Tag: depression

Categories : Mental HealthTags :

Ketamine Holds Promise as a Treatment for Depression

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New research with low doses of the anaesthetic ketamine, recently approved by the FDA for use as an antidepressant, shows the drug could provide longer-lasting relief.

Depression is often treated with selective serotonin reuptake inhibitors, or SSRIs, but they can take six weeks before symptom relief begins, and in up to 30% of people they are ineffective.

For the past two decades, however, psychiatrists have been using low doses of ketamine, normally a veterinary anaesthetic, to treat patients whose depression has not responded to other treatments. It also has hallucinogenic effects and is sometimes abused as a street drug. Its use in psychiatry was long considered “off label,” but in 2019 the U.S. Food and Drug Administration approved a nasal spray version for use as an antidepressant, followed in 2020 by expanding the approval to include patients with depression who are having suicidal thoughts or have recently tried to take their own lives or otherwise harm themselves.

The approval opened up new possibilities as well as new lines of research that may change the way psychiatrists think about depression. Dr Benjamin Brody, an assistant professor of clinical psychiatry at Cornell University is heading a programme exploring ketamine to treat the condition. “What’s so exciting about ketamine is not only that it works for people whose symptoms are not responding to traditional treatments, but it also works much more rapidly — in days or even hours,” says Dr. Brody, who developed the protocol before the spray was approved, and still prefers infusions because they allow him to tailor each dose to a patient’s weight (while the spray only comes in two pre-set doses). “For some people, ketamine really does provide almost immediate relief. That’s wonderful and very gratifying to see.”

One problem with ketamine, however, is that its positive effects wear off within weeks or months. “Another major issue,” says Dr. Brody, “is that we have so little information on the long-term effects, or what type of treatment patients will need to remain well.”

Dr Conor Liston, associate professor of neuroscience in the Feil Family Brain and Mind Research Institute, is exploring the question of how ketamine works in the long term to create more synapses in a region of the brain called the medial prefrontal cortex. The new connections seem temporary, but if they could be augmented with another treatment, a person might be permanently cured of depression.

For a study published last year in Science, Dr. Liston and his team worked with mice that exhibited depression-like behavior, as determined by their reaction to a stressful situation. A mouse that freezes more than it attempts to wriggle free, known as “motivated escape behaviour”, displays an important feature of depression. “Mice are not people, and many symptoms that we think of as core to depression — sadness, hopelessness — are hard or probably even impossible to imagine modelling in a mouse,” said Dr Liston. “But there are some things we can measure.”

Dr Liston examined the mice’s brains before administering ketamine. As predicted, lacking motivated escape behaviour was correlated with lost synapses in the medial prefrontal cortex. Just hours after one dose, the mice no longer exhibited that ‘depressed’ behaviour and their brains showed that synapses had regrown. But just like humans, depressive symptoms returned days later and the new synapses had disappeared.

Interestingly, the reduction in depressive behaviour occurred before the new synapses appeared, meaning they could not have caused the immediate relief. However, the new synapses were apparently necessary for maintaining the antidepressant effects long after the ketamine dose. If those synapses were eliminated, the mice quickly became depressed again. “We think that some kind of intervention aimed at boosting the restoration of those synapses or enhancing their survival over time could be useful for augmenting ketamine’s antidepressant effects,” said Dr. Liston, adding that it could be another drug or an intervention as simple as exercise or improved sleep, two known factors in synapse survival.

Dr Liston noted that his team’s work is just a first step and more basic science needs to be done before work involving human subjects. 

Source: Weill Cornell Medical College

Categories : CancerTags :

SSRI Antidepressants Could be Used To Fight Cancer

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Natural killer (NK) cells target a cancel cell for destruction. Credit: NCI

Long used to treat depression, selective serotonin reuptake inhibitors (SSRIs) could help improve modern cancer treatments.

In mouse experiments, they slowed the growth of pancreatic and colon cancers, and when combined with immunotherapy, they even halted cancer growth long-term. In some cases the tumours disappeared completely. The researchers’ findings will now be tested in human clinical trials.

The neurotransmitter serotonin, known as the happiness molecule, has many other functions and is mostly found outside the brain, stored in blood platelets. Serotonin reuptake inhibitors (SSRIs), which are used to treat depression, increase serotonin levels in the brain but reduce serotonin in platelets.

