Research Accomplishments

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Research Accomplishments

Most Relevant Research Accomplishments

Dr. Pinna’s major scientific achievements. The following miles stones in Dr. Pinna’s scientific achievements have been accomplished during the past 20 years at the University of Illinois at Chicago and have been published in journals of high impact, such as Proceedings of the National Academy of Science and Biological Psychiatry.

1. Proposed biomarker candidates for PTSD and depression. PTSD and depression are debilitating disorders affecting 10% of the world population and their diagnosis and treatment is based upon subjective rather than objective measures. Dr. Pinna suggested a number of biomarkers for disorders characterized by large symptom overlap and comorbidity, such as PTSD, depression, and suicide. Using biomarkers to select the most appropriate treatments will also increase treatment efficacy, which is very low with currently used medications.

2. First demonstrated decreased allopregnanolone (a neurosteroid) levels in the brain of patients with depression and PTSD, thus first suggesting a role for this neurosteroid in the neurobiology of depression and PTSD. The involvement of the neurosteroid, allopregnanolone in neuropsychiatric disorders, including depression and PTSD, has been highlighted in several recent clinical investigations. In the first study, Dr. Pinna demonstrated that allopregnanolone levels are decreased in the brain of patients with major unipolar depression, and that allopregnanolone increased in concert with clinical improvement in response to Prozac treatment. In a second study, he showed markedly low blood allopregnanolone in PTSD patients. In collaboration with Harvard University and Boston University, Dr. Pinna showed that allopregnanolone levels correlated negatively with both PTSD and depressive symptoms. Hence, the molecular mechanisms underlying major depression may include a deficit of decreased allopregnanolone levels. More recently, these and other findings in the field helped to provided a framework for phase 3 clinical trials that showed the superior efficacy of allopregnanolone versus currently used antidepressants supporting the approval of IV allopregnanolone for the treatment of postpartum depression.

3. Proposed a novel mechanism of action for the therapeutic action of SSRI antidepressants (e.g., fluoxetine, Prozac) by increasing brain neurosteroids. The mechanism of action of SSRI antidepressants is unknown. Dr. Pinna observed that brain allopregnanolone levels are decreased in patients with PTSD and major depression. This decrease in allopregnanolone is corrected by SSRI in doses that improve depressive symptoms. His studies in animal models showed that fluoxetine normalizes deficits in allopregnanolone levels and improves aberrant behaviors by a mechanism that regulate neurotransmission in brain circuits that modulate emotions. Dr. Pinna suggested that fluoxetine (Prozac) at low doses effectively ameliorates negative affect, anxiety disorders and depression by acting as a “selective brain steroidogenic stimulant” (SBSS) or, in other words, by increasing brain neurosteroids.

4. Established a mouse model of PTSD and suggested novel pharmacological agents to improve fear. Dr. Pinna demonstrated that stressed rodents show fear deficits similar as those observed in PTSD patients. This behavior was related to a decrease of neurosteroids and endocannabinoids in neurons that regulate emotions. Thus, this rodent model is suitable to study behavior and neurochemical alterations of PTSD. Using this model, Dr. Pinna discovered that drugs like cannabinoids or like neurosteroids (ganaxolone) improve PTSD symptoms. This observation suggests novel drugs for PTSD can be administered in conjunction with psychotherapy to improve symptoms. These studies resulted in two patent application filed by the University of Illinois on behalf of Dr. Pinna for the treatment of neuropsychiatric disorders, including PTSD, depression but also Alzheimer’s disease.

5. Discovered the physiological role of the neurosteroid allopregnanolone in regulating emotional behavior: A biomarker for mood disorders. Allopregnanolone, a potent neurosteroid that positively modulates anxiolytic brain targets, is synthesized in neurons. By measuring brain allopregnanolone content by gas chromatography-mass spectrometry (GC-MS), which has unsurpassed structural selectivity, and by delineating the enzymes involved in allopregnanolone production, Dr. Pinna was able to: A. Provide the first evidence suggesting that the endogenous brain neurosteroids physiologically play a permissive or facilitating role in the modulation of GABA function, implicated in emotion regulation and compulsive behaviors; B. Elucidated the neurocircuitry underlying aggression and emotional behaviors.