Clinical Studies | Mood Disorders


CLINICAL STUDY 1 — Therapy of Depression by Phenylalanine

—Fischer E, Heller B, Nachon M, Spatz H.

To 23 subjects with endogenous depression after a previous unsuccessful treatment with common antidepressive drugs (Imipramine-like or MAO inhibitors) dl- or d-phenylalanine was given in daily oral doses of 50 or 100 mg during 15 days. A complete euthymia was obtained in 17 subjects between one and 13 days of treatment. No important adverse reaction was observed. PMID: 1173765

CLINICAL STUDY 2 — Metabolism of an Amino Acid with Antidepressant Properties

—Borison RL, Maple PJ, Havdala HS, Diamond BI.

The amino acid d-phenylalanine exerts antidepressant properties which are believed to be due to its metabolism to brain phenylethylamine. We now show that in mice, the increase in brain phenylethylamine levels induced by l-phenylalanine, but not d-phenylalanine, is antagonized by drugs which block the stereospecific decarboxylase enzyme. Our results show that d-phenylalanine metabolism to phenylethylamine is independent of pathways involving l-phenylalanine. PMID: 694233

CLINICAL STUDY 3 — DL-phenylalanine as an Antidepressant – Open Study

—Beckmann H, Ludolph E.

In an open study dl-phenylalanine in doses from 75–200 mg/day was administered to 20 depressed patients for 20 days. At the end of the trial 12 patients (8 with complete, 4 with good response) could be discharged without any further treatment. 4 patients with partially untypical depressions experienced mild to moderate responses, whereas 4 patients did not respond at all to the phenylalanine administration. Depressive “core symptoms” as depressed mood, retardation and/or agitation were preferentially, anxiety and sleep disturbances moderately and hypochondriasis and compulsiveness were not influenced. It is concluded that dl-phenylalanine might have substantial antidepressant properties and that further controlled investigations are justified. PMID: 380577

CLINICAL STUDY 4 — Reduced Glutamate in the Anterior Cingulate Cortex in Depression: an in Vivo Proton Magnetic Resonance Spectroscopy Study

—Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F., Max Planck Institute of Psychiatry, Munich, Germany

BACKGROUND: Functional imaging studies suggest a specific role of the anterior brain regions in the pathogenesis of major depression. The aim of this study was to evaluate possible neurochemical alterations in the fronesial cortex in patients with major depressive episode using in vivo proton magnetic resonance spectroscopy (1 H-MRS). METHODS: Single voxel H-MRS was performed in 19 patients with major depressive episodes and 18 age-matched healthy controls within the anterior cingulate cortex and the parietal white matter. Absolute concentrations were estimated for N-acetyl-aspartate, choline-containing compounds, total creatine, myo-inositol, unresolved glutamate and glutamine (Glx) and glutamate alone (Glu). Voxel composition was analyzed by image segmentation into cerebrospinal fluid (CSF), grey and white matter. RESULTS: MANOVA test for Glx and Glu using age, percent CSF and percent grey matter contribution as covariates yielded a significant group effect within the anterior cingulate due to decrease of Glx in patients (-10.4%, p =.013). Considering only severely depressed patients, both Glx and Glu (-14.3%, p =.03) showed a significant decrease. There was no significant group effect for the neuronal marker NAA, creatine, choline or myo-inositol in either localization. CONCLUSIONS: This study suggests a possible role of altered glutamatergic neurotransmission within the anterior cingulate in the pathogenesis of mood disorders. The otherwise unremarkable findings of major brain metabolites confirms lack of neurodegenerative or membrane metabolic changes in major depression. PMID: 10686265

CLINICAL STUDY 5 — Dl-phenylalanine in Depressed Patients: an Open Study

—Beckmann H, Strauss MA, Ludolph E.

