RESEARCH PROFILE

Natural Products in the Clinical Treatment
of Mental Illness

A Profile of Dr. James Greenblatt, MD
By Joe Leonard

Inositol

Inositol is a naturally occurring isomer of glucose and a key intermediate molecule of second messenger signal transduction pathways used by serotonergic, cholinergic, and noradrenergic neurons. Inositol is believed to play an important role in the intracellular phosphatidyl inositol second messenger system to which several key serotonin receptor subtypes are linked. As such, compounds containing inositol may represent novel therapeutic agents in treating some psychiatric disorders.

Dr. James Greenblatt of McLean Hospital, a Harvard Medical School teaching hospital, is currently using inositol supplementation as part of the treatment of patients with mental illnesses, particularly depression, panic disorder, and obsessive-compulsive disorder (OCD).

A considerable body of research is accumulating that inositol plays an important role in treating these mental illnesses. Inositol is likely involved in signal transduction pathways involving serotonin, a neurotransmitter that becomes out of balance in several of these illnesses. Inositol’s efficacy in the absence of side effects makes it an attractive addition to treatment plans for specific mood disorders.

Depressive patients show decreased levels of inositol in their cerebrospinal fluid (Levine et al., 1997) and inositol has a similar therapeutic profile to pharmaceutical selective serotonin reuptake inhibitors (SSRIs) often used to treat Depression (Mishori et al., 1999).

Serotonin plays a definitive role in OCD as well and Fux et al. (1996) brought about significant improvement in OCD patients by administration of 18 grams/day of inositol in a random, double-blind, placebo-controlled study (p=0.04 relative to control).

Treatment with 12 grams of inositol per day (vs. placebo) has also been shown to significantly reduce the severity and frequency of panic attacks in patients with panic disorder (Benjamin et al., 1995) in a double-blind, placebo-controlled, crossover experiment. The average number of panic attacks per week fell from 10 to 3.5 in patients receiving inositol.

Recently, Palatnik et al. (2001) completed a double-blind, controlled, crossover trial of inositol vs. fluvoxamine (Luvox®, Faverin®) in the treatment of panic disorder that reinforces previous research that inositol is effective in treating this serious illness. Fluvoxamine is an effective drug for treating panic disorder in the short term, though its side effects of nausea and tiredness often cause patients to stop taking it.

In this study, 20 patients taking inositol (up to 18 grams/day) showed improvements on the Hamilton Rating Scale for Anxiety, agoraphobia scores, and the Clinical Global Impressions scale, that were comparable with fluvoxamine. In the first month of treatment, inositol reduced the number of panic attacks per week by 4 compared with a reduction of 2.4 per week with fluvoxamine, a significantly improved outcome (p=0.049). Side effects were considerably less with inositol than with fluvoxamine. This is the first comparison of inositol with an established drug for treatment of panic disorder and suggests inositol may be just as effective as some drugs in the treatment of this disorder, with fewer side effects.

The side effects of inositol are minimal. It is speculated that inositol’s regulation of serotonin may enhance sleep and help patients with insomnia, though there are not currently any valid clinical studies to back this up.

The action of inositol in treating psychological disorders is largely theoretical. Inositol is known to act as a second messenger for a number of neurotransmitters in the brain. Antidepressant medications, such as SSRIs, increase the amount of neurotransmitter in neuronal synapses within 24 hours by blocking the receptors that sequester them. However, Greenblatt points out that the psychological effects of this inhibition can take 2-4 weeks to manifest, suggesting that second messengers in the biochemical pathways of neurotransmission, such as inositol, are likely to be involved.

Inositol is not considered an essential dietary nutrient, because it is made in the body and is shuttled around to various tissues as needed. Overconsumption of sugar, however, may disrupt the inositol shuttle system and associated second messenger pathways, essentially leading to deficiency.

Often, the patients that Greenblatt treats are not able to make positive dietary changes, but he has shown that supranutritional doses of inositol are effective in treating illnesses even when the diet is lacking in some way. He has also used inositol in conjunction with SSRIs, particularly where high doses of SSRIs cause sleep disturbances. Inositol can be taken with the medication to alleviate these disturbances.

Greenblatt has used inositol effectively in treating obsessive-compulsive disorder in both children and adults. He has been able to use inositol to treat children with OCD without requiring any other medical intervention. In adults he has used it alone to treat sleep disturbances.

In most clinical research trials, 10-18 grams of inositol are used in treatment. Greenblatt reports that he rarely uses more than 10 grams and in children he successfully uses much lower amounts, approaching physiological doses (2 grams or less per day).

