EMPowerPlus is a 36-ingredient micronutrient formula modeled after an agri- cultural treatment for aggressive behavior in farm animals, including pigs that become violent, biting each other’s ears and tails. After hearing of the success of this strategy from David Hardy, an animal nutrition specialist, Anthony Stephan added similar nutrients to the diets of his own children, who were struggling with treatment-resistant bipolar disorder. The results were striking, and the pro- prietary supplement, developed by TrueHope Nutritional Support, Ltd., has been used in more than 7,000 psychiatric patients. EMPowerPlus, which is rec- ommended for use at high dosages, contains 12 vitamins, 12 chelated minerals, and a proprietary blend of amino acids, herbs, and trace minerals.
Kaplan et al. (2001, p. 942) discussed possible mechanisms of action of EMPowerPlus:
It is possible that bipolar disorder is an inborn error of metabolism, analogous to others such as phenylketonuria in which metabolic “errors” lead to altered brain function, but whose symptoms become clinically evident long after birth. If this is the case, the fact that a nutritional supplement may partially correct that met- abolic error suggests that the predisposing genes are coding for proteins involved in metabolic pathways dependent on some of those nutrients. Many minerals (e.g., zinc) are important in dozens of biochemical pathways vital to brain func- tion, so this observation provokes questions about the specific mechanisms by which predisposing genes might affect mental health.
Evidence for Use
Kaplan et al. (2001) reported a 6-month open trial in which 11 subjects with DSM-IV bipolar disorder (6 with type I, 4 with type II, 1 with bipolar disorder not otherwise specified [NOS]) received EMPowerPlus. The mean time from diagnosis was 7 years; subjects had tried an average of 10 medications before en- tering the study. Seven subjects had a history of hospitalization, and 3 had re- quired electroconvulsive therapy. Ongoing psychiatric medications were con- tinued during the trial, with the treating psychiatrists being free to change medications as needed. Symptom reduction was reported as early as 2 weeks af- ter adding the supplement. At 6 months, symptoms were reduced by 55%–66%, as measured by the Ham-D, Brief Psychiatric Rating Scale, and Young Mania Scale. The changes on all three outcome measures were statistically and clini- cally significant. The number of psychiatric medications required decreased by more than 50% from a mean of 2.7 before the study to 1.0 with EMPowerPlus. During the study, two subjects started taking a new medication that may have contributed to their improvement. In some cases, subjects remained well while taking EMPowerPlus alone with no other psychiatric medication. Subjects who were followed for as long as 21 months reported no significant mood symptoms while continuing to take the supplement.
In a companion article commenting on Kaplan’s study, Popper (2001) re- ported on his own observational study of 22 subjects (10 adults, 9 adolescents, and 3 preadolescents) with bipolar disorder treated with EMPowerPlus. He de- termined that 19 responded positively to the micronutrient formula and, that of those, 10 improved markedly, 7 improved moderately, and 2 experienced mild clinical improvement. Of the 15 subjects who had required psychiatric medica- tion to stabilize their illness before the study, 11 experienced no significant mood symptoms while taking EMPowerPlus without conventional medications over a 6- to 9-month follow-up period.
Kaplan et al. (2002) reported on the results of an open-label pilot study in two medication-free boys, ages 8 and 12 years, with mood lability and explosive rage who were treated with EMPowerPlus. Both boys experienced rapid and significant improvements on measures of mood, anger, and obsessional symp- toms. Clinical improvement was monitored with the Conners Parent Rating Scale, the Child Behavior Checklist, and, for one child with atypical obsessive- compulsive disorder, the children’s version of the Yale-Brown Obsessive Com- pulsive Scale. Symptoms remitted with EMPowerPlus supplementation, re- turned when the supplement was discontinued, and remitted again with retreat- ment over several cycles of treatment withdrawal and reintroduction.