In an open study dl-phenylalanine in doses from 75-200 mg/day was administered to 20 depressed patients for 20 days. Patients were classified according to the International Classification of Diseases (ICD). The AMP system, the Hamilton depression scale and the von Zerssen self rating questionnaire were used for documentation of psychopathological, neurologic and somatic changes. In addition a global clinical impression was agreed upon by experienced psychiatrists. At the end of the trial 12 patients (8 with complete, 4 with good response) could be discharged without any further treatment. 4 patients with partially untypical depressions experienced mild to moderate responses, whereas 4 patients did not respond at all to the phenylalanine administration. Depressive “core symptoms” as depressed mood, retardation and/or agitation were preferentially, anxiety and sleep disturbances moderately and hypochondriasis and compulsiveness were not influenced. It is concluded that dl-phenylalanine might have substantial antidepressant properties and that further more controlled investigations are warranted. PMID: 335027

CLINICAL STUDY 6 — Intravenous L-Dopa plus Carbidopa in Depressed Patients: Average Evoked Response, Learning, and Behavioral Changes

—Henry GM, Buchsbaum M, Murphy DL.

The peripheral decarboxylase inhibitor carbidopa (L-alphamethyl-dopa-hydrazine) allowed safe intravenous administration of l-dopa in amounts sufficient to alter cortical average evoked response (AER) and learning function in 13 depressed patients. The apparently rapid conversion of l-dopa to dopamine, as reported from studies in animals, is consistent with the 20-30 min onset of effects seen in our study. Unipolar and bipolar depressed patients responded differently to the alterations in brain biogenic amines and also to the nonspecific stress of the experiment. Intravenous l-dopa given acutely had effects on the AER that were similar to those documented with oral dopa given chronically–an augmentation of amplitude–intensity slopes in unipolar patients and a relative reduction of slopes in bipolar patients. In contrast, intravenous l-dopa did not enhance verbal learning as did chronic oral treatment, but rather was associated with reduced learning compared with placebo infusions. Different neurochemical changes following l-dopa given in single intravenous doses may be responsible for the different learning and behavioral changes form those found previously with oral dopa administered chronically. PMID: 1273240

(phenylalanine is the precursor to tyrosine, which in turn is the precursor to l-dopa)

CLINICAL STUDY 7 — Effective mood stabilization with a chelated mineral supplement: an open-label trial in bipolar disorder

—Kaplan, B. J., Simpson, J. S. A., Ferre, R. C., Gorman, C., McMullen, D., ft Crawford, S. G. (2001). Effective mood stabilization in bipolar disorder with a chelated mineral supplement Journal of Clinical Psychiatry, 62, 936-944

BACKGROUND: To determine in open trials the therapeutic benefit of a nutritional supplement for bipolar disorder. METHOD: The sample consisted of 11 patients with DSM-IV-diagnosed bipolar disorder aged 19 to 46 years, who were taking a mean of 2.7 psychotropic medications each at a study entry. Three additional patients dropped out prematurely. The intervention is a broad-based nutritional supplement of dietary nutrients, primarily chelated trace minerals and vitamins, administered in high doses. At study entry and periodically thereafter, patients were assessed with the Hamilton Rating Scale for Depression (HAM-D), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS). RESULTS: For those who completed the minimum 6-month open trial, symptom reduction ranged from 55% to 66% on the outcome measures; need for psychotropic medications decreased by more than 50%. Paired tests revealed treatment benefit on all measures for patients completing the trial: HAM-D mean score at entry =19.0, mean score at last visit = 5.4, t = 5.59, df = 9, p< .01; BPRS mean score at entry = 35.3, mean score at last visit = 7.4, t = 2.57, df = 9, p < .05: YMRS mean score at entry = 15.1, mean score at last visit = 6.0, t = 4.11, df = 9, p < .01. The effect size for the intervention was large (> .80) for each measure. The number of psychotropic medications decreased significantly to a mean ± SD of 1.0 ± 1.1 (1= 3.54, df = 10, p < .01). In some cases, the supplement replaced psychotropic medications and the patients remained well. The only reported side effect (i.e. nausea) was infrequent, minor, and transitory. CONCLUSION: Some cases of bipolar illness may be ameliorated by nutritional supplementation. A randomized, placebo-controlled trial in adults with bipolar disorder is currently underway, as well as open trials in children. PMID: 11780873

