Clinical Studies | Anxiety Disorders


CLINICAL STUDY 1 — Enhanced Resistance to Emotional Stress Through the Use of D-Phenylalanine

—Iumatov EA, Sarychev EI, Kozlovskii II, Mineeva MF, Demidov VM, Morozov IS, Kozlovskaia MM.

Stress-protective action was studied of d-phenylalanine, having an ability to decrease destruction of endogenic enkefalins. In the experiments stability of the experimental (receiving d-phenylalanine) and control groups of male rats of August line to emotional stress was compared in conditions of immobilization stress by parameters of animals survival rate, adrenal glands hypertrophy development, involution of thymus, pathologic changes in lungs (abscesses development), ulcero-dystrophic disturbances in stomach, and also the activity and kinetic properties of enzyme tyrosin-hydroxylase in the hypothalamus were determined. It was shown that by several of the mentioned physiological parameters the d-phenylalanine significantly increased the animals stability to the emotional stress and decreased tyrosinhydroxylase activity which participates in activation of catecholaminergic processes. PMID: 1676203

(phenylalanine can be the precursor to tyrosine)

CLINICAL STUDY 2 — The Participation of Prostanoids in the Realization of the Cardioprotective, Antistressor and Anti-Arrhythmic Effects of Enkephalins

—Lishmanov IuB, Maslov LN, Rebrova TIu, Fedotova TV

It has been established that preliminary administration of D-Ala2-Leu5-Arg6-enkephalin, D-Met2-Pro5-enkephalinamide, and d-phenylalanine to experimental animals prevents a stress-induced increase of the content of thromboxane in the blood plasma and myocardium and induces a rise of the level of prostacyclin, PGF2 and PGE in the heart and blood plasma. The authors hold that the changes in the level of prostanoids may mediate cardioprotective and anti-stressor rather than antiarrhythmic effects of enkephalins. PMID: 1284224

CLINICAL STUDY 3 — Amphetamine Increases Glutamate Efflux in the Rat Ventral Tegmental Area by a Mechanism Involving Glutamate Transporters and Reactive Oxygen Species

—Wolf ME, Xue CJ, Li Y, Wavak D. Department of Neuroscience, FUHS/The Chicago Medical School, North Chicago, Illinois, USA

We have shown that amphetamine produces a delayed and sustained increase in glutamate levels in the ventral tegmental area, a region containing dopamine cell bodies important in acute and chronic effects of amphetamine administration. The present study characterized the mechanism underlying amphetamine-induced glutamate efflux. It was abolished by the glutamate uptake inhibitor dihydrokainate, but unaffected by perfusion with a low Ca(2+)/high Mg(2+) solution, implicating glutamate transporters. Because reactive oxygen species inhibit glutamate uptake, we examined the effect of amphetamine on hydroxyl radical formation by perfusing with d-phenylalanine (5 mM) and monitoring p-tyrosine production. Although no increase in hydroxyl radical formation was detected, D-phenylalanine completely prevented the amphetamine-induced increase in glutamate efflux, as did systemic injection of another trapping agent, alpha-phenyl-N-tert-butyl nitrone (60 mg/kg). Thus, amphetamine-induced glutamate efflux may involve reactive oxygen species. In other studies, we found that repeated coadministration of alpha-phenyl-N-tert-butyl nitrone with amphetamine attenuated the development of behavioral sensitization. This supports prior results indicating that the increase in glutamate efflux produced by each amphetamine injection in a chronic regimen is important in triggering drug-induced adaptations in ventral tegmental area dopamine neurons, and that such adaptations may in part represent a response to metabolic and oxidative stress. PMID: 10987845

(phenylalanine is the precursor to tyrosine)

CLINICAL STUDY 4 — Dietary Tyrosine Suppresses the Rise in Plasma Corticosterone following Acute Stress in Rats

—Reinstein DK, Lehnert H, Wurtman RJ.

