In the apparent rubble of Alzheimer’s trials there is one area of therapy development that appears to offer modest hope. Several drugs for the treatment of neuropsychiatric symptoms have met endpoints in Phase 2 and 3 trials. Thus far, these compounds look safer than the atypical antipsychotics previously used to treat the mood and behavior problems that torment both patients and their caregivers. The new crop of neuropsychiatric drugs took center stage at the 7th Clinical Trials on Alzheimer’s Disease conference November 20 to 22 in Philadelphia, with two of the four symposia devoted, somewhat redundantly, to the topic. Speakers hailed the progress to date as potentially leading to a new era when psychiatric symptoms will be better managed, improving quality of life for patients and caregivers. The data generated a sense of momentum at a conference that otherwise delivered few major trial results, as most other large AD trials are a ways away from reading out. Jacques Touchon of University Hospital of Montpellier, France, who co-organizes CTAD, singled out the neuropsychiatric talks as a highlight of the meeting.

“Over the next three years, trials may establish a new treatment paradigm for agitation in AD,” predicted Susan Abushakra of Transition Therapeutics, San Mateo, California. “To me, this conference had the flavor of a new approach to treating this aspect of dementia,” said Michael Rafii of the University of California, San Diego, who is evaluating one such drug in adults with Down’s syndrome.

The need for these medications is great. Most Alzheimer’s patients have at least one neuropsychiatric symptom sometime during their illness, said Constantine Lyketsos of Johns Hopkins University, Baltimore. Besides agitation and aggression, these include depression, apathy, anxiety, emotional lability, and delusions. For caregivers, these are more distressing and difficult to deal with than the disease’s signature memory loss. They are the leading reason caregivers place loved ones in nursing homes (for a caregiver perspective, see Aug 2014 book review). For example, it is a fairly typical scenario in Alzheimer’s care that a wife will devote years of her life to caring for an increasingly incapacitated spouse, but when he tries to strangle her in a confused rage she commits him to institutional care. Behavioral problems add an estimated $10,000 per person per year to care costs. Moreover, patients with psychiatric symptoms progress faster to severe dementia and die earlier than people without these symptoms, Lyketsos said (see Rabins et al., 2012).

There are no good treatments. Atypical antipsychotics are used, but they sedate patients, can cause movement problems, and carry a black-box warning from the Food and Drug Administration because they increase the risk of death (see Oct 2005 news storyJan 2009 news story).

Researchers are testing new and repurposed drugs with different mechanisms of action. Unlike atypical antipsychotics, which block dopamine receptors, the new compounds act on serotonin, acetylcholine, and norepinephrine. In Alzheimer’s, these neurotransmitter systems malfunction, Abushakra said. Acetylcholine transmission drops the most, by 50 to 85 percent, but serotonin, dopamine, and norepinephrine signaling are also suppressed. Paul Rosenberg of Johns Hopkins noted that neurotransmission goes haywire in patterns that correspond to particular psychiatric symptoms. For example, in agitated patients, hippocampal serotonin falls while dopamine turnover in the cerebellum rises (see Vermeiren et al., 2014Vermeiren et al., 2014). The hope is that the new drugs may help to restore balance to brain signaling, speakers said.

Gentler Ways to Tame Agitation
Several current drug programs target agitation. Patients with this symptom become hyperactive and pace ceaselessly. Some lash out at caregivers, punching or choking them. Agitated patients may yell or curse in public places. They resist dressing or bathing. Some refuse to swallow food and medications in the belief that caregivers are trying to poison them. These symptoms not only put caregivers through the wringer, they also challenge trial personnel, who have to medicate and evaluate participants. 

That said, it’s not just the patients. In the past, Lyketsos said, these studies were unable to demonstrate therapeutic effects because the outcome measures were inadequate, the placebo effect strong, and there was no good clinical definition of agitation (see Soto et al., 2014). To improve this, the International Psychogeriatric Association recently approved new criteria for defining this condition (see Cummings et al., 2014). Trials now are applying more detailed outcome measures and incorporating design features such as run-in periods and crossover from placebo to drug to minimize placebo effects. Several of these new studies are reporting successful results.

