Lack of Psychiatric Drug Research Creates Clinical 'Crisis'

Liam Davenport

March 21, 2016

MADRID — Psychiatry is facing an ongoing crisis because pharmaceutical companies are not investing in psychiatric drug research, warned an investigator who has turned to nonpsychiatric drugs in a bid to find optimally effective treatments for his patients with mental illness.

Dominik Wincewicz, MD, Department of Clinical Pharmacology, Medical University of Bialystok, in Poland, told delegates attending the ​European Psychiatric Association (EPA) 24th Congress that researchers will need to look beyond psychiatry into other specialties, such as cardiology, where already approved drugs have shown benefits in managing stress and cognitive impairment.

The comments were made at his presentation on angiotensin type 1 receptor (AT1) blockade in a model of chronic stress. Results showed that the angiotensin 2 receptor antagonist telmisartan (Micardis, Boehringer Ingelheim Pharmaceuticals, Inc) upregulates gene expression in the brain in response to stress, which may explain its neuroprotective effects.

An "Uncomfortable Position"

Speaking to Medscape Medical News, Dr Wincewicz said that the majority of recent drug developments in psychiatry have been related to improvements in safety rather than efficacy. Furthermore, he believes that, aside from the dopamine and serotonin pathways, "clearly we are not really good at picking up parallel signaling pathways."

Dr Dominik Wincewicz

This, Dr Wincewicz said, "raises huge questions and puts weight on searching for novel treatment options, because it seems like the two commonly established psychotic affective drugs are not doing their job effectively enough."

The lack of developments from the pharmaceutical industry has put psychiatrists in an "uncomfortable position."

"On the one hand, it's business; it's an unreasonable way to spend money if nothing comes out of it," he said. "But if we're not spending money in the first place, we are getting nowhere," he said.

The consequence for Dr Wincewicz is clear: "As a physician devoted to searching for the most effective way of pharmacological treatment, it is reasonable to screen for those drugs that are already on the market but have different, nonpsychiatric indications of usage, and there is some mechanism in the background that maybe beneficial."

He noted that several previous in vivo studies have shown that angiotensin receptor blockers (ARBs) have antistress effect.

It is clear that, along with angiotensin 2, there are binding sites for ARBs on peroxisome proliferator–activated receptor gamma (PPAR-gamma).

Dr Wincewicz pointed out that there are two angiotensin systems ― the widely recognized peripheral system, and the central angiotensin system in the brain.

"The central angiotensin system is independent from the peripheral because angiotensin 2 itself does not cross the blood-brain barrier," he noted, "although we do have angiotensin 2 receptor blockers, mainly candesartan [Atacand, AstraZeneca Pharmaceuticals LP] and telmisartan, that are highly lipophilic and do effectively cross the blood-brain barrier."

Neuroprotective Effects

It has previously been shown that telmisartan provides neuroprotective effects in cases of chronic psychological stress by reducing the overexpression of nitric oxide synthase, as well as through neuronal apoptosis, macrophage accumulation, microglia activation, and the reduction of overexpression of cyclooxygenase-2. It also increases neuronal differentiation.

To investigate the mechanisms of action of the neuroprotective effect of telmisartan within the brain, Dr Wincewicz devised a series of experiments in which Wistar rats were exposed to stress for 2.5 hours per day for 21 days while being given one of four interventions.

The interventions consisted of telmisartan 1 mg/kg, the selected PPAR-gamma antagonist GW9662 0.5 mg/kg, a combination of the two medications, or control medication.

Expression of the brain-derived neurotrophic factor gene (BDNF) in the hippocampus and medial prefrontal cortex was assessed using reverse transcription polymerase chain reaction. Expression of TATA box binding protein was also measured for the purpose of control expression analysis.

The results showed that chronic stress reduced BDNF expression in the hippocampus, but not significantly, in control rats. Administration of telmisartan significantly increased BDNF expression (P < .05), even in the presence of the PPAR-gamma antagonist GW9662.

In the medial prefrontal cortex, chronic stress led to significantly reduced expression of BDNF (P < .05), which was partially restored by application of GW9662. In contrast, telmisartan increased BDNF expression markedly (P < .01). In the presence of GW9662, expression became attenuated but was still significantly increased.

"Therefore, we can assume that all of those neuroprotective effects that we've seen are actually the effect of deactivation of the hypothalamic-pituitary-adrenal axis as a result of angiotensin type 1 blockade, not PPAR-gamma activation," said Dr Wincewicz.

"I said [at the beginning of the presentation] that the hippocampus might be the most vulnerable structure to stress, although the results I presented are totally opposite to this fact. But when we consider that the medial prefrontal cortex is phylogenetically the youngest structure of the brain, it makes perfect sense that it is also the most vulnerable structure for stress and pharmacological influence," he added.

Lack of Interest?

Session chair Gianluca Serafini, PhD, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, Italy, was at a loss to explain why the pharmaceutical industry is investing so little in novel psychiatric drugs.

Dr Gianluca Serafini

"I don't what are the reasons for this," he told Medscape Medical News. "Probably companies are much more interested in harder frontiers, such as the glutaminergic system; this is the most promising target, based on the current literature, then other possible targets, such as neurotrophic factors and potential techniques to enhance these factors, and so on. But I do not know why the pharmaceutical industries are not interested in this [area of research]."

Although Dr Serafini found the results "very interesting," he added that "it will be very, very difficult to translate Dr Wincewicz's results into clinical practice, because, with depressed patients, with schizophrenia, with bipolar patients, it's a very, very complicated task to undergo of these type of experiments."

Nevertheless, he sees potential utility.

"I believe that one of the most promising frontiers in the future will be to target angiotensin 2 receptors with antihypertensive therapies."

Dr Wincewicz was more specific about the future direction for research with AT1 blockers in the clinic.

"I believe that, even at this point, there is a patient that suffers from major depressive disorder, [with] hypertension as parallel comorbidity and no history of myocardial infarction, for example," he said.

"In this patient...maybe it makes sense to use angiotensin receptor blockers in the first place, as they are very widely used, well-tolerated, safe drugs, and then we should compare the results of this treatment with maybe other antihypertensives and, obviously, people that haven't received this kind of therapy," he added.

The study was funded by the Medical University of Bialystock. Dr Wincewicz and Dr Serafini report no relevant financial relationships.

European Psychiatric Association (EPA) 24th Congress: Presented March 14, 2016.

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