124/jpet.105.092304.

47. Reis FLV, Masson S, De Oliveira AR, et al. Dopamin- ergic mechanisms in the conditioned and unconditioned fear as assessed by the two-way avoidance and light switch-off tests. Pharmacol Biochem Behav 2004;79:359–365. doi:10.1016/j.pbb.2004.08.006.

48. Carlezon WA, Thomas MJ. Biological substrates of reward and aversion: A nucleus accumbens activ- ity hypothesis. Neuropharmacology 2009;56:122–132. doi:10.1016/j.neuropharm.2008.06.075.

49. Schwaninger M, Schöfl C, Blume R, et al. Inhibition by antide- pressant drugs of cyclic AMP response element-binding pro- tein/cyclic AMP response element-directed gene transcription. Mol Pharmacol 1995;47:1112–1118.

50. Tejeda HA, Counotte DS, Oh E, et al. Prefrontal corti- cal kappa-opioid receptor modulation of local neurotransmis- sion and conditioned place aversion. Neuropsychopharmacology 2013;38:1770–1779. doi:10.1038/npp.2013.76.

51. Wise RA. Brain dopamine and reward. Annu Rev Psychol 1989;40:191–225. doi:10.1146/annurev.psych.40.1.191.

52. Todtenkopf M, Marcus JF, Portoghese PS, Carlezon WA Jr. Ef- fects of κ-opioid receptor ligands on intracranial self-stimulation in rats. Psychopharmacology 2004;172:463–470.

53. Wise RA. Drug-activation of brain reward pathways. Drug Alco- hol Depend 1998;51:13–22. doi:10.1016/S0376-8716(98)00063- 5.

54. Carlezon WA, Chartoff EH. Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc 2007;2:2987–2995. doi:10.1038/nprot.2007.441.

55. Maisonneuve IM, Archer S, Glick SD. U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extra- cellular dopamine in the nucleus accumbens of rats. Neurosci Lett 1994;181:57–60.

56. Di Chiara G, Imperato A. Drugs abused by humans preferen- tially increase synaptic dopamine concentrations in the mesolim- bic system of freely moving rats. Proc Natl Acad Sci U S A 1988;85:5274–5278. doi:10.1073/pnas.85.14.5274.

57. Spanagel R, Shippenberg TS. Modulation of morphine-induced sensitization by endogenous κ-opioid systems in the rat. Neu- rosci Lett 1993;153:232–236. doi:10.1016/0304-3940(93)90329- J.

58. Potter DN, Damez-Werno D, Carlezon WA, Jr., et al. Repeated exposure to the kappa-opioid receptor agonist salvinorin A modulates extracellular signal-regulated kinase and reward sensitivity. Biol Psychiatry 2011;70:744–753. doi:10.1016/j.biopsych.2011.05.021.

59. Urbano M, Guerrero M, Rosen H, et al. Antagonists of the kappa opioid receptor. Bioorg Med Chem Lett 2014;24:2021–2032. doi:10.1016/j.bmcl.2014.03.040.

60. Rorick-Kehn LM, Witkin JM, Statnick MA, et al. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa- selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology 2014;77:131–144. doi:10.1016/j.neuropharm.2013.09.021.

61. Allain F, Minogianis EA, Roberts DCS, et al. How fast and how often: the pharmacokinetics of drug use are deci- sive in addiction. Neurosci Biobehav Rev 2015;56:166–179. doi:10.1016/j.neubiorev.2015.06.012.

62. Insel T, Cuthbert B, Garvey M, et al. Research domain cri- teria (RDoC): toward a new classification framework for re- search on mental disorders. Am J Psychiatry 2010;167:748–751. doi:10.1176/appi.ajp.2010.09091379.

63. Tomasiewicz HC, Todtenkopf MS, Chartoff EH, et al. The κ- opioid agonist U69,593 blocks cocaine-induced enhancement of brain stimulation reward. Biol Psychiatry 2008;64:982–988. doi:10.1016/j.biopsych.2008.05.029.

64. Bruijnzeel AW. kappa-Opioid receptor signaling and brain reward function. Brain Res Rev 2009;62:127–146. doi:10.1016/j.brainresrev.2009.09.008.

65. Ebner SR, Roitman MF, Potter DN, et al. Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nu- cleus accumbens. Psychopharmacology (Berl) 2010;209:241– 252. doi:10.1007/s00213-010-1836-5.

