Nutraceuticals May Treat Negative Symptoms of Schizophrenia

Fran Lowry

June 13, 2018

MIAMI — Recent clinical trials on the use of herbal and nutraceutical agents as adjunctive treatment for schizophrenia show that these agents have some benefit in alleviating the negative symptoms of the disease.

Herbal and nutraceutical agents have anti-inflammatory, immunomodulatory, antiapoptotic, and antioxidant effects and can potentiate N-methyl-d-aspartate (NMDA) receptors, which could be useful in the treatment of schizophrenia, researchers say.

These mechanisms are not addressed by dopamine-receptor antagonists, the current mainstay of treatment.

Dr Robert Post and Dr Alan Brieir

"Antipsychotics do not treat schizophrenia's negative symptoms, such as impaired cognition, restriction of emotions, and lack of ambition, symptoms that prevent people with the disorder from leading productive lives," said Alan Breier, MD, Indiana University School of Medicine, Indianapolis.

The findings were presented here at the American Society of Clinical Psychopharmacology (ASCP) 2018 annual meeting.

"Desperate Need" for Treatments

While there is "a desperate need" to find effective agents to treat negative symptoms, there is also an urgent need to find a treatment for the progressive loss of brain mass that occurs in patients with schizophrenia, Breier told Medscape Medical News.

"Finding a medicine that might not contribute to brain mass loss, may even prevent it, and be effective for other symptom complexes like negative symptoms is very important. And if you had to think about an ideal medicine, you'd want one that is very safe, does not cause side effects, and is inexpensive. N-acetylcysteine [NAC] is a neuroprotective agent that looked like it might have those properties," he said.

The investigators assessed the effect of NAC, an agent that, when added to an antipsychotic medication in the treatment of patients with early schizophrenia, has been shown to improve general symptoms, negative symptoms, and cognitive impairment.

The researchers randomly assigned 60 patients to receive either NAC plus an antipsychotic or placebo plus an antipsychotic during a period of 52 weeks.

The results showed that NAC was effective with respect to negative symptoms of schizophrenia but had no impact on positive symptoms.

Use of NAC led to significant improvements in total symptom score (P < .001), negative symptom score (P = .024), and score on symptoms of disorganized thought (P < .001) on the Positive and Negative Syndrome Scale (PANSS) compared with placebo.

NAC had no effect in preventing progressive brain mass loss, although in patients with the highest degree of cortical thickness at study entry, there was a trend toward greatest improvement in total symptoms with NAC, Breier said.

"N-acetylcysteine has a variety of properties, including effects on oxidative stress, inflammation, and glutamatergic modulation, which have all been hypothesized to contribute to progressive brain mass loss. We found that baseline cortical thickness was associated with NAC-related improvement in total symptoms, which hints that there is a link between NAC and brain mass loss, but we were unable to show a prevention of brain mass loss on our follow-up scans," he said.

Progressive brain mass loss, which has been consistently observed in patients with schizophrenia, may be caused by the drugs used to treat schizophrenia or by the disease itself, so new drugs are needed, he added.

"Ideally, finding a medicine that might not contribute to brain mass loss, and may even prevent it, and also be effective for other symptom complexities, like negative symptoms, is very important," he said.


Jessica Gannon, MD, University of Pittsburgh School of Medicine, in Pennsylvania, presented the results of a randomized, placebo-controlled clinical trial in which a standardized extract of Withania somnifera (WSE), also known as ashwagandha, was added to antipsychotic medication for patients with schizophrenia who were experiencing symptom exacerbation.

The 66 patients were randomly allocated to receive either 1000 mg of standardized extract of WSE plus an antipsychotic or placebo plus an antipsychotic for 12 weeks.

Treatment with WSE resulted in significantly greater reductions in negative, general, and total symptoms, but not positive symptoms, in comparison with placebo.

Beginning at week 4 of treatment and continuing to the end of treatment, WSE produced significantly greater reductions in PANSS negative (Cohen's d = 0.83), general (Cohen's d = 0.76), and total symptoms (Cohen's d = 0.83), but not positive symptoms, compared with placebo.

Scores on the Perceived Stress Scale also improved significantly with WSE treatment compared with placebo (Cohen's d = 0.58).

C-reactive protein levels and S100 calcium-binding protein B levels declined more in the WSE group than in the group that received placebo, but the differences were not statistically significant.

"We were really excited about the significant decreases in negative symptoms, because there are no approved treatments for negative symptoms in schizophrenia," said Gannon.

"Negative symptoms include apathy, anhedonia, anergia. These are the type of patients who say it is very difficult for them to get motivated, to accomplish the sorts of things that they need to do to maintain a life in the community," she said.

Gannon noted that negative symptoms do not respond to antipsychotics. Along with cognitive symptoms, they generally carry the greatest morbidity.

"This is what really holds patients back from functioning. It may look like demoralization, depression, but it is actually an inherent part of the illness that doesn't respond to current treatment," she said.

These findings suggest that WSE may have promise in schizophrenia, particularly in the treatment of negative and general symptoms and associated stress, she added.