Simmons (2003) performed an observational study of 19 subjects with bipo- lar disorder (14 with type I and 5 with type II) taking a mean of 2.7 medications at baseline who were treated with EMPowerPlus. Of the 19 subjects, 15 subjects were determined to have improved: 12 with marked, 3 with moderate, and 1 with mild improvement. Overall, 13 subjects were able to discontinue all med- ications over a mean period of 5.2 weeks (range 3–10 weeks) and reported that their symptoms remained stable while they were taking EMPowerPlus alone. In all, 11 subjects chose to continue taking EMPowerPlus instead of conventional psychiatric medications and were followed for an average period of 13 months; 4 eventually discontinued EMPowerPlus because of gastrointestinal side effects, 3 discontinued the medication because of recurrent psychiatric symptoms, and 1 was lost to follow-up.
Guidelines for Use
Perhaps the main challenge in treating patients with EMPowerPlus is managing potential interactions with conventional psychiatric medications. Although EMPowerPlus augments the desirable effects obtained with psychiatric medica- tions, it also increases the sever ity of adverse effects. The distributor of EMPowerPlus recommends decreasing and, when appropriate, discontinuing psychiatric medications when EMPowerPlus is used. Managing the transition is sometimes complicated as Popper (2001, p. 934) reported: “Introducing micro- nutrients too quickly can increase the adverse effects of medications, including
agitation, while withdrawing psychiatric medications too quickly can result in symptom exacerbation.” Both complications can take place at the same time. Popper cautioned, “Clinicians who mistakenly approach these new findings as encouragement to combine micronutrients with psychiatric medications may find that they have stepped into a serious quagmire” (p. 934). Treating medica- tion-naïve patients is reportedly less challenging.
EMPowerPlus dosing generally starts at 32 tablets per day (8 tablets qid) and is gradually reduced to a maintenance regimen of 8 tablets per day. The specific ingredients are listed on the distributor’s Web site (www.TrueHope.com). To assist in managing the complications involved in adding this supplement to on- going conventional psychiatric medications and maximize the chances for a good outcome, TrueHope offers live phone support to patients and physicians.
Safety
The adverse effects reported with EMPowerPlus are predominantly gastrointes- tinal in nature, including nausea (particularly if taken on an empty stomach), di- arrhea, vomiting, flatulence, and, less commonly, agitation. There are no reports of serious adverse events with EMPowerPlus. Nutrients in the supplement are present at much higher doses than recommended daily levels. Because it con- tains high levels of vitamin A, EMPowerPlus should not be used by pregnant or lactating women. The safety of vitamin A supplementation at this level carries an unknown risk. (Nutrient DRIs were developed to prevent deficiency disor- ders in the general population, not to establish limits of toxicity.) Proponents of EMPowerPlus argue that the risk of toxicity is moderated by the fact that nutri- ent absorption is impaired in vitamin-deficient individuals.
Discussion
Although the double-blind, placebo-controlled trials currently being conducted have not been completed, early evidence supports the beneficial effects of EMPowerPlus. Popper (2001, p. 933) wrote, “In view of the 50 years of expe- rience with lithium, the notion that minerals can treat bipolar disorder is unsur- prising.” Further evidence regarding EMPowerPlus and other multinutrient treatment strategies is eagerly awaited. A controlled, double-blind clinical trial of EMPowerPlus is under way in Canada. In the United States, a three-arm double-blind trial comparing EMPowerPlus with placebo and a comparator drug in bipolar patients has received FDA approval and awaits funding.
There has been controversy in Canada surrounding EMPowerPlus and its manufacturers. Consumer advocacy groups opposed to alternative medical prac- tices had applied significant pressure to the Canadian agency responsible for su- pervising pharmaceutical research, delaying authorization of the study (men- tioned above) that is now in progress. That authorization was ultimately granted
through a new branch of Health Canada, which is charged with oversight of all natural health products, including research on dietary supplements.