66. Wee S, Koob GF. The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychophar- macology (Berl) 2010;210:121–135. doi:10.1007/s00213-010- 1825-8.

67. Land BB, Bruchas MR, Lemos JC, et al. The dyspho- ric component of stress is encoded by activation of the dynorphin κ-opioid system. J Neurosci 2008;28:407–414. doi:10.1523/JNEUROSCI.4458-07.2008.

Depression and Anxiety

2015 ADAA Scientific Research Symposium: KORs in Psychiatric Illness 905

68. Peters MF, Zacco A, Gordon J, et al. Identifica- tion of short-acting κ-opioid receptor antagonists with anxiolytic-like activity. Eur J Pharmacol 2011;661:27–34. doi:10.1016/j.ejphar.2011.04.017.

69. Schindler AG, Messinger DI, Smith JS, et al. Stress pro- duces aversion and potentiates cocaine reward by releasing endogenous dynorphins in the ventral striatum to locally stimulate serotonin reuptake. J Neurosci 2012;32:17582–17596. doi:10.1523/JNEUROSCI.3220-12.2012.

70. Carr GV, Lucki I. Comparison of the kappa-opioid receptor an- tagonist DIPPA in tests of anxiety-like behavior between wis- tar kyoto and sprague dawley rats. Psychopharmacology (Berl) 2010;209:295–302. doi:10.1007/s00213-010-1832-9.

71. Carroll FI, Harris LS, Aceto MD. Effects of JDTic, a se- lective κ-opioid receptor antagonist, on the development and expression of physical dependence on morphine using a rat continuous-infusion model. Eur J Pharmacol 2005;524:89–94. doi:10.1016/j.ejphar.2005.09.013.

72. Jones RM, Portoghese PS. 5’-Guanidinonaltrindole, a highly se- lective and potent kappa-opioid receptor antagonist. Eur J Phar- macol 2000;396:49–52.

73. Negus SS, Mello NK, Linsenmayer DC, et al. Kappa opi- oid antagonist effects of the novel kappa antagonist 5’- guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys. Psychopharmacology (Berl) 2002;163:412–419.

74. Walker BM, Koob GF. Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol de- pendence. Neuropsychopharmacology 2008;33:643–652. doi:10.1038/sj.npp.1301438.

75. Grimwood S, Lu Y, Schmidt AW, et al. Pharmacological characterization of 2-methyl-N-((2’- (pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a high-affinity antagonist selective for κ- opioid receptors. J Pharmacol Exp Ther 2011;339:555–566. doi:10.1124/jpet.111.185108.

76. Carey AN, Borozny K, Aldrich JV, et al. Reinstatement of co- caine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. Eur J Pharmacol 2007;569:84–89. doi:10.1016/j.ejphar.2007.05.007.

77. Aldrich JV, Patkar KA, McLaughlin JP. Zyklophin, a systemically active selective kappa opioid receptor pep- tide antagonist with short duration of action. Proc Natl Acad Sci U S A 2009;106:18396–18401. doi:0910180106 [pii]\r10.1073/pnas.0910180106.

78. Emrich HM, Vogt P, Herz A, et al. Antidepressant effects of buprenorphine. Lancet 1982;2:709. doi:S0140-6736(82)90727- 9 [pii].

79. Khroyan TV, Wu J, Polgar WE, et al. BU08073 a buprenor- phine analog with partial agonist activity at μ-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice. Br J Pharmacol 2015;172:668–680. doi:10.1111/bph.12796.

80. Ducharme S, Fraser R, Gill K. Update on the clinical use of buprenorphine: in opioid-related disorders. Can Fam Physician 2012;58:37–41.

81. Mattick RP, Breen C, Kimber J, et al. Buprenorphine main- tenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2014;2:CD002207. doi:10.1002/14651858.CD002207.pub4.Copyright.

82. Falcon E, Maier K, Robinson SA, et al. Effects of buprenor- phine on behavioral tests for antidepressant and anxiolytic drugs in mice. Psychopharmacology (Berl) 2015;232:907–915. doi:10.1007/s00213-014-3723-y.

83. Browne CA, van Nest DS, Lucki I. Antidepressant-like effects of buprenorphine in rats are strain dependent. Behav Brain Res 2015;278:385–392. doi:10.1016/j.bbr.2014.10.014.