CLINICAL STUDY 8 — Treatment of mood lability and explosive rage with minerals and vitamins: two case studies in children

—Kaplan, B. J., Crawford, S. G., Gardner, B., & Farrelly, G. (2002). Journal of Child and Adolescent Psychopharmacology, 12(3), 203-218

A micronutrient supplement containing a broad range of dietary minerals and vitamins is being examined for the treatment of mood lability in both adults and children (Kaplan et al. 2001; Popper 2001). During pilot work, two medication-free boys with mood lability and explosive rage were studied in an open-label treatment followed by reversal and retreatment. One child was an 8-year-old with atypical obsessive-compulsive disorder, and the other was a 12-year-old with pervasive developmental delay. Both boys were monitored using the mood and temper items from the Conners Parent Rating Scale, as well as the Child Behavior Checklist. In addition, the boy with atypical obsessive-compulsive disorder was monitored with the child version of the Yale-Brown Obsessive Compulsive Scale. Both boys benefited from the micronutrient supplement when examined in ABAB designs: mood, angry outbursts, and obsessional symptoms improved when initially treated, returned when not taking the supplement, and remitted when the micronutrient supplement was reintroduced. Both boys have been followed and are stable on the nutritional supplement for over 2 years. These cases suggest that mood lability and explosive rage can, in some cases, be managed with a mixture of biologically active minerals and vitamins, without using lithium or other traditional psychopharmacologic agents. PMID: 12427294

CLINICAL STUDY 9 — Improved mood and behavior during treatment with a mineral-vitamin supplement: an open-label case series of children

—Bonnie J. Kaplan, Jennifer E. Fisher, Susan G. Crawford, Catherine J. Field, and Bryan Kolb. Journal of Child and Adolescent Psychopharmacology. July 2004, 14(1): 115-122

Several studies have demonstrated that psychiatric symptoms such as depression, mood swings, and aggression may be ameliorated by supplementation with broad-based nutrient formulas containing vitamins, minerals, and sometimes essential fatty acids. These findings have been reported in young criminal offenders as well as in adults with mood disturbance and other psychiatric disorders. The purpose of the current case series was to explore the potential efficacy of a nutrient supplement in children. Children with mood and behavioral problems (N = 11; 7 boys, 4 girls; 8-15 years old) participated; 9 completed this open-label trial. Parents completed the Child Behavior Checklist (CBCL), Youth Outcome Questionnaire (YOQ), and Young Mania Rating Scale (YMRS) at entry and following at least 8 weeks of treatment. Intent-to-treat analyses revealed decreases on the YOQ (p < 0.001) and the YMRS (p < 0.01) from baseline to final visit. For the 9 completers, improvement was significant on seven of the eight CBCL scales, the YOQ, and the YMRS (p values from 0.05-0.001). Effect sizes for all outcome measures were relatively large. The findings suggest that formal clinical trials of broad nutritional supplementation are warranted in children with these psychiatric symptoms. PMID: 15142398

CLINICAL STUDY 10 — Successful treatment of bipolar disorder II and ADHD with a micronutrient formula

—Rucklidge, J. J., & Harrison, R. (2010). 15(5):231-237.

Bipolar disorder with co-occurring attention-deficit/hyperactivity disorder (ADHD) is a challenge to treat. Ten previous reports have shown potential benefit of a micronutrient treatment (consisting mainly of vitamins and minerals) for various psychiatric symptoms, including mood and ADHD. This case study aimed to investigate the longer term impact of the micronutrients on both psychiatric and neurocognitive functioning in an off-on-off-on (ABAB) design with 1 year follow-up. A 21-year-old female with bipolar II disorder, ADHD, social anxiety, and panic disorder entered an open-label trial using a nutritional treatment following a documented 8 year history of on-going psychiatric symptoms not well managed by medications. After 8 weeks on the formula she showed significant improvements in mood, anxiety, and hyperactivity/impulsivity. Blood test results remained normal after 8 weeks on the formula. She did not report any adverse side effects associated with the treatment. She then chose to come off the formula; after 8 weeks her depression scores returned to baseline, and anxiety and ADHD symptoms worsened. The formula was reintroduced, showing gradual improvement in all psychiatric symptoms. This case represents a naturalistic ABAB design showing on-off control of symptoms. After 1 year, the patient is now in remission from all mental illness. Neurocognitive changes mirrored behavioral changes, showing improved processing speed, consistency in response speed, and verbal memory. A placebo response and expectancy effects cannot be ruled out although previous poor response to treatment and the duration of the current positive response decrease the likelihood that other factors better explain change. These consistently positive outcomes alongside an absence of side effects indicate that further research, particularly larger and more controlled trials, is warranted using this multinutrient approach. PMID: 20448519