Serotonin was already known to be involved  in carcinogenesis. Until now, however, the underlying mechanisms had remained obscure. Now, researchers at the University of Zurich (UZH) and University Hospital Zurich (USZ) have shown that SSRIs or other drugs that lower peripheral serotonin levels can also slow cancer growth in mice.

Pierre-Alain Clavien, Director, Department of Surgery and Transplantation, University of Zurich, said: “Drugs that are already approved for clinical use as antidepressants could help improve treatment of hitherto incurable pancreatic and colorectal cancers.”

Although recent years have seen new, effective treatments such as targeted antibodies or immunotherapies, most patients with advanced-stage abdominal tumours such as colon or pancreatic cancer die within a few years of diagnosis. Tumour cells eventually become resistant to the drugs and are no longer recognised by the immune system. Now, the researchers have discovered the role serotonin plays in this tumour cell resistance mechanism.

Cancer cells use serotonin to boost production of an immunoinhibitory molecule, PD-L1, which binds to killer T cells, rendering them dysfunctional. The cancer cells thus escape destruction by the immune system. In mouse models, the researchers were able to show that SSRIs or peripheral serotonin synthesis inhibitors prevent this mechanism. “This class of antidepressants and other serotonin blockers cause immune cells to recognise and efficiently eliminate tumor cells again. This slowed the growth of colon and pancreatic cancers in the mice,” Clavien said.
PD-L1, via which serotonin exerts its effect, is also the target of modern immunotherapies, also called immune checkpoint inhibitors. The researchers then tested a dual treatment approach in mice: immunotherapy, which increases the activity of killer T cells, was combined with drugs that reduce peripheral serotonin. Cancer growth was suppressed in the animal models in the long term, and in some mice, the tumours disappeared completely.

“Our results provide hope for cancer patients, as the drugs used are already approved for clinical use. Testing such drug combinations on cancer patients in clinical trials can be fast-forwarded due to the known safety and efficacy of the drugs,” said Clavien.

Source: University of Zurich

Categories : Mental HealthTags :

Histamine Involvement in Depression Revealed

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Image by Falkurian Design on Unsplash

Histamine from inflammation dampens serotonin levels and antidepressants’ ability to boost them, according to experiments in mice models.

The findings, published in The Journal of Neuroscience add to mounting evidence that inflammation, and the accompanying release of the molecule histamine, affects serotonin, a key molecule responsible for mood in the brain.

Inflammation triggers the release of histamine in the body, increasing blood flow to affected areas to flood them with immune cells. While these effects help the body fight infections, both long-term and acute inflammation is increasingly linked to depression. There is already strong evidence that patients with both depression and severe inflammation are the ones most likely not to respond to antidepressants.

Dr Parastoo Hashemi, Lead Author, Imperial’s Department of Bioengineering, said: “Our work shines a spotlight on histamine as a potential key player in depression. This, and its interactions with the ‘feel-good molecule’ serotonin, may thus be a crucial new avenue in improving serotonin-based treatments for depression.”

Chemical messengers
Serotonin is a key target for depression-tackling drugs, and selective serotonin reuptake inhibitors (SSRIs) inhibit the re-absorption of serotonin in the brain, allowing it to circulate for longer and improve mood.

However, although SSRIs bring relief to many who take them, an increasing number of people are resistant to it. This could be due to the specific interactions between chemical messengers, or neurotransmitters, including serotonin and histamine.

With this in mind, researchers set out to investigate the relationship between histamine, serotonin, and SSRIs. They created tiny serotonin-measuring microelectrodes and put them into the hippocampus of the brains of live mice, an area known to regulate mood. The technique, known as fast scan cyclic voltammetry (FSCV), allowed them to measure brain serotonin levels in real time..

After placing the microelectrodes, they injected half the mice with lipopolysaccharide (LPS), an inflammation-causing toxin found in some bacteria, and half the mice with a saline solution as a control.

Within minutes of LPS injection, brain serotonin levels dropped, whereas they remained the same in control mice, demonstrating the rapid action of inflammatory responses on the brain and serotonin. Since LPS cannot cross the blood-brain barrier, it could not cause the drop in serotonin.
The inflammatory response triggered histamine in the brain which directly inhibited the release of serotonin by attaching to inhibitory receptors. 