5-HYDROXYTRYPTOPHAN
Two essential amino acids, tryptophan and phenylalanine, are precursors of the monoamine neurotransmitters, which are thought play an important role in the regulation of mood. Tryptophan becomes 5-hydroxytryptophan (5-HTP), a precursor of serotonin, and phenylalanine becomes tyrosine, a precursor of dopamine and norepinephrine. Evidence supporting the use of tyrosine, pheny- lalanine, or tryptophan in depression is inconclusive. Evidence supporting the use of 5-HTP in mental health care is somewhat stronger and is presented here. The theoretical basis for using neurotransmitter precursors to treat depression stems from the hypothesis that the depletion or deficiency of certain neurotransmit- ters leads to depression. The goal of amino acid supplementation is to increase the pool of available neurotransmitter precursors, with the aim of increasing the pro- duction, release, and therapeutic effects of the neurotransmitter that is deficient. Amino acid supplementation does not appear to result in increased neurotransmit- ter production and release, at least in the short term. Meyers (2000), in a review of studies on neurotransmitter precursors in depression, framed the unanswered ques- tion of whether the increased neurotransmitter production and release result in long-term, ongoing stimulation of neurotransmitter signaling, creating observable therapeutic effects. Neurotransmitter systems include feedback loops that maintain homeostasis by adapting to changes in nutrition, stress, and physical activity. Con- ventional antidepressants almost immediately block neurotransmitter reuptake, re- sulting in rapid increases in neurotransmitter concentration in the synaptic cleft. The fact that clinical improvement is delayed with conventional antidepressants by weeks suggests that something other than the neurotransmitter concentration in the synaptic space is responsible for the beneficial effects of these medications. There- fore, the fact that supplementation with L-tryptophan or 5-HTP acutely increases
serotonin release, as demonstrated by the increased concentration of serotonin me- tabolites in CSF fluid, does not guarantee an antidepressant effect.
Serotonin does not cross the blood-brain barrier and must be produced in the brain from its precursor, 5-HTP, a modified form of tryptophan. Although tryp- tophan faces competition for absorption from the gut into the bloodstream and for transport across the blood-brain barrier, 5-HTP does not face these obstacles and appears to be a more reliable route for increasing CNS levels of serotonin. A significant percentage of orally administered 5-HTP is converted into serotonin in the peripheral circulation before reaching the CNS, thus reducing its potential clinical efficacy. To facilitate increased efficacy at lower doses of 5-HTP (with a commensurate reduction in nausea), a peripheral decarboxylase inhibitor (e.g., carbidopa) is sometimes administered with 5-HTP to block peripheral conver-
sion into serotonin. Some studies have demonstrated increased blood levels of 5- HTP with carbidopa, but none using this strategy have shown increased clinical benefit or reduced side effects. 5-HTP supplementation results in increased levels of serotonin and its metabolites in the brain. Proponents of amino acid supple- mentation argue that 5-HTP has significant beneficial effects in the treatment of depression, fibromyalgia, binge eating, headaches, obesity, and insomnia.
Evidence for Use
Byerley and Risch (1987) analyzed the results of six open and seven controlled studies in which 5-HTP was used to treat depression. Within the pooled group of 292 subjects, 29%–69% of subjects responded favorably to 5-HTP. However, these results are of limited use because of the small sample sizes, mixed diag- noses, and uncontrolled study designs. Van Hiele (1980) reported the results of an open study of 99 subjects with refractory depression who had been symp- tomatic for an average of 9 years and treated with 5-HTP 50–600 mg/day over several months. In all, 43 of the 99 subjects experienced complete recovery and 8 improved significantly. In an open trial of 25 depressed patients, Zmilacher et al. (1988) found no difference in the efficacy of 5-HTP with and without car- bidopa. Although a head-to-head comparison was not done, both treatments were considered to have equivalent efficacy to conventional antidepressants.