Acute, uncontrollable stress increases norepinephrine (NE) turnover in the rat’s brain (depleting NE) and diminishes the animal’s subsequent tendency to explore a novel environment. Pre-treatment with tyrosine can reverse these adverse effects of stress, presumably by preventing the depletion of NE in the hypothalamus. Numerous studies suggest that NE inhibits the release of adrenocorticotropic hormone (ACTH) by suppressing corticotropic releasing factor (CRF) secretion in the hypothalamus. In the present study, we found that pre-treatment with supplemental tyrosine not only prevented the behavioral depression and hypothalamic NE depletion observed after an acute stress, but also suppressed the rise in plasma corticosterone. These results support a role for brain NE in stress-induced corticosterone secretion and demonstrate that supplemental tyrosine can protect against several adverse consequences of such stress. PMID: 4068899

(phenylalanine is the precursor to tyrosine)

CLINICAL STUDY 5 — Separation-Induced Body Weight Loss, Impairment in Alternation Behavior, and Autonomic Tone: Effects of Tyrosine

—Hao S, Avraham Y, Bonne O, Berry EM. – Department of Human Nutrition and Metabolism, Hadassah Medical School, Hebrew University, Jerusalem, Israel

We have investigated the effects of tyrosine on alternation behavior and hippocampal adrenergic and cholinergic tone in a model of self-induced weight loss caused by separation stress. Separation decreased body weight in mice (P < .001) and spontaneous alternations in the T-maze (P < .001). This impairment was associated with depletion of both norepinephrine (NE, P < .001) and dopamine (P < .01) while increasing MHPG (P < .05) and the ratio of MHPG/NE (P < .05). Increasing tyrosine availability restored performance to control levels (P < .001) and repleted dopamine (P < .05) and presumably also NE (indicated by increases in both MHPG, P < .001, and MHPG/NE, P < .05). Stress increased adrenergic alpha(2)-receptor density (P < .001) without changing its K (d) and the B (max) and K (d) of beta-receptors, suggesting that it decreased NE transmission through action on alpha (2) receptors. The balance between beta- and alpha (2) receptors appeared

to be related to alternation behavior as shown by the decrease (P < .01) and increase (P < .05) in their ratios induced by stress and tyrosine, respectively. With regard to cholinergic tone, separation stress increased M1 receptor density (P < .05) and its mRNA signal (P < .001). Tyrosine further increased M1 receptor density of stressed mice (P < .05). Tyrosine might be a potential therapy for cognitive and mood problems associated with the maintenance of a reduced body weight in the treatment of obesity and in the extreme case of anorexia nervosa. PMID: 11267632

(phenylalanine is the precursor to tyrosine)

CLINICAL STUDY 6 — Anterior Cingulate Glutamate-Glutamine Levels Predict Symp Severity in Women with Obsessive-Compulsive Disorder

—Yücel M, Wood SJ, Wellard RM, Harrison BJ, Fornito A, Pujol J, Velakoulis D, Pantelis C. – Melbourne Neuropsychiatry Centre, National Neuroscience Facility, Carlton South, Australia

OBJECTIVE: Abnormalities of the anterior cingulate cortex (ACC) have consistently been identified in obsessive-compulsive disorder (OCD), but very few studies have examined the biochemical basis of such changes. The purpose of the present study was to investigate how ACC biochemistry in OCD varies as a function of gender, hemisphere, subregion, and sympatology. METHOD: 3 T proton-magnetic resonance spectroscopy (MRS) was used to probe ACC biochemistry in 20 OCD patients (10 male, 10 female) and a comparable group of 26 healthy comparison subjects. Data were acquired from the left and right dorsal and rostral subregions of the ACC. Metabolites assessed included N-acetylaspartate (NAA), glutamate-glutamine (Glx), choline-containing compounds (Cho), creatine/phosphocreatine (Cr), and myoinositol-containing compounds (mI). RESULTS: Female OCD patients had significantly reduced levels of Glx in all but one subregion of the ACC when compared to matched controls. Levels of Glx were correlated with clinical measures of symp severity in female but not male patients. State levels of anxiety and depression did not explain this association. In addition, both male and female OCD patients had relatively higher concentrations of mI in their right ACC (rostral and dorsal) compared with healthy controls. No other compounds had any statistically significant group differences, nor were the concentrations of any other compounds correlated with symp measures. CONCLUSIONS: To the authors’ knowledge this is the first study to demonstrate gender-specific neurochemical changes in OCD. Although these findings are tentative and require replication, they raise the possibility that MRS techniques may be of use in objectively monitoring patient progress and assessing the effectiveness of various treatments. PMID: 18465373