To counter this, the researchers administered SSRIs to the mice, but they were much less able to boost serotonin levels than in control mice. They posited that this is because the SSRIs directly increased the amount of histamine in the brain, cancelling out its serotonin boosting action.

The researchers then administered histamine reducing drugs alongside the SSRIs to counter histamine’s inhibitory effects, and saw serotonin levels rise back to control levels. This appears to confirm the theory that histamine directly dampens serotonin release in the mouse brain. These histamine reducing drugs cause a whole-body reduction in histamine and are distinct from antihistamines taken for allergies, which block histamine’s effects on neurons.

A new molecule of interest
More work is needed before progressing to human studies. However, it is not currently feasible to use microelectrodes to make similar measurements in human brains, so the researchers are now looking at other ways to get a snapshot of the brain by looking at other organs which use serotonin and histamine, like the gut.

Source: Imperial College London

Categories : Mental HealthTags :

Low Doses of Nitrous Oxide can Relieve Stubborn Depression

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A small dose of nitrous oxide may be able to relive the symptoms of medication-resistant depression. Photo by Mockup Graphics on Unsplash

A new study at the University of Chicago Medicine and Washington University found that inhaling low doses of nitrous oxide gas rapidly relieved symptoms of treatment-resistant depression, with few adverse side effects. They found that this was as effective as higher doses of the gas, with fewer unpleasant side effects.

These findings add to the growing body of evidence of non-traditional treatments that may be a viable option for patients with depression that is unresponsive to typical antidepressant medications. It may also be a fast-acting and effective treatment option for patients in crisis.

Often called ‘laughing gas’, nitrous oxide is widely used as an anaesthetic, providing short-term pain relief in dentistry, emergency response and surgery.

A previous study tested a one-hour inhalation session with 50% nitrous oxide gas, which resulted in rapid improvements in depressive symptoms that lasted for at least 24 hours. However, several patients reported negative side effects, including nausea, vomiting and headaches.

“This investigation was motivated by observations from research on ketamine and depression,” said Peter Nagele, MD, Chair of Anesthesia and Critical Care at UChicago Medicine. “Like nitrous oxide, ketamine is an anaesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression. We wondered if our past concentration of 50% had been too high. Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.”

The new study used a similar protocol with 20 patients, this time adding an additional inhalation session with 25% nitrous oxide. They found that the halved-concentration treatment was nearly as effective as 50% nitrous oxide, but there were only one quarter of the negative side effects.

Additionally, researchers tested the patients’ depression scores following treatment over a longer period of up to two weeks compared to 24 hours in the previous protocol. Surprisingly, they found that after only a single administration, some patients had improvements that lasted for the entire follow-up period.

“The reduction in side effects was unexpected and quite drastic, but even more excitingly, the effects after a single administration lasted for a whole two weeks,” said Dr Nagele. “This has never been shown before. It’s a very cool finding.”

These findings point to nitrous oxide being a promising, rapid and effective treatment for those suffering from severe depression which is unresponsive to the usual medication such as SSRIs.

“A significant percentage — we think around 15% — of people who suffer from depression don’t respond to standard antidepressant treatment,” said Charles Conway, MD, Professor of Psychiatry and Director of the Treatment Resistant Depression and Neurostimulation Clinic at Washington University School of Medicine. “These ‘treatment-resistant depression’ patients often suffer for years, even decades, with life-debilitating depression. We don’t really know why standard treatments don’t work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals.”

Despite its ‘laughing gas’ name, patients actually fall asleep after such a low dose.

“They’re not getting high or euphoric, they get sedated,” Dr Nagele said.

Non-traditional treatments for depression faces an uphill battle for acceptance in the mainstream, though researchers hope that the findings from this and similar studies will help open physicians’ minds towards these other possible solutions.

“These have just been pilot studies,” said Dr Nagele. “But we need acceptance by the larger medical community for this to become a treatment that’s actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we’ll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice.”

With broader public acceptance, Dr Nagele hopes that these results help those patients who are struggling to find adequate therapies for their depression.

“There is a huge unmet need,” he said. “There are millions of depressed patients who don’t have good treatment options, especially those who are dealing with suicidality. If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side — that’s a very gratifying line of research.”

Source: University of Chicago Medical Center

Journal information: P. Nagele et al., “A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression,” Science Translational Medicine (2021). 

