But dementia affects more than cognition.

Hallucinations occur in up to 50% of the 50 million cases of dementia worldwide, and delusions occur in up to 75% of cases, together collectively referred to as "dementia-related psychosis." Although not as well known as the hallmark cognitive decline, dementia-related psychosis takes a heavy toll on people who experience psychosis symptoms and those who care for them.

There are no approved medications for dementia-related psychosis. Off-label use of antipsychotic medications, developed to treat the psychosis symptoms associated with schizophrenia, is common in clinical practice. But, the use of traditional antipsychotics for dementia-related psychosis  is problematic because these drugs are often ineffective and come with a litany of dangerous side-effects, including excessive sedation, cardiovascular problems, and increased cognitive decline. In fact, the FDA issued a black-box warning against treating dementia-related psychosis with some traditional antipsychotic medications due to safety concerns. With limited treatment options for dementia-related psychosis and the number of cases of dementia increasing by 10 million per year, developing safe and effective medications for dementia-related psychosis is a major clinical need.

Now, as the result of work conducted by researchers at the University of Exeter and Acadia Pharmaceuticals, scientists may have identified a drug that can prevent dementia-related psychosis for a long period of time with few side-effects. The drug, called pimavanserin, affects the brain differently than the antipsychotics developed for schizophrenia by specifically and strongly blocking a type of serotonin receptor in the brain called 5-HT2A.

The likely explanation for why traditional antipsychotic medications don't work for dementia-related psychosis is that they were never developed to treat episodes of psychosis in elderly people with dementia; they were developed for young people with schizophrenia. Dementia and schizophrenia are different diseases with different neurological causes, so there is no guarantee that their symptoms will respond to the same medications. In addition, levels of neurotransmitters in the brain change as humans age, which could influence the effects of psychoactive drugs.

In preclinical studies, pimavanserin reduced psychotic behavior in rodents and clinical testing sponsored by Acadia Pharmaceuticals showed that pimavanserin improved psychosis symptoms in people with Parkinson's disease and Alzheimer's disease. In 2016, pimvanserin became the first drug to receive FDA approval as a treatment for Parkinson's-related psychosis and was taken to market by Acadia Pharmaceuticals under the brand name NUPLAZID.

With positive clinical data for psychosis symptoms in Alzheimer's disease and FDA approval for psychosis symptom's in Parkinson's disease, Acadia Pharmaceuticals initiated a clinical trial of pimavanserin for additional subtypes of dementia-related psychosis in 2017. A total of 392 people with Alzheimer's disease, Parkinson's disease, Lewy body, frontotemporal, or vascular dementia participated in the study and the results were published in the New England Journal of Medicine in July of 2021.

For the first 12-weeks of the study, all the participants received pimavanserin open-label. After week 12, participants who met a certain threshold of symptomatic improvement were randomly assigned to receive either pimavanserin or a placebo for 26 weeks to determine if the drug could prevent relapse of psychosis symptoms. The drug was found to be so effective at preventing relapse of psychosis symptoms, however, that the trial was stopped before its intended endpoint at 26 weeks because it would have been unethical to continue giving the control group the placebo. When the trial was stopped, relapse occurred in 28.3% of the placebo group compared to just 12.6% in the pimavanserin group, with minimal side-effects.

The results of the study are encouraging, but it had several limitations due to the participants it included. One of the more glaring issues is that over 98% of study participants included in the trial after week 12 were white. This, despite “white” individuals being at a lower risk of dementia compared to “African American” and “Hispanic” individuals according to the Centers for Disease Control and Prevention. In addition, 15% of the participants had dementia-related psychosis due to Parkinson’s disease, a condition for which pimavanserin has already been approved for as a treatment. Therefore, as the researchers admit, the data generated by these participants “may have skewed the results in favor of pimavanserin.”

But the study's most significant limitation, at least as far as FDA approval is concerned, is that the trial had insufficient statistical power to detect whether pimavanserin improved psychosis symptoms in individual subtypes of dementia. In April of 2021, the FDA notified Acadia Pharmaceuticals that after reviewing the existing clinical trial data the agency would not approve pimavanserin as a treatment for dementia-related psychosis, citing an insufficient number of participants with less-common dementia subtypes and a lack of statistical significance in some subgroups of dementia.

For the team at Acadia Pharmaceuticals, the FDA's decision came as a surprise. Generating and analyzing clinical data from study populations that include a mix of dementias without necessarily separating them has become an accepted practice when treating the psychosis symptoms associated with dementia.

Although next steps are not certain, Acadia CEO Stephen Davis outlined three possible outcomes. First, as is the company's position, they could proceed by performing additional statistical analyses of the existing data without additional clinical trials and seek FDA approval for pimavanserin as a broad-spectrum medication for multiple dementia subtypes. Second, rather than seeking broad-spectrum approval, the company could seek approval for pimavanserin as a medication for a smaller number of dementia subtypes such as Alzheimer's dementia or dementia with Lewy bodies, the subtypes for which the company believes they have the strongest data. Under this scenario, the company would not conduct additional clinical trials. Third, as is the FDA's position, the company could conduct additional clinical trials of pimavanesin in each dementia subtype.