CLINICAL STUDY 11 — Database analysis of children and adolescents with bipolar disorder consuming a micronutrient formula

—Rucklidge, J.J., Gately, D., Kaplan, B.J. (2010). BMC Psychiatry, 10:74 doi:10.1186/1471-244X-10-74.

BACKGROUND: Eleven previous reports have shown potential benefit of a 36-ingredient micronutrient formula (known as EMPowerplus) for the treatment of psychiatric symptoms. The current study asked whether children (7-18 years) with pediatric bipolar disorder (PBD) benefited from this same micronutrient formula; the impact of Attention-Deficit/Hyperactivity Disorder (ADHD) on their response was also evaluated. METHODS: Data were available from an existing database for 120 children whose parents reported a diagnosis of PBD; 79% were taking psychiatric medications that are used to treat mood disorders; 24% were also reported as ADHD. Using Last Observation Carried Forward (LOCF), data were analyzed from 3 to 6 months of micronutrient use. RESULTS: At LOCF, mean symptom severity of bipolar symptoms was 46% lower than baseline (effect size (ES) = 0.78) (p < 0.001). In terms of responder status, 46% experienced >50% improvement at LOCF, with 38% still taking psychiatric medication (52% drop from baseline) but at much lower levels (74% reduction in number of medications being used from baseline). The results were similar for those with both ADHD and PBD: a 43% decline in PBD symptoms (ES = 0.72) and 40% in ADHD symptoms (ES = 0.62). An alternative sample of children with just ADHD symptoms (n = 41) showed a 47% reduction in symptoms from baseline to LOCF (ES = 1.04). The duration of reductions in symptom severity suggests that benefits were not attributable to placebo/expectancy effects. Similar findings were found for younger and older children and for both sexes. CONCLUSIONS: The data are limited by the open label nature of the study, the lack of a control group, and the inherent self-selection bias. While these data cannot establish efficacy, the results are consistent with a growing body of research suggesting that micronutrients appear to have therapeutic benefit for children with PBD with or without ADHD in the absence of significant side effects and may allow for a reduction in psychiatric medications while improving symptoms. The consistent reporting of positive changes across multiple sites and countries are substantial enough to warrant a call for randomized clinical trials using micronutrients. PMID: 20875144

CLINICAL STUDY 12 — Nutritional and safety outcomes from an open-label micronutrient intervention for pediatric bipolar spectrum disorders

—Frazier EA, Gracious B, Arnold LE, Failla M, Chitchumroonchokchai C, Habash D, and Fristad MA. Journal of Child and Adolescent Psychopharmacology.