Categories : Mental HealthTags :

Inflammation a Predictor of Future Depression in Widowed Spouses

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Researchers at Rice University have found that future depression in widowed spouses can be predicted by bodily inflammation after the death of their partners.

The study will be published in the June 2021 edition of the journal Psychoneuroendocrinology. The study was led by lead author Lydia Wu, a Rice psychology graduate student, and Christopher Fagundes, associate professor of psychology and principal investigator for the Biobehavioral Mechanisms Explaining Disparities (BMED) lab at Rice. The researchers recruited 99 participants who had lost their spouses within 2-3 months of the study, and evaluated them on a number of factors, including physical and mental health, over three months.

“Prior research has already linked bodily inflammation to a host of health issues, including cancer, memory issues, heart problems and depression,” Wu said. “We were interested in how systemic inflammation affects the mental health of spouses after losing a loved one. In particular, can inflammation help us identify who will experience clinical levels of depression at a future point in time?”

The researchers found that widowed spouses with higher levels of bodily inflammation immediately after the loss of their partners had more severe symptoms of depression three months later compared to those with lower inflammation levels. This was even more pronounced if they didn’t experience significant depression initially.

Prof Fagundes said that it is normal to experience depression following the death of a spouse, and research shows that undergoing psychotherapy right after the event can actually interfere with people’s natural coping ability.

“We know that most people are remarkably resilient,” he said.

In the case of persistent depression, or depression occurring six or more months after a spouse’s death, it may be a sign that clinical intervention is needed, Prof Fagundes said.

“Until this study, it was difficult to know who was at risk for these persistently high levels of depression and grief until the six-month mark,” he said. “This study identifies a potential biomarker that could help us predict who is at greatest risk for long-term repercussions of loss.”

“This information makes early intervention possible,” Wu said. “We can identify at-risk bereaved persons and introduce them to interventions early on to improve their mental health.”

The researchers said more research is needed to determine who might be at greatest risk.

Source: Rice University

Journal information: E. Lydia Wu et al, Inflammation and future depressive symptoms among recently bereaved spouses, Psychoneuroendocrinology (2021). DOI: 10.1016/j.psyneuen.2021.105206

Categories : Mental Health New Compounds and TreatmentsTags :

Zuranolone, a New Drug for MDD Shown to Be Safe and Effective in Trials

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A recent trial showed that nightly 30mg doses of zuranolone, a new drug to treat major depressive disorder (MDD), are safe and only requires about two courses to achieve clinical improvement.

Zuranolone is one of a new class of neuroactive steroid drugs that positively modulates GABAA receptors. It has high bioavailability, can be taken orally and has a half-life suitable for daily administration. 

The SHORELINE Study is a Phase III, open-label, one year longitudinal study to evaluate the safety, tolerability, and need for repeat dosing with zuranolone in adults with MDD. Two cohorts with either zuranolone 30mg or 50mg as a starting dose taken once nightly for 14 days. Need for repeated dosing is assessed every 14 days based on a patient-reported assessment, with a maximum of five courses over a year.

Analysis of the data showed that the study’s primary endpoint of safety and tolerability show that zuranolone was generally well-tolerated in both dosage cohorts, with adverse events being generally consistent with those seen in previous zuranolone trials.

Secondary endpoints included response and remission as evaluated by the 17-item Hamilton Rating Scale for Depression (HAMD-17) and the number of times a patient received retreatment. A mean of 2.2 treatments resulted in patients with a clinical response (baseline HAMD-17 reduction of ≥50%) to the initial course of zuranolone 30mg. Additional data from patients in the 50 mg dose cohort is expected to be reported in late 2021.

“Sage embarked on the LANDSCAPE clinical program to evaluate the safety and efficacy of zuranolone with the ambition of reimagining the treatment for depression with the goal of a rapid-acting, durable, treat-as-needed option in a disease where innovation is lacking and the incidence rate has unfortunately increased exponentially in the last 20 years,” said Barry Greene, Chief Executive Officer at Sage Therapeutics. “Today we are announcing additional positive data from the SHORELINE Study that demonstrate continued strong results from the 30 mg dose and strengthens our confidence in the potential of the 50 mg dose. Designed as a naturalistic study, these data approximate real-world evidence of use of zuranolone at 30 mg and 50 mg doses. We look forward to the results of the WATERFALL and CORAL Phase 3 pivotal data readouts in MDD this year.”

Source: Sage Therapeutics