"The data show large effect sizes, and the number needed to treat to get ≥20% improvement in our PANSS negative subscale was only 3. That's pretty exciting. I'm a late convert to nutraceuticals, but I think the bottom line is we just don't have adequate treatments for our patients with schizophrenia," said Gannon.

Brain Function Recovery?

Adjunctive treatment with ashwagandha may lead to recovery of some of the neurophysiological auditory processing deficits observed in schizophrenia, according to preliminary data presented by Dean Salisbury, PhD, University of Pittsburgh School of Medicine.

"Schizophrenia is associated with profound auditory abnormalities, from complex verbal hallucinations to more basic sensory processing deficits," Salisbury told Medscape Medical News.

"These patients have sensory abnormalities in hearing and seeing. The mismatched negativity brain wave is robustly impaired in these patients and is one of the largest deficits observed in the disorder," he said.

Salisbury examined whether ashwagandha could improve mismatch negativity in 11 patients with long-term schizophrenia. Six of the patients received placebo, and five received ashwagandha.

The six patients who received placebo showed no change in mismatch negativity amplitude, whereas the patients who received ashwagandha showed a larger mismatch response after treatment, Salisbury reported.

"These data are very preliminary and suggest that adjunctive treatment with ashwaganda may recover some of the neuropsychiological auditory processing deficits observed in schizophrenia," he said.

"We hypothesize this action is due to recovery of parvalbumin interneurons silenced by neuroinflammatory processes induced by oxidative stress, in turn caused by chronic antagonism at the glutamate NMDA receptor," he said.

"This needs to be replicated in a larger sample. If so, it would provide a new pharmacologic treatment option that may treat deficits in the disorder not currently ameliorated by the dopamine antagonist medications that are successful in treating schizophrenia's positive symptoms but not negative or cognitive symptoms," Salisbury added.

"People have really begun to understand that there is neuroinflammation in the brain and that this plays a role in some of the psychiatric disorders, like schizophrenia. Ashwhagandha is working through its anti-inflammatory properties," Salisbury said.

The scientific evidence for ashwagandha's benefits has increased, he added.

"Many people see nutraceuticals as snake oil. There's still this idea that this is some sort of late-night TV thing, but a lot of the medications for the nutraceuticals come out of a long history of Chinese or Indian medicine. That's how a lot of drugs work. For example, aspirin comes from the bark of the willow tree," Salisbury said.

Interest in nutraceuticals for the treatment of schizophrenia has also increased.

"There are animal models that demonstrate the benefits of these agents. There is definitely a growing understanding and strong scientific support to show that neuroinflammation and oxidative stress play a role in major psychiatric disorders. The field just has to go along with that now. There's too much evidence to think that it's just someone trying to make a profit. The science is very strong," he said.

Encouraging Signals

Steven Marder, MD, Semel Institute at the University of California, Los Angeles, who was chair of the panel, told Medscape Medical News that he used to be skeptical about the utility of herbals and nutraceuticals.

"But then I started to do some research in this area, and I found that there were studies showing some benefit for these agents. I now believe that this is an up and coming field," Marder, who was not part of any of the studies, said.

There is a bias against studies of herbals and nutraceuticals, but this is based on inflated claims that have been made for them by the companies that market these agents, he said.

"But, as one looks more closely at these agents, particularly when they are administered at a dose that is likely to make a difference, and in a pure, nontoxic formulation, there are some encouraging signals," Marder said.

Data from animal studies on NAC and ashwagandha show that they have real effects on the glutamatergic system, he said.

"Glutamate is a very common neurotransmitter that regulates brain function, and there is a large literature suggesting that glutamate is involved in schizophrenia. For example, drugs like PCP [phencyclidine], which block glutamate at NMDA receptors, actually cause schizophrenialike symptoms, and all of these agents, in some way, interact with glutamate. So there's a plausible pharmacology to explain their effects. I definitely feel that interest in these agents is growing," Marder said.

Still, getting funding to support good-quality randomized controlled trials of herbals and nutraceuticals for the treatment of schizophrenia remains difficult, and things are not expected to improve soon, Marder said.

"All of the above trials were funded by the Stanley Medical Research Institute, a family-run, not-for-profit organization. And in fact, Stanley has died, so it's going to be even more difficult to do these studies," he said.

"Funding is a serious problem. And NIMH [National Institute of Mental Health] is less interested in these kinds of agents, despite their promise in schizophrenia, especially in this era of grant cutting.

"The presentations demonstrated that these agents are well tolerated. They are also relatively inexpensive. So my hope is that cumulative evidence from small trials, as we have seen, will eventually mount and help funding prospects for people who want to do further studies with these agents," Marder said.

The studies were sponsored by the Stanley Medical Research Institute. Dr Breier, Dr Gannon, and Dr Salisbury have disclosed no relevant financial relationships. Dr Marder has financial relationships with Allergan, Lundbeck, Otsuka, and Teva.

American Society of Clinical Psychopharmacology (ASCP) 2018. Abstract 3001185, presented May 29, 2018.

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