OBJECTIVE: The purpose of this study was to report the safety, tolerability, and serum micronutrient concentrations and their correlations with mood changes from an 8 week pilot feasibility study of a 36 ingredient multinutrient supplement, EMPowerplus (EMP+), for pediatric bipolar spectrum disorders (BPSD). METHODS: Ten children ages 6-12 received EMP+ escalating from one to four capsules t.i.d., with four children increased to the maximum suggested dose, five capsules t.i.d. Outcome measures were micronutrient concentrations in serum and red blood cells, vital signs, body mass index (BMI), dietary intake (Food Frequency Questionnaire and 24 hour dietary recall interview), and mood and global functioning ratings. RESULTS: Seven children (70%) completed the study. Three (30%) terminated early for tolerability and compliance issues. Adverse effects were mild and transient, and chiefly consisted of initial insomnia or gastrointestinal (GI) upset. No differences occurred in BMI (p = 0.310) or waist-hip ratio (WHR; p = 0.674) pre- to postsupplementation. Four of the tested serum vitamin concentrations increased from pre- to postsupplementation: vitamin A-retinol, vitamin B6, vitamin E-α-tocopherol; and folate (all p<0.05). The increase in serum 25-OH vitamin D approached significance (p = 0.063). No differences were found in dietary intake pre- to postsupplementation, suggesting that blood nutrient level increases were caused by EMP+. CONCLUSIONS: In this open prospective study, short-term use of EMP+ in children with BPSD appeared safe and well-tolerated, with a side effect profile preferable to first-line psychotropic drugs for pediatric bipolar spectrum disorders. A double-blind, randomized clinical trial is feasible, appears safe, and is warranted by open-label clinical outcomes and plausible mechanisms of action, combined with documentation of increased serum concentrations of specific micronutrients. PMID: 24138009

CLINICAL STUDY 13 — Broad-spectrum micronutrient formulas for the treatment of psychiatric symptoms: a systematic review

—Rucklidge, J. J., & Kaplan, B. J. (2013). Expert Review of Neurotherapeutics, 13(1).

Ingesting minerals and vitamins in combination makes physiological sense, and research on the use of broad-spectrum formulations for psychiatric symptoms is increasing rapidly. This review covers formulas consisting of at least four vitamins and/or minerals and includes four experimental designs: randomized controlled trials, open-label trials, case-control studies and case studies with within-subject crossovers. Nevertheless, there is evidence for the efficacy of micronutrients in the treatment of stress and antisocial behaviors as well as depressed mood in nonclinical and elderly populations. Many reports studied mood changes in healthy populations, making it difficult to generalize to clinical samples. There is also preliminary support for the treatment of autism with micronutrients. However, despite positive preliminary findings, there are less data available to support efficacy of micronutrient formulas in treating bipolar disorder, attention deficit-hyperactivity disorder and substance abuse/dependence and no clinical trials have been done with clinically depressed or anxious patient samples, psychosis or eating disorders. PMID: 23253391

CLINICAL STUDY 14 — Vitamins, minerals, and mood

—Kaplan, BJ, Crawford, S., Field, C, and Simpson, JSA. (2007). Psychological Bulletin, 133(5), 747-760.

In this article, the authors explore the breadth and depth of published research linking dietary vitamins and minerals (micronutrients) to mood. Since the 1920s, there have been many studies on individual vitamins (especially B vitamins and Vitamins C, D, and E), minerals (calcium, chromium, iron, magnesium, zinc, and selenium), and vitamin-like compounds (choline). Recent investigations with multi-ingredient formulas are especially promising. However, without a reasonable conceptual framework for understanding mechanisms by which micronutrients might influence mood, the published literature is too readily dismissed. Consequently, 4 explanatory models are presented, suggesting that mood symptoms may be expressions of inborn errors of metabolism, manifestations of deficient methylation reactions, alterations of gene expression by nutrient deficiency, and/or long-latency deficiency diseases. These models provide possible explanations for why micronutrient supplementation could ameliorate some mental symptoms. PMID: 17723028

CLINICAL STUDY 15 — Feasibility of a nutritional supplement as treatment for pediatric bipolar spectrum disorders

—Frazier EA, Fristad MA, Amold LE (2012). Journal of Alternative and Complementary Medicine. 18(7):678-685.

