Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial.

Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials.

Current progress in the pharmacological therapy of fibromyalgia.

Fibromyalgia (FM) is a chronic musculoskeletal pain disorder often associated with fatigue, dyscognition, and sleep disturbances. Recent research advances highlight a critical role for aberrant central pain processing in FM, and, consistent with these data, the first three drugs approved by the FDA for FM over the past 2 years have a predominantly central mode of action. The first drug, pregabalin, may counteract central pain transmission by inhibiting presynaptic release of excitatory neurotransmitters, including substance P and glutamate. The serotonin-norepinephrine reuptake inhibitors duloxetine and milnacipran have been approved more recently and are believed to reduce pain by increasing serotonin and norepinephrine concentrations in descending inhibitory pain pathways. Agents with multiple other mechanisms of action are in development and promise an assortment of therapeutic options for this complex disorder in the near future.

The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM). METHODS: A 27-week, randomized, double-blind, multicenter study compared milnacipran 100 and 200 mg/day with placebo in the treatment of 888 patients with FM. Two composite responder definitions were used to classify each patient's individual response to therapy. "FM responders" concurrently satisfied response criteria for improvements in pain (visual analog scale 24-h morning recall), patient global impression of change (PGIC), and physical functioning (SF-36 Physical Component Summary); while "FM pain responders" concurrently satisfied response criteria for improvements in pain and PGIC. RESULTS: At the primary endpoint, after 3-month stable dose treatment, a significantly higher percentage of milnacipran-treated patients met criteria as FM responders versus placebo (milnacipran 200 mg/day, p = 0.017; milnacipran 100 mg/day, p = 0.028). A significantly higher percentage of patients treated with milnacipran 200 mg/day also met criteria as FM pain responders versus placebo (p = 0.032). Significant pain reductions were observed after Week 1 with both milnacipran doses. At 15 weeks, milnacipran 200 mg/day led to significant improvements over placebo in pain (realtime, daily and weekly recall; all measures, p < 0.05), PGIC (p < 0.001), fatigue (p = 0.016), cognition (p = 0.025), and multiple SF-36 domains. Milnacipran was safe and well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events. CONCLUSION: Milnacipran is safe and effective for the treatment of multiple symptoms of FM.

Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea.

OBJECTIVE: Mirtazapine is an a2A antagonist and mixed 5-HT2/5-HT3 antagonist that has been proposed as a potential treatment for obstructive sleep apnea (OSA). A small, randomized, controlled trial has previously found an approximate halving in the severity of OSA with daily doses of 4.5 and 15 mg. We aimed to confirm and extend these findings in 2 randomized placebo-controlled, proof-of-concept trials. METHODS: Two randomized, double-blind, placebo-controlled trials of mirtazapine for OSA (apnea-hypopnea index 10-40/h). Study 1: 3-way crossover, dose-finding study testing the self-administration of mirtazapine (7.5, 15, 30, and/or 45 mg) or placebo 30 minutes prior to bedtime for 2 weeks at each dose. Twenty patients were randomly assigned to 1 of 6 different dose-sequence groups, with each patient exposed to a maximum of 3 doses. Study 2: 3-arm, randomized, parallel-group trial of mirtazapine at 15 mg or mirtazapine 15 mg + Compound CD0012 or placebo for 4 weeks in 65 patients with OSA. RESULTS: Two patients withdrew from Study 1 after complaints of unacceptable lethargy. Fifteen patients were withdrawn from study 2, 7 after complaints of unacceptable lethargy or other side-effects. No measurement of sleep apnea improved due to mirtazapine in either study. Weight gain was significantly greater on mirtazapine than on placebo in both trials. CONCLUSIONS: Mirtazapine did not improve sleep apnea in either trial. Mirtazapine caused weight gain, which may further worsen OSA. Therefore, mirtazapine is not recommended for the treatment of OSA.

Understanding the fibromyalgia syndrome.

The fibromyalgia syndrome (FMS) is the most frequent cause of chronic, widespread pain. This review, which is targeted at the psychiatry and psychopharmacology communities, summarizes the state-of-the-art as it relates to both the pathophysiology and treatment of FMS. Toward this end, the anatomy and physiology of pain pathways are summarized, followed by a review of the altered biology of pain processing, neurotransmitter function, and neuroendocrine systems in FMS. The categories of current drugs employed to treat the disorder are detailed, along with a critical review of the literature supporting such use.

Stress-induced muscle and cutaneous hyperalgesia: differential effect of milnacipran.

