Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Cognitive and Cellular Effects of Combined Organophosphate Toxicity and Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) is considered the most common neurological disorder among people under the age of 50. In modern combat zones, a combination of TBI and organophosphates (OP) can cause both fatal and long-term effects on the brain. We utilized a mouse closed-head TBI model induced by a weight drop device, along with OP exposure to paraoxon. Spatial and visual memory as well as neuron loss and reactive astrocytosis were measured 30 days after exposure to mild TBI (mTBI) and/or paraoxon. Molecular and cellular changes were assessed in the temporal cortex and hippocampus. Cognitive and behavioral deficits were most pronounced in animals that received a combination of paraoxon exposure and mTBI, suggesting an additive effect of the insults. Neuron survival was reduced in proximity to the injury site after exposure to paraoxon with or without mTBI, whereas in the dentate gyrus hilus, cell survival was only reduced in mice exposed to paraoxon prior to sustaining a mTBI. Neuroinflammation was increased in the dentate gyrus in all groups exposed to mTBI and/or to paraoxon. Astrocyte morphology was significantly changed in mice exposed to paraoxon prior to sustaining an mTBI. These results provide further support for assumptions concerning the effects of OP exposure following the Gulf War. This study reveals additional insights into the potentially additive effects of OP exposure and mTBI, which may result in more severe brain damage on the modern battlefield.

Sexual dimorphism of the posterior cervical spine muscle attachments.

Cervical spinal injury and neck pain are common disorders with wide physical implications. Neck pain and disability are reported to occur in females more often than in males, and chronic or persistent neck pain after whiplash is twice as common in females. Female athletes also sustain a higher percentage of concussions compared to male athletes. Still, while sexual differences in clinical presentation and outcome are well-established, the underlying etiology for the disparity remains less clear. It is well-established that the origin and insertion landmarks of posterior neck muscles are highly variable, but we do not know if these interindividual differences are associated with sex. Expanding our knowledge on sexual dimorphism in the anatomy of the cervical muscles is essential to our understanding of the possible biomechanical differences between the sexes and hence improves our understanding as to why females suffer from cervical pain more than males. It is also of paramount importance for accurate planning of posterior cervical spine surgery, which cuts through the posterior cervical musculature. Therefore, our main objective is to characterize the anatomy of posterior neck musculature and to explore possible sexual differences in the location of their attachment points. Meticulous posterior neck dissection was performed on 35 cadavers, 19 females, and 16 males. In each specimen, 8 muscle groups were examined bilaterally at 45 osseous anatomical landmarks. Muscles and their attachment sites were evaluated manually then photographed and recorded using Microscribe Digitizer technology built into 3D models. A comparison of attachment landmarks between males and females for each muscle was conducted. Out of the eight muscles that were measured, only two muscles demonstrated significant sex-related anatomical differences-Spinotranversales (splenius capitis and cervicis) and Multifidus. Male Spinotransversales muscle has more attachment points than female. It showed more cranial insertion points in the upper cervical attachments (superior nuchal line, C1 posterior tubercle, and mastoid process) and more caudal insertion points in the spinous processes and transverse processes of the lower cervical and upper thoracic vertebrae. Thus, the male subjects in this study exhibited a greater coverage of the posterior neck both cranially and caudally. Female Multifidus has more attachment points on the spinous processes and articular processes at middle and lower cervical vertebrae and at the transverse processes of the upper thoracic vertebrae. All remaining muscles exhibited no sexual differences. Our findings highlight, for the first time, a sexual dimorphism in attachment points of posterior cervical musculature. It reinforces the notion that the female neck is not a scaled version of the male neck. These differences in muscle attachment could partially explain differences in muscle torque production and range of motion and thus biomechanical differences in cervical spine stabilization between sexes. It sheds a much-needed light on the reason for higher whiplash rates, concussion, and chronic cervical pain among females. Surgeons should take these sexual morphological differences into consideration when deliberating the best surgical approach for posterior cervical surgery.