5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants.

Most depressed patients don't respond to their first drug treatment, and the reasons for this treatment resistance remain enigmatic. Human studies implicate a polymorphism in the promoter of the serotonin-1A (5-HT(1A)) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT(1A) autoreceptors in raphe nuclei without affecting 5-HT(1A) heteroreceptors, generating mice with higher (1A-High) or lower (1A-Low) autoreceptor levels. We show that this robustly affects raphe firing rates, but has no effect on either basal forebrain serotonin levels or conflict-anxiety measures. However, compared to 1A-Low mice, 1A-High mice show a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressant, modeling patients with the 5-HT(1A) risk allele. Furthermore, reducing 5-HT(1A) autoreceptor levels prior to antidepressant treatment is sufficient to convert nonresponders into responders. These results establish a causal relationship between 5-HT(1A) autoreceptor levels, resilience under stress, and response to antidepressants.

Attitudes of patients and family members towards implantable psychiatric medication.

INTRODUCTION: Medication is a necessary part of treatment for severe psychiatric illnesses such as schizophrenia and nonadherence to prescribed medication is one of the most important public health issues in psychiatry today. The devastating consequences of nonadherence have motivated the development of novel therapeutic strategies, including a new long-term implantable medication delivery system. METHODS: The current study assesses attitudes towards implantable medication in psychiatric patients and their family members. Patients included in the study had diagnoses of Schizophrenia, Schizoaffective Disorder, Mood or Anxiety related disorders. RESULTS: 49.62% of patients and 74.47% of family members endorse support for implantable medication. CONCLUSIONS: This study demonstrates that implants may be an acceptable alternative to oral and injectable medication for a subset of psychiatric patients and their families.

Evaluation of in vitro release and in vivo efficacy of mPEG-PLA-haloperidol conjugate micelle-like structures.

Polymeric prodrugs of mPEG-PLA-haloperidol (methoxy poly(ethylene glycol)-b-poly (lactic acid)), self-assemble into nanoscale micelle-like structures in aqueous solutions. The micelles range in size from 28 to 52 nm in diameter and have been shown to be spherical in shape using cryogenic transmission electron microscopy. In this current work there is evidence shown that suggests these micelle-like structures do not dissociate below their critical micelle concentration (CMC) when the PEG weight percent is at least 68, releasing physically entrapped drug from intact micelles over a 3-day period. However, 55 wt % PEG micelles dissociate below their CMC, and release their physically entrapped drug within 8 h. Conjugate polymer micelles most closely approach a linear release profile over a 5-day period. Conjugate micelles with free drug incorporated, known as combination micelle-like structures, release drug over 4 days. However, these combination micelles have the fastest burst release indicating that free drug was potentially dominating the first 8 h of release, after which hydrolysis of covalently linked drug took over. In vivo behavioral studies can assess haloperidol bioactivity from drug loaded micelle-like structures on ketamine induced hyperlocomotion. Results are consistent with in vitro release data, showing that conjugate and combination micelles continue to release haloperidol 4 days post injection, attenuating the effects of the ketamine induced hyperlocomotion. Furthermore, results indicate that the sedative side effects of haloperidol were reduced with the micelle delivery systems as compared to the acute haloperidol injection.

Effects of nicotine vary across two auditory evoked potentials in the mouse.

BACKGROUND: Schizophrenia patients display sensory processing deficits, reduced alpha7-nicotine receptor expression, and increased incidence of smoking, prompting investigation of nicotine receptor agonists as possible treatments. We evaluated the effects of acute and chronic nicotine, using an animal model that incorporates genetic variation for sensory processing and nicotine sensitivity. METHODS: C57BL/6J and DBA/2Hsd mice received 2 weeks of 4.2 mg/kg chronic nicotine or saline. Auditory evoked potentials were recorded before and after acute nicotine injection of 1.05 mg/kg on day 14, with a paired-click paradigm (S1/S2). Amplitude and gating of the P20 and N40 were compared between conditions. RESULTS: Acute nicotine increased the amplitude and gating of the P20 and decreased the amplitude and gating of the N40 across all groups, primarily by acting on S1. Chronic nicotine attenuated the effects of acute nicotine on the N40. CONCLUSIONS: Our data support the notion that the mouse P20 shares pharmacological response properties with the human P50. In addition, findings suggest that nicotine might increase the initial sensory response (S1), with a resulting improvement in gating of some components.

Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits.

RATIONALE: Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems. OBJECTIVES: The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits. MATERIALS AND METHODS: Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits. RESULTS: Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits. CONCLUSIONS: The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations.

Effect of drug type on the degradation rate of PLGA matrices.

We compare the rate of drug release through the degradation of 50:50 polylactic-co-glycolic acid polymer pellets, for six different drugs: Thiothixene, Haloperidol, Hydrochlorothiozide, Corticosterone, Ibuprofen, and Aspirin. Despite using the same polymer matrix and drug loading (20% by weight), we find that the rate of polymer degradation and the drug release profile differ significantly between the drugs. We conclude that the design of biodegradable polymeric drug carriers with high drug loadings must account for the effect of the drug on the polymer degradation and drug release rate.