We previously demonstrated that repeated swim stress produces long-term cutaneous hyperalgesia in rats. We have now determined the effect of stress upon muscle nociception and the anti-nociceptive efficacy of the norepinephrine-serotonin reuptake inhibitor, milnacipran (MIL) in this model. Rats were subjected to either 10-20 min daily sessions of forced swimming (FS) for 3 days, or sham swimming (SS) or control (CT). Maximal forelimb grip strength and hot plate response latencies were estimated before and after the conditioning to assess muscle and thermal nociception, respectively. MIL (1-30 mg/kg/i.p.) or vehicle was started 7 days before the conditioning protocol. There were significant reductions in maximal grip strength and hot plate latencies only in FS/vehicle rats. Subsequent carrageenan administration (2 mg/75 microl each triceps) diminished grip strength in all groups 24 h later, with grip strength lower in FS/vehicle and SS/vehicle rats than in CT/vehicle rats. Treatment with MIL before the stress prevented the reduction in grip strength in all groups but it was ineffective in preventing FS-induced reductions in hot plate response latencies. Thus, repeated stress produces muscle hyperalgesia that can be pharmacologically dissociated from cutaneous hyperalgesia, suggesting that different mechanisms may underlie these two phenomena.

Choriocarcinoma - a rare association with squamous cell carcinoma of esophagus.

Extragenital choriocarcinoma involving the gastrointestinal tract is rare. We report a 60-year-old woman with squamous cell carcinoma of esophagus with a choriocarcinomatous focus. She was palliated with chemotherapy and an endoprosthesis.

A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia.

Fibromyalgia syndrome is a systemic disorder of widespread pain which is thought to result from abnormal pain processing within the central nervous system. There are no currently approved treatments for this indication. Antidepressants appear, however, to be effective, especially those with an action on noradrenergic neurotransmission. The objective of the present study was to test the efficacy of the dual action noradrenaline and serotonin reuptake inhibitor antidepressant, milnacipran, in the treatment of fibromyalgia. The 125 patients, who were enrolled in a double-blind, placebo-controlled, flexible dose escalation trial, were randomized to receive placebo or milnacipran for 4 weeks of dose escalation (up to 200 mg/day), followed by 8 weeks at a constant dose. The study evaluated the efficacy and safety of milnacipran for the treatment of pain and associated symptoms such as fatigue, depressed mood and sleep. 75% of milnacipran-treated patients reported overall improvement, compared with 38% in the placebo group (p < 0.01). Furthermore, 37% of twice daily milnacipran-treated patients reported at least 50% reduction in pain intensity, compared with 14% of placebo-treated patients (p < 0.05). 84% of all milnacipran patients escalated to the highest dose (200 mg/day) with no tolerability issues. Most adverse events were mild to moderate in intensity, and transient in duration. These results suggest that milnacipran may have the potential to relieve not only pain but several of the other symptoms associated with fibromyalgia.

The management of fibromyalgia.

Fibromyalgia is one of a number of overlapping "functional somatic syndromes", including irritable bowel syndrome, tension headache, chronic idiopathic lower back pain, chronic fatigue syndrome and others. These conditions affect females more frequently than males and probably share common underlying neurobiological mechanisms, as well as frequent psychological, cognitive and behavioral comorbidities. Since the pain in these conditions is most likely "central" in origin, classes of drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) and opioids, which are quite effective for "peripheral" pain, are relatively ineffective for the pain seen in these syndromes. Instead, tricyclic and other classes of antidepressants, antiseizure drugs and a number of other neuroactive compounds seem to be more effective. In addition, nonpharmacological therapies such as aerobic exercise and cognitive behavioral therapy are quite effective and frequently underutilized in clinical practice.

Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity.

BACKGROUND: Though selective serotonin reuptake inhibitors have revolutionized the field of psychiatry with demonstrated efficacy in affective and anxiety disorders with minimal side effects, norepinephrine-serotonin reuptake inhibitors may provide efficacy similar to tricyclic antidepressants without the adverse side effects associated with tricyclic antidepressants. METHODS: The affinity and selectivity of milnacipran, duloxetine, venlafaxine, citalopram, amitriptyline, and nortriptyline were determined for the human serotonin, norepinephrine, and dopamine transporters. RESULTS: Both milnacipran and duloxetine were potent inhibitors of serotonin and norepinephrine uptake. Unlike duloxetine and venlafaxine, milnacipran appears serotonin transporter selective in binding (ratio = 2.61) and norepinephrine transporter selective in uptake (ratio =.45). CONCLUSIONS: Milnacipran's binding and uptake inhibition profile more closely resembles that of the tricyclic antidepressants than that of duloxetine. Whether these differences observed in vitro manifest themselves in vivo is not clear.

Pharmacological therapies in fibromyalgia.