The company has scheduled a meeting with the FDA to discuss the path forward for pimavanserin's development and expects to report on the outcome of this meeting before year end.

Despite the set backs regarding FDA approval, the trial results are an important step forward for clinical neuroscience and dementia research. Although the clinical trial results may be insufficient for FDA approval at present, they suggest that a badly needed safe and effective medication for dementia-related psychosis could come in the next few years.

In a first-of-its-kind study recently published in The New England Journal of Medicine, researchers at the Center for Psychedelic Research at Imperial College London compared psilocybin and escitalopram, an SSRI drug sold under the name Lexapro, as treatments for major depression. The six-week long study enrolled 59 volunteers with moderate-to-severe major depression. They were randomly and blindly assigned to receive treatment with psilocybin and an escitalopram control, or escitalopram and a psilocybin control. All the participants also received psychological support.

To evaluate the two treatments, the researchers compared the change from baseline on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16), a basic clinical measure of depression symptoms. Based on results of the QIDS-SR-16, psilocybin and escitalopram both reduce depression symptoms. The researchers did not detect a statistically significant difference between the two treatments.

The results of other measures taken in the study, however, suggest that psilocybin may be more effective than escitalopram. When designing the study, the researchers determined that the QIDS-SR-16 most directly addressed their experimental question and would therefore be the primary outcome measure, but they also evaluated depression symptoms with a number of additional scales. Nearly all secondary outcome measures favored psilocybin over escitalopram, but their results hold less weight than the QIDS-SR-16 because of how the study was designed.

The study was also limited by its small size, non-random enrollment of interested volunteers, and the possibility that participants may have been unblinded by the strong subjective effects of psilocybin or the well-known side-effects of SSRIs. Nonetheless, as the most rigorous evaluation of the therapeutic potential of psilocybin conducted to date, the results provide a benchmark for the design of future investigations.

But authorities warn that opioid tapering can come with risks. In a new large-scale study, researchers demonstrate the potential dangers associated with opioid tapering. 

The results were recently published in the Journal of the American Medical Association by a team of researchers at the University of California, Davis. To evaluate the potential harm of tapering opioid prescriptions, the researchers looked at the health data of 113, 618 people who were prescribed stable, high-dose opioid therapy for at least a one year period of time from 2008 to 2019. Next, they compared the health outcomes of people whose opioid therapy was tapered to the health outcomes of people before opioid tapering or whose opioid therapy was not tapered. They found that opioid tapering is associated with an elevated risk of both drug overdose and mental health crises, specifically depression, anxiety, and suicide attempts.

The researchers caution that interpretation of their findings is limited by the study’s observational design. Nonetheless, the results raise questions about the risks of opioid tapering, highlighting the importance of taking steps to minimize those risks, such as careful planning, monitoring, and coordination between patients and doctors.

Measuring circadian rhythms could significantly improve medical care. Doctors could better prevent and treat illness by more accurately assessing individual risk of disease and recommending times to eat, take medication, and rest. Circadian rhythms are not used as a clinical indicator at present because there is not an efficient way to measure them. Based on the results of a new study, however, that could change soon.

The results were recently reported in the Journal of Biological Rhythms by a team of researchers at the University of Colorado at Boulder. The researchers sought to develop a circadian rhythm test that is more efficient than the standard dim-light melatonin assessment, which requires hourly collection of blood over the course of an entire day to measure the amount of a sleep-inducing molecule in the body called melatonin. The test is accurate, but it is impractical for clinical use.

To develop an efficient circadian rhythm test, the researchers invited 16 participants into their sleep lab. Over the next two weeks, the researchers took regular blood samples and analyzed them to measure the levels of melatonin and approximately 4,000 metabolites, molecules that are produced by biochemical reactions in the body. Then, they used machine learning to determine which metabolites are associated with different phases of the circadian rhythm. When the analysis was complete, the researchers could measure circadian rhythms by testing a single blood sample for 65 metabolites with similar results to the dim-light melatonin assessment.

The new test does have some limitations; it worked best for people who had adequate sleep and whose food intake was controlled, which limits its practical application, and it would be more efficient if fewer metabolites had to be analyzed. Nonetheless, the study results are exciting and suggest an efficient circadian rhythm test may be available soon.

In fact, research shows that moderate coffee consumption (3–5 cups per day) can enhance concentration and alertness and improve health outcomes by decreasing risk of chronic disease. In a new large-scale study, however, researchers found that drinking over six cups per day may negatively impact brain function. 