Greenblatt is excited about current research on inositol for treating mental illnesses in children because it seems it sometimes can be used alone without the need for pharmaceutical drugs. He is anxious to get the word out to other psychiatrists who are reluctant to use a new and purely nutritional product without the research to back it up. The body of published literature on inositol in treating mental illness is significant, but it still has not been incorporated into mainstream clinical thinking because of the difficulty in getting past the heavy drug company influence in mental health. A major academic question Greenblatt asks is, why?

“There is scientific literature in peer reviewed psychiatric journals demonstrating that inositol appears to work as effectively as SSRIs (Prozac, Zoloft, and Paxil),” Greenblatt said. “Studies show consistent improvement in symptoms, significantly better than placebo.”

Because inositol is a natural substance that is safe and effective, without significant side effects, Greenblatt believes it may be particularly effective for use in the treatment of geriatric and pediatric populations before addressing their illnesses with pharmaceutical medications.

Greenblatt has been interested in nutritional medicine since the early 1980s in medical school. He completed traditional training in adult psychiatry and child psychiatry and believes medications play an important role in mental health. However, he does not believe this role should be primary to effective nutritional and dietary approaches to treating illness.

One of Greenblatt’s main goals is to educate mental health professionals in the use of nutrition and dietary supplements as alternatives to pharmaceuticals. Since the mid 1980s, he has treated thousands of children with both therapy and medication, but during the past 10 years he has become primarily interested in helping people find alternative therapies for treating psychiatric disorders.

“Patients are looking for alternatives,” he said. “They are going to alternative practitioners and coming home with a list of perhaps 30 synthetic supplements to take for depression. There is little scientific research to support the use of many of these supplements, and more importantly, they are not getting better.”

Greenblatt did an internship with allergist Marshal Mandel in the 1970s. His introduction to using alternative medicine in mental illness was observing the behavioral responses of people to food allergies . “I saw tapes of very sick patients, be it ADHD, schizophrenia, or depression, before and after eliminating certain foods that they were allergic to,” Greenblatt said. “The differences were dramatic!”

The future of inositol in mental health

In spite of the evidence that inositol is effective in treating mental illness, the medical community is slow to adopt its use. In order to get the word out, Greenblatt wants to examine inositol in a host of pediatric disorders that are responsive to SSRIs: depression, panic disorder, and OCD. He intends to repeat previous successful adult studies on children. Inositol in pediatric OCD will be the first study he plans to conduct. It may take a year or more to complete and two years before appearing in a peer-reviewed journal.

“It is important to wait for scientific research,” he said. “But it is also OK to begin to utilize nutritional interventions that are not harmful and appear to be therapeutic. Inositol is often a third line treatment for OCD. Medications are used first, and it doesn’t make a lot of sense that inositol is not used first, particularly in children and geriatric populations [on whom drugs may have the most adverse effects].

“What does it take for the medical community to accept inositol when the research has been done? I don’t know of any other nutrient in the psychiatric literature that has undergone the kind of scientific study that inositol has.

Many medications that we use in children are not approved for use in children. Most have only been studied in adults, with not a single study on children. Yet, we use them every day in children. We have no idea how they affect brain development or if they even work when we use them in children. Yet professionals are reluctant to use a safe herbal or nutritional supplement just because they say, ‘There is no research on it.’

“Up until a few years ago, all the antidepressants and neuroleptics (antipsychotics) had never been studied in children,” he said. “Now a few studies are coming out like the use of Luvox for OCD in children. These studies are funded by the drug companies. They are very short and they do show some benefit, but we just don’t know what their effects are over time. In addition, whenever you treat these disorders, particularly OCD, you always get a subset, sometimes 30% or 40%, that does not respond to medication. That is a whole other segment of the population that could benefit from nutritional intervention.”

Greenblatt recommends emphasizing nutrition with whole foods and whole food concentrates with higher-dose supplementation in certain cases.

“The difficult concept is that what we want to recommend to our patients is to stop eating sugar, junk food, and white flour, which is going to help a large majority of our child patients,” Greenblatt said. “When you look at even the adult mentally ill patients, they are just living on junk food. To address these lifestyle issues is clearly the first goal. But, if they are not able to change their diet right away, are there other alternatives that we can use? Clearly the food we are feeding our children as a culture is destroying brain cells and having an adverse effect on growth and development. The kids who are biologically vulnerable to mental illnesses are going to develop them at much earlier ages and I think in much more severe forms.”