CTAD attendees voiced excitement about Avanir Pharmaceuticals’ AVP-923, a combination of the cough syrup ingredient dextromethorphan and quinidine to improve dextrometrophan’s pharmacology. Trade-named Nuedexta, this is the only medication approved to treat pseudobulbar affect. PBA is a socially embarrassing condition where people burst into uncontrolled crying and laughing; it occurs in several neurodegenerative diseases. It is rare in AD, but the drug may hold other benefits for dementia patients. At CTAD, Avanir’s Joao Siffert said that patients with amyotrophic lateral sclerosis and multiple sclerosis who took AVP-923 for PBA became noticeably less agitated. This led the company to test their drug in agitated dementia patients, where it met its endpoints in Phase 2 and is now headed for Phase 3 (see Oct 2014 conference story). Like other drugs under investigation for agitation, AVP-923 affects multiple neurotransmitter systems, inhibiting particularly reuptake of norepinephrine to enhance its signaling.

Other drugs are also posting encouraging results. Earlier this year the antidepressant citalopram, a selective serotonin reuptake inhibitor, was reported to dampen agitation (see Feb 2014 news story). In the Phase 3 CitAD study of 186 people with Alzheimer’s and agitation, those who took the drug for nine weeks improved. However, a worrisome safety issue emerged as well. The maximum dose of 30 mg/day slightly slowed down the heart by lengthening the “QT interval,” a portion of the heart’s normal rhythm. This change is believed to heighten the risk of tachycardia and sudden cardiac death. The FDA recommends that older adults take no more than 20 mg/day citalopram for any indication. At CTAD, Daniel Weintraub of the University of Pennsylvania, Philadelphia, said that in CitAD, the QT interval lengthened by about 18 milliseconds in patients on 30 mg/day citalopram. This is significant because an increase of 20 milliseconds or more is associated with risk of arrhythmia. Nonetheless, other researchers were optimistic about the drug, noting that adjusting the dose might alleviate this problem. Rosenberg said that to his mind, the QT prolongation is a question mark, not a stop signal. “I see the glass two-thirds full,” he said.

Anton Porsteinsson of the University of Rochester, New York, was an investigator of the CitAD trial. He told Alzforum that he is planning a new study to clarify whether lower doses of citalopram will control agitation without cardiac effects. He also wants to evaluate longer treatment. Weintraub reported that many patients, particularly younger people, improved only late into the trial. Conveniently for the manufacturer, this would imply that more people might benefit if they stayed on drug for longer periods of time.

Meanwhile, researchers are squeezing every last drop of data out of the Phase 3 study, but they were not forthcoming with it at CTAD. Weintraub said that six more CitAD papers will appear soon, on how genetic and other factors predicted patient response, and how blood levels of drug related to behavioral outcomes.

Elan Pharmaceuticals’ ELND005, also known as scyllo-inositol, appears to act via a different pathway. Scyllo-inositol has been reported to prevent Aβ aggregation and was initially tested for cognitive benefits in AD patients, but missed primary endpoints (see Aug 2010 news storyAug 2011 conference story). In this trial, too, patients on the study drug seemed less agitated (see Jun 2012 conference story). Why might this be? Scyllo-inositol is an isomer of myoinositol, an intracellular messenger that kicks off the inositol trisphosphate (IP3) signaling pathway. In cell culture, scyllo-inositol lowers neuronal uptake of myoinositol, helping dial down the IP3 pathway, said Abushakra, who led development of the compound while at Elan. AD patients with psychiatric symptoms have high levels of myoinositol; other mood-stabilizing drugs, such as lithium, also lower myoinositol, she added.

Elan soon began a 12-week Phase 2 study of scyllo-inositol for agitation. The dose for the trial was selected to cut brain myoinositol levels by half. Participants will take 1,000 mg daily for four weeks in an initial “loading phase” of the trial, then 250 mg daily for eight weeks for maintenance. The trial will enroll 400 AD patients; 280 have signed up so far, Abushakra said. The main outcome measure will be change on an expanded version of the Neuropsychiatric Inventory agitation subscale. Whereas the older NPI-A assessed agitation and aggression with a combined eight items, the modified NPI-C subscale assesses agitation with 13 items and aggression with another eight questions. Thus, the NPI-C includes more specific behaviors and may be more sensitive, Abushakra said.