The results were recently published in the journal Nutritional Neuroscience by a team of researchers at the University of South Australia. To look at the association between coffee consumption and brain health, the researchers conducted a prospective analysis of data collected by the UK Biobank, which has amassed detailed health information on over half a million participants in the UK.

The scientists analyzed the data associated with 398,646 UK Biobank participants. They compared self-reported consumption of caffeinated coffee and measures of brain volume acquired via MRI and found an inverse association between coffee consumption and total brain volume (brain volume isn't associated with intelligence, though brains tend to shrink as we age). In addition, their analysis revealed that drinking more than six cups of coffee per day is associated with a 53 percent greater probability of dementia compared to drinking 1–2 cups of coffee per day. 

The results build on previous research showing that drinking large amounts of coffee is associated with worsened health outcomes such as anxiety and insomnia. Luckily, because most coffee drinkers drink about three cups of coffee per day, odds are you can continue to enjoy your morning brew without worry. 

Cocaine is generally thought to produce its rewarding effects by increasing levels of the chemical messengers dopamine and serotonin within the brain. Medications that block these chemical messengers, however, have demonstrated limited efficacy in clinical trials, suggesting that cocaine may affect other chemical messengers as well. 

Recently, I and my fellow researchers at Davidson College published study results which suggest that cocaine may target an additional chemical messenger called acetylcholine. In the study, we administered cocaine to small nematode worms often used to study human biology called Caenorhabditis elegans. We observed that cocaine caused the worms to lay eggs. Next, we tested which chemical messengers had to be present in the brain circuit that controls worm egg laying, to make the link between cocaine and egg laying behavior. We found that acetylcholine is necessary for cocaine to cause worm egg laying, suggesting that cocaine might increase acetylcholine signaling.

Additional research in other animals such as rats and mice, and eventually humans, is necessary to find out if cocaine can increase acetylcholine signaling in the brain to cause addiction. If this is the case, however, then neuroscientists may be able to design medications that block acetylcholine to prevent cocaine addiction.

The story behind these numbers is complex, but opioids have played a major role. Opioid overdose deaths first started rising in the late 1990s due to increased prescribing of prescription opioids. The second wave began in 2010, with a rapid increase in overdose deaths involving heroin. Most recently, the introduction of the synthetic opioid fentanyl in 2013 ushered in the third wave of the opioid epidemic. The drug is 50 to 100 times more potent than morphine, so just a few hundred micrograms can cause an overdose. 

Adding to the danger, fentanyl is often found in combination with other drugs such as cocaine. The proportion of overdose deaths involving fentanyl and other opioids increased between 2019 and 2020 in part due to the insidious practice by people manufacturing the drugs of mixing small but potentially lethal amounts of fentanyl with other drugs without the knowledge of the person who uses it. 

Although shocking in its magnitude, the increase in overdose deaths didn’t come as a surprise to healthcare officials. Limitations on social mobility due to COVID-19 had the effect of reducing access to social support networks and harm-reduction initiatives, such as narcan administration, that are key to combating drug overdose. 

The 2020 data on drug overdoses is concerning, but there may be hope that the situation can be meaningfully improved in the short term. Since COVID-19 eroded the support systems that prevent drug overdose, the pandemic’s end should enable those systems to be repaired, allowing us to combat two public health crises at once. Even if overdose death rates can be reversed in the short term, however, it will take a concerted effort by governments and communities to reverse the underlying trends of the overdose epidemic.

Now, scientists may have discovered a new way to prevent seizures from a surprising source: tree resin.

The results were recently reported in the journal Epilepsia by a team of researchers at Linköping University in Sweden. The team was studying a group of molecules called resin acids, which are found in the liquid that oozes out when a tree is cut or a branch falls off.

The scientists produced chemically-modified resin acids and found that some of the chemically-modified resin acids can cause a subtype of potassium channel to open. These channels, located on the surface of neurons (cells that transmit information in our brains), decrease the electrical activity in the brain when opened. When these channels are closed for too, long electrical activity in the brain can become dangerously elevated and cause a seizure.

The researchers also found that some chemically-modified resin acids prevent seizure activity in the larvae of small fish called zebrafish. The study is just the first step on the long road from testing in zebrafish to testing in humans, but the results are encouraging for the development of anti-seizure medications.

To find a therapy for people diagnosed with treatment-resistant depression, researchers have been testing some unconventional drugs. These include the clinical anesthetic ketamine, as well as the active ingredient in magic mushrooms, psilocybin. Now, we can add laughing gas to the list.

A paper recently published in Science Translational Medicine reports results from a small, early-stage clinical trial conducted by researchers at the University of Chicago and Washington University School of Medicine. They found that inhaling a mixture of oxygen and nitrous oxide, the active chemical in laughing gas, significantly improved depression symptoms compared to inhaling oxygen alone in people diagnosed with treatment-resistant depression.

Larger studies will be necessary to validate these results. Nonetheless, early indications are that laughing gas may offer new hope for people diagnosed with treatment-resistant depression.