Many studies have compared 5-HTP with antidepressants in the treatment of depression. In two open, controlled, crossover studies (Nolen et al. 1985, 1988), 5-HTP was not found to be beneficial when compared with MAOIs in depressed patients who had failed to respond to TCAs or SSRIs. Angst et al. (1977) reported no difference between the efficacy of 5-HTP and TCAs in a short-term study of depressed patients. Poldinger et al. (1991) compared 5-HTP 300 mg/day with fluvoxamine 150 mg/day for 6 weeks in a double-blind fash- ion in 69 nonpsychotic, depressed outpatients and found equivalent efficacy be- tween the two treatments. In two double-blind studies, researchers concluded that augmenting conventional antidepressant therapy with 5-HTP (versus pla- cebo) resulted in significant clinical improvement in depressed inpatients already taking MAOIs (Alino et al. 1976) or TCAs (Nardini et al. 1983).
Kahn and colleagues (Kahn and Westenberg 1985; Kahn et al. 1987) re- ported the results of two trials of 5-HTP in DSM-III (American Psychiatric As- sociation 1980) anxiety disorders. In an open trial, 10 patients with anxiety dis- orders who were treated for 12 weeks with carbidopa 50 mg tid and 5-HTP 300 mg/day showed significant reductions in anxiety, as measured using three dif- ferent anxiety scales (Kahn and Westenberg 1985). In a double-blind study of 45 patients with an anxiety disorder, 5-HTP was compared with clomipramine and placebo. The 5-HTP group experienced a moderate decrease in anxiety but no reduction in depressive symptoms, whereas the clomipramine group experi- enced significant improvement on all measures (Kahn et al. 1987).
Van Praag and de Hann (1980) examined the efficacy of 5-HTP in preventing depression in a double-blind crossover study comparing 5-HTP with placebo for 1 year each. The authors followed 20 patients, 14 with recurrent unipolar depression and 6 with bipolar depression, over 2 years. There were 7 relapses (1 each in 5 sub- jects and 2 in 1 subject) during the year of active treatment with 5-HTP, compared with 24 relapses in 17 subjects (more than 1 per person) during the year of placebo administration. Overall, 13 patients from both groups were identified as being “low serotonin producers”; only 1 such patient relapsed while taking 5-HTP, whereas 5 of 7 patients with normal serotonin production relapsed while taking 5-HTP. The authors suggested that patients with impaired serotonin production constitute a dis- tinct subtype of depression. These findings indicate that 5-HTP may be effective in preventing depressive episodes, especially in individuals who have impaired seroto- nin production. In a later study, van Praag and Lemus (1986) reported that in about 20% of depressed patients who responded to 5-HTP, the antidepressant effects of 5-HTP waned after 1 month of treatment. Although serotonin levels were still in- creased from baseline at 1-month follow-up, dopamine and norepinephrine levels had fallen. Tyrosine supplementation reportedly restored the antidepressant effect in this subgroup.
Guidelines for Use
Research findings suggest that it is reasonable to begin dosing 5-HTP at 50 mg tid, although the sedation effects of 5-HTP may necessitate starting at a lower dosage. The dosage can be eventually increased to a maximum of 150 mg qid, as tolerated. Because the half-life of 5-HTP is 2–5 hours, it should be taken three to four times daily on an empty stomach, ideally about 20 minutes before meals. Nausea, which is a dose-dependent side effect, is a frequent obstacle to achieving therapeutic doses. Enteric-coated preparations reportedly reduce nau- sea. Clinical improvement in mood may be evident within 3–14 days. Although many studies report rapid benefits (after 3–5 days) with 5-HTP, one found ben- efits as late as 2 months into treatment. If the response to 5-HTP wanes, L-tyro-
sine 500 mg tid and/or DL-phenylalanine 100 mg tid may be added, taken with
a protein meal. The appropriate dosing of 5-HTP for insomnia is 100–300 mg taken 30–45 minutes before bedtime. Doses up to 600 mg have been shown to be effective in treating insomnia but may increase the incidence of vivid dreams.