84. Wee S, Vendruscolo LF, Misra KK, et al. A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence. Sci Transl Med 2012;4:146ra110. doi:10.1126/scitranslmed.3003948.

85. Cordery SF, Taverner A, Ridzwan IE, et al. A non-rewarding, non-aversive buprenorphine/naltrexone combination attenu- ates drug-primed reinstatement to cocaine and morphine in rats in a conditioned place preference paradigm. Addict Biol 2014;19:575–586. doi:10.1111/adb.12020.

86. Almatroudi A, Husbands SM, Bailey CP, et al. Com- bined administration of buprenorphine and naltrexone pro- duces antidepressant-like effects in mice. J Psychopharmacol 2015;29:812–821. doi:10.1177/0269881115586937.

87. Buda JJ, Carroll FI, Kosten TR, et al. A double-blind, placebo-controlled trial to evaluate the safety, tolerability, and pharmacokinetics of single, escalating oral doses of JDTic. Neuropsychopharmacology 2015;40:2059–2065.

88. Kosten TR, Kleber HD, Morgan C. Treatment of cocaine abuse with buprenorphine. Biol Psychiatry 1989;26:637–639. doi:10.1016/0006-3223(89)90090-5.

89. Schottenfeld RS, Pakes JR, Oliveto A, et al. Buprenorphine vs methadone maintenance treatment for concurrent opioid depen- dence and cocaine abuse. Arch Gen Psychiatry 1997;54:713–720. doi:10.1001/archpsyc.1997.01830200041006.

90. Montoya ID, Gorelick DA, Preston KL, et al. Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence. Clin Pharmacol Ther 2004;75:34–38. doi:10.1016/j.clpt.2003.09.004.

91. Bodkin JA, Zornberg GL, Lukas SE, et al. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol 1995;15:49–57. doi:10.1097/00004714-199502000-00008.

92. Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to antidepressants and electrocon- vulsive therapy. J Clin Psychopharmacol 2008;28:593–595. doi:10.1097/JCP.0b013e31818638a4.

93. Karp JF, Butters MA, Begley AE, et al. Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment- resistant depression in midlife and older adults. J Clin Psychiatry 2014;75:e785–93. doi:10.4088/JCP.13m08725.

94. Bershad AK, Jaffe JH, Childs E, et al. Opioid partial agonist buprenorphine dampens responses to psychosocial stress in humans. Psychoneuroendocrinology 2015;52:281–288. doi:10.1016/j.psyneuen.2014.12.004.

95. Yovell Y, Bar G, Mashiah M, et al. Ultra-low-dose buprenor- phine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry 2015;appi- ajp201515040535.

96. McCann DJ. Potential of buprenorphine/naltrexone in treating polydrug addiction and co-occurring psychiatric disorders. Clin Pharmacol Ther 2008;83:627–630. doi:10.1038/sj.clpt.6100503.

97. Rothman RB, Gorelick DA, Heishman SJ, et al. An open-label study of a functional opioid κ antagonist in the treatment of opioid dependence. J Subst Abuse Treat 2000;18:277–281.

98. Gerra G, Fantoma A, Zaimovic A. Naltrexone and buprenorphine combination in the treatment of opi- oid dependence. J Psychopharmacol 2006;20:806–814. doi:10.1177/0269881106060835.

99. Ehrich E, Turncliff R, Du Y, et al. Evaluation of opioid modu- lation in major depressive disorder. Neuropsychopharmacology 2014;40:1–8. doi:10.1038/npp.2014.330.

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100. Insel TR, Scolnick EM. Cure therapeutics and strategic preven- tion: raising the bar for mental health research. Mol Psychiatry 2006;11:11–17. doi:10.1038/sj.mp.4001777.

101. Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 2010;9:203–214. doi:10.1038/nrd3078.

102. Bennett MA, Murray TF, Aldrich JV. Structure–activity rela- tionships of arodyn, a novel acetylated kappa opioid receptor antagonist. J Pept Res 2005;65:322–332.

103. Stevens WC, Jones RM, Subramanian G, et al. Potent and selective indolomorphinan antagonists of the kappa- opioid receptor. J Med Chem 2000;43:2759–2769. doi:10.1021/ jm0000665.

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