In addition to these compounds, the antihypertensive drug prazosin has entered a trial for agitation in AD after promising results in a small pilot study (see Jan 2013 news story). A poster at CTAD showed results from the pilot, noting that patients who did not respond to the drug had a drop in blood pressure when standing up, whereas those who responded did not. This difference might serve as a marker of therapeutic response, the authors suggested.

Other candidates in this crowded field include the dopamine receptor agonist brexpiprazole, which is in Phase 3 testing for agitation in Alzheimer’s. Researchers are also testing the oral cannabinoid Namisol in a Phase 2 trial to see if it can ameliorate behavioral problems in Alzheimer’s patients.

Can Neuropsychiatric Drugs Boost Memory While Soothing Anxiety?
Some companies hope that their neurotransmitter-tweaking drug can calm a person’s fears while also sharpening his or her thinking. Lundbeck’s idalopirdine, an antagonist of the serotonin 5-HT6 receptor that was originally developed by Eli Lilly, potentiates the effects of acetylcholinesterase inhibitors and facilitates central neurotransmission, Alireza Atri of Massachusetts General Hospital, Boston, said at CTAD. The compound appears to stimulate excitatory glutamatergic transmission and suppress inhibitory GABAergic signaling, suggesting that it shifts the balance in the brain toward excitatory activity, Atri said.

In Phase 2 trials of Alzheimer’s disease, idalopirdine added to the acetylcholinesterase inhibitor donepezil improved cognitive scores more than donepezil alone (see Jun 2012 news storyOct 2014 news story). The combination lowered anxiety, and other psychiatric symptoms trended lower, Atri said. This drug was originally developed for schizophrenia but switched over to Alzheimer’s.

Three Phase 3 studies in mild to moderate AD are now ongoing, flourishing names such as StarbeamStarshine, and Starbright. (Increasingly in pharma, Phase 3 studies get their own names, making individual trials sound like marketed products.) There is a Phase 3 extension study, as well. These studies will look for effects on both cognition and anxiety, Atri said. Pfizer has a similar 5-HT6 antagonist, PF-05212377, currently in a Phase 2 trial that will look for both cognitive and neuropsychiatric change.

What about other serotonin receptors? A poster at CTAD introduced Intra-Cellular Therapies Inc.’s ITI-007, an antagonist of the serotonin 5-HT2A receptor. At increasing doses, this antipsychotic compound also affects dopamine receptors, enhances glutamatergic transmission, and inhibits serotonin reuptake, the researchers claim. “The data are fairly clear that it is difficult to see efficacy in CNS diseases with molecules that target only one receptor,” the company’s Robert Davis told Alzforum.

The compound improved symptoms in schizophrenics in a Phase 2 study, and it is now in tests for AD. In a small Phase 1/2 safety study, 30 cognitively normal adults and eight Alzheimer’s patients tolerated seven days of dosing with up to 30 mg ITI-007. The trial was not powered to detect cognitive change, but the researchers reported improved word recall in both healthy elderly and dementia patients on the drug. Agitation could not be assessed because the AD patients did not have this symptom. The researchers are preparing for a larger Phase 2 study to start next year, which will measure behavior as a primary outcome and cognition as a secondary.

While the main focus at CTAD revolved around agitation in Alzheimer’s, drugs for other indications and patient groups are inching forward as well, said Jeffrey Cummings of the Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas. For example, ACADIA Pharmaceuticals’ pimavanserin, which selectively dials down the activity of the serotonin 5-HT2A receptor, met its endpoints in Phase 3 trials for psychosis in Parkinson’s patients (see Nov 2013 news story) and is being submitted for FDA approval. After gaining Breakthrough Therapy status (see MarketWatch), pimavanserin is now in a Phase 2 study for psychosis in AD, as well as a Phase 2 trial in schizophrenia.

The antidepressants paroxetine (Paxil) and venlafaxine (Effexor) each improved depression in Parkinson’s patients in Phase 3 (see Richard et al., 2012), and the stimulant ritalin relieved apathy in Alzheimer’s patients in Phase 2 (see Rosenberg et al., 2013).