Safety
5-HTP is reasonably well tolerated, with no serious adverse reactions having been reported. The most problematic side effects include nausea and sedation, both of which are dose dependent and diminish with continued treatment. Other less problematic side effects include heartburn, gastrointestinal upset, and, less commonly, headache, insomnia, palpitations, dry mouth, dizziness, and
constipation. Study dosages up to 15 times the generally recommended maxi- mum (9,000 mg/day) for up to 3 years have been well tolerated. Serotonin syn- drome has not been reported in two studies combining 5-HTP with MAOIs or TCAs; results of studies combining 5-HTP with SSRIs have not been reported. Monitoring for serotonin syndrome is indicated when 5-HTP is combined with conventional serotonergic drugs. There is no evidence to support the safety of 5-HTP in pregnant or lactating women. As with any antidepressant, there is a risk of inducing mania in patients with bipolar disorder.
Despite the fact that 5-HTP is manufactured using a different process than that used for tryptophan, one case of eosinophilic myalgia syndrome has been reported in a patient taking 5-HTP. In this case, the contaminant responsible for the fatal eosinophilia with tryptophan supplementation was identified in the 5- HTP preparation. Clinicians should caution patients to use only reputable sup- pliers when selecting a 5-HTP supplement. Compounding pharmacies guaran- tee pure pharmaceutical-grade 5-HTP, which requires a prescription from a physician. There have been reports of anxiety when carbidopa or another pe- ripheral carboxylase inhibitor was combined with 5-HTP.
Discussion
The available research evidence for 5-HTP is of little clinical utility in view of the small sample sizes, uncontrolled study conditions, and heterogeneous patient populations in most of the studies. Large prospective, controlled studies with homogeneous patient populations are required before the antidepressant efficacy of 5-HTP can be determined. The report by van Praag and Lemus (1986) of a 20% relapse rate among 5-HTP responders after the first month of treatment makes the typical short study duration even more of a concern. The finding in this group that norepinephrine and dopamine levels were decreased even as se- rotonin levels rose with 5-HTP supplementation highlights our incomplete un- derstanding of the complex effects of using amino acids as neurotransmitter pre- cursors for treating depression. Furthermore, nausea and sedation are significant obstacles to achieving potentially therapeutic doses. The most useful role for 5-HTP may be in the treatment of insomnia.
INOSITOL
Inositol is a naturally occurring isomer of glucose present in high concentrations in brain tissue. Unlike amino acid supplements, which are precursors to neurotrans- mitter synthesis, inositol is a precursor to the phosphatidylinositol (PI) cycle, an im- portant intracellular second-messenger system. The PI cycle relays the message to the cell interior that serotonin, norepinephrine, dopamine, and other neurotrans- mitters are occupying receptor sites on the cell membrane. Inositol’s intracellular action is unique among psychotropic agents that typically act at the cell membrane.
A role for inositol in affective disorders was first suggested by an interaction between lithium and the PI cycle. Patients with unipolar and bipolar depression have been found to have markedly low levels of CSF inositol (Barkai et al. 1978). Dietary supplementation with inositol 12 g/day raises levels by as much as 70%.
Evidence for Use
In a 1997 review of eight controlled studies, Levine (1997) concluded that inos- itol is beneficial in treating the same spectrum of psychiatric illnesses that re- spond to SSRIs, including depression, panic disorder, and obsessive-compulsive disorder. Controlled studies of inositol do not support its use in the treatment of schizophrenia, Alzheimer’s disease, attention-deficit/hyperactivity disorder, autism, or electroconvulsive therapy–induced memory loss.
Depression
In an open 4-week study (Levine et al. 1993) of 11 patients with treatment-re- sistant depression taking inositol 6 g/day, 9 of 11 patients improved, with mean Ham-D scores dropping from 32 to 16. In a 4-week double-blind, placebo-