OPC

Dr. Greenblatt is also interested in the use of oligoproanthocyanidins (OPCs) in the treatment of mental disorders, particularly for Attention Deficit Hyperactivity Disorder (ADHD). OPCs have been used for many years in Europe for vascular complaints such as hemorrhoids and varicose veins. Greenblatt has seen improvements in the electroencephalograms (EEGs) of patients with ADHD and improved handwriting, attention, and behavior in children with ADHD, an effect also observed with stimulant drugs used to treat ADHD.

“We have found that people respond to OPC herbal cancer cure whether or not they have a diagnosis of ADHD,” Greenblatt said. “They are generally more focused and more attentive. Depressed patients show an improvement of mood and energy level. PMS is a common complaint for which we have used OPC herbal cancer cure with good success.”

In treating ADHD with OPC, Greenblatt sees about a 60% success rate in adults and slightly less than that in children. “It is not that every patient gets better,” Greenblatt said. “But for a non-medical intervention it has been quite successful.”

As a consequence of administering OPC herbal cancer cure to treat psychiatric illnesses, Greenblatt is also hearing qualitative reports from patients of very rapid improvements in joint pain that are noticeable within a couple weeks of starting OPC. “Older patients will often report that the joint pain they have had for 20 years is better,” Greenblatt said. “Then they will suggest it to their relatives. Joint pain has really been probably the most dramatic improvement I have seen with the OPC.”

The effect on joint pain may be because OPC prevents the breakdown of collagen, a structural molecule in joints and blood vessels. This may also explain why OPC is reported to improve varicose veins.

Diet is a major component of Greenblatt’s supplement protocol. Adults and children who can make positive dietary changes have a much higher likelihood of success. “OPC sometimes can work without significant dietary interventions and lifestyle changes, but clearly it works better with those changes.”

OPC is found in pine bark, grape seed, Ginkgo biloba, and other plant sources and a question arises as to what is the best source of OPC to use therapeutically. Clinically, Greenblatt has observed that some people respond to one source of OPC better than another, but in general patients do better taking a mixed source of OPC, such as OPC Synergy™ (Standard Process Inc.).

References

Benjamin, J. et al. 1995. Double-blind, placebo-controlled, crossover trial of inositol treatment of panic disorder. Am J Psychiatry 52: 1084-1086.

Fux, M. et al. 1996. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 153(9): 1219-1221.

Levine, J et al. 1997. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol 7(2): 147-155.

Mishori, et al. 1999. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry 45: 270-273.

Palatnik, A. et al. 2001. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21(3): 335-339.




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RESEARCH PROFILE

Natural Products in the Clinical Treatment
of Mental Illness

A Profile of Dr. James Greenblatt, MD
By Joe Leonard

Inositol

Inositol is a naturally occurring isomer of glucose and a key intermediate molecule of second messenger signal transduction pathways used by serotonergic, cholinergic, and noradrenergic neurons. Inositol is believed to play an important role in the intracellular phosphatidyl inositol second messenger system to which several key serotonin receptor subtypes are linked. As such, compounds containing inositol may represent novel therapeutic agents in treating some psychiatric disorders.

Dr. James Greenblatt of McLean Hospital, a Harvard Medical School teaching hospital, is currently using inositol supplementation as part of the treatment of patients with mental illnesses, particularly depression, panic disorder, and obsessive-compulsive disorder (OCD).

A considerable body of research is accumulating that inositol plays an important role in treating these mental illnesses. Inositol is likely involved in signal transduction pathways involving serotonin, a neurotransmitter that becomes out of balance in several of these illnesses. Inositol’s efficacy in the absence of side effects makes it an attractive addition to treatment plans for specific mood disorders.

Depressive patients show decreased levels of inositol in their cerebrospinal fluid (Levine et al., 1997) and inositol has a similar therapeutic profile to pharmaceutical selective serotonin reuptake inhibitors (SSRIs) often used to treat Depression (Mishori et al., 1999).

Serotonin plays a definitive role in OCD as well and Fux et al. (1996) brought about significant improvement in OCD patients by administration of 18 grams/day of inositol in a random, double-blind, placebo-controlled study (p=0.04 relative to control).

Treatment with 12 grams of inositol per day (vs. placebo) has also been shown to significantly reduce the severity and frequency of panic attacks in patients with panic disorder (Benjamin et al., 1995) in a double-blind, placebo-controlled, crossover experiment. The average number of panic attacks per week fell from 10 to 3.5 in patients receiving inositol.

Recently, Palatnik et al. (2001) completed a double-blind, controlled, crossover trial of inositol vs. fluvoxamine (Luvox®, Faverin®) in the treatment of panic disorder that reinforces previous research that inositol is effective in treating this serious illness. Fluvoxamine is an effective drug for treating panic disorder in the short term, though its side effects of nausea and tiredness often cause patients to stop taking it.