The fibromyalgia syndrome (FMS) is a common, chronic, widespread pain disorder that mainly affects middle-aged women. In addition to pain complaints, fatigue and disturbed sleep are symptoms frequently reported by these patients. Many FMS patients also meet diagnostic criteria for mood disorders (e.g. depression) as well as other so-called 'functional somatic syndromes', including irritable bowel syndrome, temporomandibular joint disorder, and subsets of chronic low-back pain. A wide variety of medications are used to manage the eclectic symptomatology of FMS patients, although relatively few have been rigorously tested. This chapter provides a contemporary update of the state of FMS pharmacotherapy, with an emphasis on compounds that have been tested in double-blind, randomized, controlled trials. Particular attention is paid to the efficacy of these therapies on the associated symptoms and co-morbid syndromes commonly seen in FMS patients.

The psychopharmacology of fibromyalgia: a drug development perspective.

The fibromyalgia syndrome (FMS) is the most frequent cause of chronic widespread pain. In this review, we summarize the state of the art on the syndrome and its pathophysiology, with an emphasis on identifying bases for the development of novel therapies. Toward this end, the anatomy and physiology of pain pathways are summarized, followed by a review of the altered biology of pain processing, neurotransmitter function, and neuroendocrine systems in FMS. The categories of drugs currently employed to treat the disorder are detailed, along with a critical review of the literature supporting such use. Throughout the article, FMS is compared with and related to both major depressive disorder and neuropathic pain, conditions that may share some common biological processes with FMS but for which new drug discovery efforts are significantly more active due to the more established nature of these diagnoses.

The neuropharmacology of centrally-acting analgesic medications in fibromyalgia.

As demonstrated above, the anatomy and neuropharmacology of the pain pathways within the CNS, even to the level of the midbrain, are extraordinarily complex. Indeed, discussions of the effects of these agents on the neuropharmacology of the thalamus, hypothalamus, and cortex were excluded from this review owing to their adding further to this complexity. Also, the dearth of data regarding FMS pain pathophysiology necessitated a relatively generic analysis of the pain pathways. As mentioned in the introduction, the current thought is that central sensitization plays an important role in FMS. However, we see in this chapter that the behavioral state of central sensitization may be a result of alterations in either the ascending systems or in one or more descending systems. Studies to assess the presence or relative importance of such changes in FMS are difficult to perform in humans, and to date there are no animal models of FMS. Accepting these limitations, it is apparent that many drugs considered to date for the treatment of FMS do target a number of appropriate sites within both the ascending and descending pain pathways. The data regarding clinical efficacy on some good candidate agents, however, is extremely preliminary. For example, it is evident from the present analysis that SNRIs, alpha 2 agonists, and NK1 antagonists may be particularly well suited to FMS, although current data supporting their use is either anecdotal or from open-label trials [114,149]. Other sites within the pain pathways have not yet been targeted. Examples of these include the use of CCKB antagonists to block on-cell activation or of nitric oxide synthetase antagonists to block the downstream mediators of NMDA activation. Efficacy of such agents may give considerable insight into the pathophysiology of FMS. Finally, as indicated previously, FMS consists of more than just chronic pain, and the question of how sleep abnormalities, depression, fatigues, and so forth tie into disordered pain processing is being researched actively. Future research focusing on how the various manifestations of FMS relate to one another undoubtedly will lead to a more rational targeting of drugs in this complex disorder.

The physiological role of 5-HT2A receptors in working memory.

Dorsolateral prefrontal cortex has an essential role in the cognitive process of working memory, dysfunction of which is considered to be a core deficit in schizophrenia. Although this cortical region is densely innervated with 5-HT2A receptors to which atypical antipsychotic drugs bind with high affinity, little is known of the influence of this serotonin receptor subtype on prefrontal function. We addressed this issue by examining the effects of iontophoresis of selective receptor ligands on prefrontal neurons possessing spatially tuned delay activity, or "memory fields," in monkeys performing a delayed-response task. Memory fields of putative pyramidal cells were attenuated by iontophoresis of 5-HT2A antagonists, which primarily produced a reduction in delay activity for preferred target locations. Conversely, 5-HT2A stimulation by alpha-methyl-5-HT or 5-HT itself, accentuated the spatial tuning of these neurons by producing a modest increase in activity for preferred target locations and/or a reduction in activity for nonpreferred locations. The agonist effects could be reversed by the selective antagonist MDL100,907, and were dose-dependent, such that high levels attenuated spatial tuning by profoundly reducing delay activity. A role for feedforward inhibitory circuitry in these effects was supported by the finding that 5-HT2A blockade also attenuated the memory fields of putative interneurons. We conclude that prefrontal 5-HT2A receptors have a hitherto unrecognized role in the cognitive function of working memory, which involves actions at both excitatory and inhibitory elements within local circuitry.