OBJECTIVES: Current psychotropic medications for childhood bipolar spectrum disorders (BPSD) are associated with significant adverse events. As nutrients play an important role in physical and mental health, they may be useful in treating mood disorders with few side-effects. This open-label study explored the feasibility of testing therapeutic effects of a multinutrient supplement, EMPowerplus™ (EMP+), for pediatric BPSD. DESIGN: EMP+ was started at one capsule t.i.d. and escalated to a goal of four capsules t.i.d., which eight children attained. Four (4) of these increased to the maximum dose, five capsules t.i.d. Mood symptoms were assessed seven times over 8 weeks. SUBJECTS: Ten (10) children, age 6-12 with BPSD, were enrolled in 6.5 months. Seven (7) participants completed the full trial. Three (3) dropped out due to palatability and/or adherence issues. RESULTS: Mean medication adherence was 91%. With one-tailed nonparametric Fisher’s randomization tests, intent-to-treat analyses demonstrated a 37% decrease in depression scores (p<0.06) and a 45% decrease in mania scores (p<0.01) from the start of treatment through final visit, suggesting improvement and possible treatment response. Study completers demonstrated significant decreasing trends in both depression and mania scores from baseline to final visit (p<0.05). Side-effects were minor and transient, mostly temporary gastric discomfort. CONCLUSIONS: Future randomized, placebo-controlled trials of EMP+ are warranted and feasible. PMID: 22747095

CLINICAL STUDY 16 — Multinutrient Supplement as Treatment: Literature Review and Case Report of a 12-Year-Old Boy with Bipolar Disorder

—Elisabeth A. Frazier, Mary A. Fristad, and L. Eugene Arnold. Journal of Child and Adolescent Psychopharmacology. August 2009, 19(4): 453-460. doi:10.1089/cap.2008.0157

Early-onset bipolar disorder has significant morbidity and mortality. Development of safe, effective treatments to which patients will adhere is critical. Pharmacologic interventions for childhood bipolar spectrum disorders are limited and are associated with significant risk for adverse events. Diet and nutrition research suggests vitamins, minerals, and other nutrients are important underpinnings of general physical and mental health; furthermore, they may even be useful in treating mood dysregulation by providing a more favorable risk–benefit ratio than contemporary psychotropic agents. This article reviews the literature on multinutrient supplementation and mental health, and examines a case study of a 12-year-old boy with bipolar disorder and co-morbid diagnoses treated for 6 years with conventional medication and finally a multinutrient supplement. The multinutrient supplement in this case study is a 36-ingredient supplement containing 16 minerals, 14 vitamins, 3 amino acids, and 3 antioxidants. It was used to treat a 12-year-old boy initially diagnosed with bipolar disorder not otherwise specified (BP-NOS) at age 6, and whose diagnosis evolved by age 10 to bipolar I (BP-I), mixed, with psychotic features. He also met criteria for generalized anxiety disorder by age 8 and obsessive-compulsive disorder by age 10. After 6 years of conventional treatment (ages 6–12), he received 14 months of EMP+. Symptom manifestation over 7 years is described in conjunction with treatment history, resulted in outcome superior to conventional treatment. This report adds to accumulating preliminary evidence that further basic science and clinical studies of multinutrient supplements are warranted. PMID: 19702498

CLINICAL STUDY 17 — Database Analysis of Adults with Bipolar Disorder Consuming a Micronutrient Formula

—Gately, D., Kaplan, B.J. (2009). Clinical Medicine: Psychiatry, 4, 3‐16

Bipolar disorder is a lifelong problem with imperfect available treatments. Recent research has shown potential benefit of nutritional treatment for mood symptoms. The goal of the current study was to determine whether adults with bipolar disorder reported treatment benefit from consuming a micronutrient formula. Self-report data were available from 682 adults who reported a diagnosis of bipolar disorder; 81% were taking psychiatric medications. Those reporting additional diagnoses were excluded, as well as those who provided data 60 times during 180 days of using the micronutrients, leaving 358 for analysis. Mean symptom severity was 41% lower than baseline after 3 months (effect size = 0.78), and 45% lower after 6 months (effect size = 0.76) (both paired t-tests significant, p 0.001). In terms of responder status, 53% experienced 50% improvement at 6 months. Half the sample were taking medications approved for bipolar disorder (lithium, anticonvulsants, atypical antipsychotics), and half were either medication-free or taking other medications: the magnitude of treatment benefit did not differ between these two groups. Regression analyses indicated that decreased symptom severity over the 6 months was associated with increasing micronutrient dosage and with reducing medication. Symptom improvements were significant and sustained at 6 months, suggesting that benefits were not attributable to placebo/expectancy effects. Further research on this micronutrient formula is warranted. Source:

Learn more about Mood Disorders »