In this study, 20 patients taking inositol (up to 18 grams/day) showed improvements on the Hamilton Rating Scale for Anxiety, agoraphobia scores, and the Clinical Global Impressions scale, that were comparable with fluvoxamine. In the first month of treatment, inositol reduced the number of panic attacks per week by 4 compared with a reduction of 2.4 per week with fluvoxamine, a significantly improved outcome (p=0.049). Side effects were considerably less with inositol than with fluvoxamine. This is the first comparison of inositol with an established drug for treatment of panic disorder and suggests inositol may be just as effective as some drugs in the treatment of this disorder, with fewer side effects.

The side effects of inositol are minimal. It is speculated that inositol’s regulation of serotonin may enhance sleep and help patients with insomnia, though there are not currently any valid clinical studies to back this up.

The action of inositol in treating psychological disorders is largely theoretical. Inositol is known to act as a second messenger for a number of neurotransmitters in the brain. Antidepressant medications, such as SSRIs, increase the amount of neurotransmitter in neuronal synapses within 24 hours by blocking the receptors that sequester them. However, Greenblatt points out that the psychological effects of this inhibition can take 2-4 weeks to manifest, suggesting that second messengers in the biochemical pathways of neurotransmission, such as inositol, are likely to be involved.

Inositol is not considered an essential dietary nutrient, because it is made in the body and is shuttled around to various tissues as needed. Overconsumption of sugar, however, may disrupt the inositol shuttle system and associated second messenger pathways, essentially leading to deficiency.

Often, the patients that Greenblatt treats are not able to make positive dietary changes, but he has shown that supranutritional doses of inositol are effective in treating illnesses even when the diet is lacking in some way. He has also used inositol in conjunction with SSRIs, particularly where high doses of SSRIs cause sleep disturbances. Inositol can be taken with the medication to alleviate these disturbances.

Greenblatt has used inositol effectively in treating obsessive-compulsive disorder in both children and adults. He has been able to use inositol to treat children with OCD without requiring any other medical intervention. In adults he has used it alone to treat sleep disturbances.

In most clinical research trials, 10-18 grams of inositol are used in treatment. Greenblatt reports that he rarely uses more than 10 grams and in children he successfully uses much lower amounts, approaching physiological doses (2 grams or less per day).

Greenblatt is excited about current research on inositol for treating mental illnesses in children because it seems it sometimes can be used alone without the need for pharmaceutical drugs. He is anxious to get the word out to other psychiatrists who are reluctant to use a new and purely nutritional product without the research to back it up. The body of published literature on inositol in treating mental illness is significant, but it still has not been incorporated into mainstream clinical thinking because of the difficulty in getting past the heavy drug company influence in mental health. A major academic question Greenblatt asks is, why?

“There is scientific literature in peer reviewed psychiatric journals demonstrating that inositol appears to work as effectively as SSRIs (Prozac, Zoloft, and Paxil),” Greenblatt said. “Studies show consistent improvement in symptoms, significantly better than placebo.”

Because inositol is a natural substance that is safe and effective, without significant side effects, Greenblatt believes it may be particularly effective for use in the treatment of geriatric and pediatric populations before addressing their illnesses with pharmaceutical medications.

Greenblatt has been interested in nutritional medicine since the early 1980s in medical school. He completed traditional training in adult psychiatry and child psychiatry and believes medications play an important role in mental health. However, he does not believe this role should be primary to effective nutritional and dietary approaches to treating illness.

One of Greenblatt’s main goals is to educate mental health professionals in the use of nutrition and dietary supplements as alternatives to pharmaceuticals. Since the mid 1980s, he has treated thousands of children with both therapy and medication, but during the past 10 years he has become primarily interested in helping people find alternative therapies for treating psychiatric disorders.

“Patients are looking for alternatives,” he said. “They are going to alternative practitioners and coming home with a list of perhaps 30 synthetic supplements to take for depression. There is little scientific research to support the use of many of these supplements, and more importantly, they are not getting better.”

Greenblatt did an internship with allergist Marshal Mandel in the 1970s. His introduction to using alternative medicine in mental illness was observing the behavioral responses of people to food allergies . “I saw tapes of very sick patients, be it ADHD, schizophrenia, or depression, before and after eliminating certain foods that they were allergic to,” Greenblatt said. “The differences were dramatic!”

The future of inositol in mental health

In spite of the evidence that inositol is effective in treating mental illness, the medical community is slow to adopt its use. In order to get the word out, Greenblatt wants to examine inositol in a host of pediatric disorders that are responsive to SSRIs: depression, panic disorder, and OCD. He intends to repeat previous successful adult studies on children. Inositol in pediatric OCD will be the first study he plans to conduct. It may take a year or more to complete and two years before appearing in a peer-reviewed journal.