Researchers are also turning their attention to people with Down’s syndrome, who are often overlooked in research. Carrying an extra copy of the amyloid precursor protein on their triplicated chromosome 21, people with Down’s develop Alzheimer’s pathology by middle age. This population also has behavioral symptoms of dementia, which tend to be the reason their distressed caregivers bring their loved ones to the clinic, said Rafii. At CTAD, Rafii reported results of a four-week Phase 2 trial of scyllo-inositol in 24 participants with Down’s syndrome. The trial had two active arms, at 250 or 500 mg daily. In the low-dose arm, plasma concentrations of the drug remained well below the efficacious dose, but in the high-dose arm, drug concentrations started overlapping with the efficacious range. Participants on this dose were less severely agitated, Rafii reported, but this initial trial was not powered to evaluate efficacy. The drug was well-tolerated, clearing the way for future studies to test higher doses and longer time frames, he added.—Madolyn Bowman Rogers

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  1. Inositol was trialled for Bipolar and Unipolar depression in a variety of ways, reviewed by Chengappa, et al, in 2000, and by Harwood in 2005. I understand several case reports of induction of mania after administration of Inositol were documented, and that anger and agitation in depression were proposed as markers of favorable response. Pineal utilization of the IP3 pathways was noted. Geoff Burnstock has written extensively on the purines.

    References:

    . Inositol as an add-on treatment for bipolar depression. Bipolar Disord. 2000 Mar;2(1):47-55. PubMed.

    . Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited. Mol Psychiatry. 2005 Jan;10(1):117-26. PubMed.

    . Introduction and perspective, historical note. Front Cell Neurosci. 2013 Nov 21;7:227. PubMed.

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References

News Citations

  1. Book Review: 'Slow Dancing With a Stranger'
  2. More Trouble for Atypical Antipsychotics—Dementia Patients at Risk
  3. Antipsychotics on Trial Again—DART-AD Confirms Increased Mortality
  4. A New Drug to Calm Agitation, Uncontrollable Laughing and Crying, in Alzheimer’s?
  5. Citalopram Calms Agitation in Alzheimer’s, but Carries Risks
  6. Anti-Aβ Oligomer Headed for Phase 3 Clinical Trial
  7. Paris: More Trial News, Mixed at Best
  8. Stockholm: Therapeutics Roundup—Some New, Some Not So Much
  9. NIH Funds Four Clinical Trials in ADCS Renewal
  10. Therapy Reported to Boost Cognition in Phase 2 Clinical Trial
  11. Phase 2 Trial Hints Idalopirdine May Work as Adjunct Therapy in Alzheimer’s
  12. Parkinson’s Antipsychotic Looks Good in Phase 3 Trial

Therapeutics Citations

  1. AVP-923
  2. ELND005
  3. Prazosin
  4. Brexpiprazole
  5. Idalopirdine
  6. PF-05212377

Paper Citations

  1. . Predictors of progression to severe Alzheimer's disease in an incidence sample. Alzheimers Dement. 2012 Nov 1; PubMed.
  2. . Monoaminergic neurotransmitter alterations in postmortem brain regions of depressed and aggressive patients with Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2691-700. Epub 2014 Jun 6 PubMed.
  3. . Brain region-specific monoaminergic correlates of neuropsychiatric symptoms in Alzheimer's disease. J Alzheimers Dis. 2014;41(3):819-33. PubMed.
  4. . Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design. Int Psychogeriatr. 2014 Sep 16;:1-17. PubMed.
  5. . Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr. 2015 Jan;27(1):7-17. Epub 2014 Oct 14 PubMed.
  6. . A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology. 2012 Apr 17;78(16):1229-36. Epub 2012 Apr 11 PubMed.
  7. . Safety and efficacy of methylphenidate for apathy in alzheimer's disease: a randomized, placebo-controlled trial. J Clin Psychiatry. 2013 Aug;74(8):810-6. PubMed.

External Citations

  1. Phase 3 CitAD study
  2. FDA recommends
  3. Phase 2 study
  4. trial 
  5. Phase 3
  6. Phase 2
  7. Starbeam
  8. Starshine
  9. Starbright
  10. extension study
  11. Phase 2 trial
  12. Phase 2 study
  13. Phase 1/2 safety study
  14. MarketWatch
  15. Phase 2 study
  16. Phase 2 trial
  17. Phase 3
  18. Phase 2
  19. Phase 2 trial

Further Reading