“It is important to wait for scientific research,” he said. “But it is also OK to begin to utilize nutritional interventions that are not harmful and appear to be therapeutic. Inositol is often a third line treatment for OCD. Medications are used first, and it doesn’t make a lot of sense that inositol is not used first, particularly in children and geriatric populations [on whom drugs may have the most adverse effects].

“What does it take for the medical community to accept inositol when the research has been done? I don’t know of any other nutrient in the psychiatric literature that has undergone the kind of scientific study that inositol has.

Many medications that we use in children are not approved for use in children. Most have only been studied in adults, with not a single study on children. Yet, we use them every day in children. We have no idea how they affect brain development or if they even work when we use them in children. Yet professionals are reluctant to use a safe herbal or nutritional supplement just because they say, ‘There is no research on it.’

“Up until a few years ago, all the antidepressants and neuroleptics (antipsychotics) had never been studied in children,” he said. “Now a few studies are coming out like the use of Luvox for OCD in children. These studies are funded by the drug companies. They are very short and they do show some benefit, but we just don’t know what their effects are over time. In addition, whenever you treat these disorders, particularly OCD, you always get a subset, sometimes 30% or 40%, that does not respond to medication. That is a whole other segment of the population that could benefit from nutritional intervention.”

Greenblatt recommends emphasizing nutrition with whole foods and whole food concentrates with higher-dose supplementation in certain cases.

“The difficult concept is that what we want to recommend to our patients is to stop eating sugar, junk food, and white flour, which is going to help a large majority of our child patients,” Greenblatt said. “When you look at even the adult mentally ill patients, they are just living on junk food. To address these lifestyle issues is clearly the first goal. But, if they are not able to change their diet right away, are there other alternatives that we can use? Clearly the food we are feeding our children as a culture is destroying brain cells and having an adverse effect on growth and development. The kids who are biologically vulnerable to mental illnesses are going to develop them at much earlier ages and I think in much more severe forms.”

OPC

Dr. Greenblatt is also interested in the use of oligoproanthocyanidins (OPCs) in the treatment of mental disorders, particularly for Attention Deficit Hyperactivity Disorder (ADHD). OPCs have been used for many years in Europe for vascular complaints such as hemorrhoids and varicose veins. Greenblatt has seen improvements in the electroencephalograms (EEGs) of patients with ADHD and improved handwriting, attention, and behavior in children with ADHD, an effect also observed with stimulant drugs used to treat ADHD.

“We have found that people respond to OPC whether or not they have a diagnosis of ADHD,” Greenblatt said. “They are generally more focused and more attentive. Depressed patients show an improvement of mood and energy level. PMS is a common complaint for which we have used OPC with good success.”

In treating ADHD with OPC, Greenblatt sees about a 60% success rate in adults and slightly less than that in children. “It is not that every patient gets better,” Greenblatt said. “But for a non-medical intervention it has been quite successful.”

As a consequence of administering OPC to treat psychiatric illnesses, Greenblatt is also hearing qualitative reports from patients of very rapid improvements in joint pain that are noticeable within a couple weeks of starting OPC. “Older patients will often report that the joint pain they have had for 20 years is better,” Greenblatt said. “Then they will suggest it to their relatives. Joint pain has really been probably the most dramatic improvement I have seen with the OPC.”

The effect on joint pain may be because OPC prevents the breakdown of collagen, a structural molecule in joints and blood vessels. This may also explain why OPC is reported to improve varicose veins.

Diet is a major component of Greenblatt’s supplement protocol. Adults and children who can make positive dietary changes have a much higher likelihood of success. “OPC sometimes can work without significant dietary interventions and lifestyle changes, but clearly it works better with those changes.”

OPC is found in pine bark, grape seed, Ginkgo biloba, and other plant sources and a question arises as to what is the best source of OPC to use therapeutically. Clinically, Greenblatt has observed that some people respond to one source of OPC better than another, but in general patients do better taking a mixed source of OPC, such as OPC Synergy™ (Standard Process Inc.).

References

Benjamin, J. et al. 1995. Double-blind, placebo-controlled, crossover trial of inositol treatment of panic disorder. Am J Psychiatry 52: 1084-1086.

Fux, M. et al. 1996. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 153(9): 1219-1221.

Levine, J et al. 1997. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol 7(2): 147-155.

Mishori, et al. 1999. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry 45: 270-273.

Palatnik, A. et al. 2001. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21(3): 335-339.

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