CLINICAL STUDY 7 — Successful treatment of OCD with a micronutrient formula following partial response to Cognitive Behavioral Therapy (CBT)

—Rucklidge, J. J. (2009). Journal of Anxiety Disorders, 23: 836-840

Obsessive Compulsive Disorder (OCD) affects 0.5-2% of young people many of whom are resistant to conventional treatments. This case study describes an 18-year-old male with OCD who first underwent cognitive behavioral therapy (CBT) for a 1-year period with a modest response (his OCD had shifted from severe to moderate). Within a year, his anxiety had deteriorated back to the severe range and he now had major depression. He then entered an ABAB design trial using a nutritional formula consisting mainly of minerals and vitamins (together, known as micronutrients). After 8 weeks on the formula, his mood was stabilized, his anxiety reduced, and his obsessions were in remission. The treatment was then discontinued for 8 weeks, during which time his obsessions and anxiety worsened and his mood dropped. Reintroduction of the formula again improved the symptoms. This case illustrates the importance of considering the effect micronutrients have on mental illness. PMID: 19329277

CLINICAL STUDY 8 — Efficacy and cost of micronutrient treatment of childhood psychosis

—Rodway M, Vance A, Watters A, Lee H, Bos E, Kaplan BJ (2012). BMJ Case Reports. doi:10.1136/bcr-2012-007213.

Psychosis is difficult to treat effectively with conventional pharmaceuticals, many of which have adverse long-term health consequences. In contrast, there are promising reports from several research groups of micronutrient treatment (vitamins, minerals, amino acids and essential fatty acids) of mood, anxiety and psychosis symptoms using a complex formula that appears to be safe and tolerable. We review previous studies using this formula to treat mental symptoms, and present an 11-year-old boy with a 3-year history of mental illness whose parents chose to transition him from medication to micronutrients. Symptom severity was monitored in three clusters: anxiety, obsessive compulsive disorder and psychosis. Complete remission of psychosis occurred, and severity of anxiety and obsessional symptoms decreased significantly (p<0.001); the improvements are sustained at 4-year follow-up. A cost comparison revealed that micronutrient treatment was <1% of his inpatient mental healthcare. Additional research on broad-spectrum micronutrient treatment is warranted. PMID: 23144350

CLINICAL STUDY 9 — Psychological functioning 1 year after a brief intervention using micronutrients to treat stress and anxiety related to the 2011 Christchurch earthquakes: a naturalistic follow-up

—Rucklidge JJ., Blampied N., Gorman B., and Sole E. Human Psychopharmacology: Clinical and Experimental, 29(3): 230-43.

OBJECTIVE: We investigated whether micronutrients given acutely following the Christchurch earthquakes continued to confer benefit 1 year following the treatment. METHODS: Sixty-four adults from the original 91 participants experiencing heightened anxiety or stress 2-3 months following the 22nd February 2011 earthquake and who had been randomized to receive three different doses of micronutrients completed on-line questionnaires assessing mood, anxiety, stress, and symptoms associated with post-traumatic stress disorder 1 year after completing the initial study. Twenty-one out of 29 nonrandomized controls who did not receive the treatment also completed the questionnaires. RESULTS: Both the treated and control groups experienced significant improvement in psychological functioning compared with end-of-trial. However, treated participants had better long-term outcomes on most measures compared with controls (ES=0.69-1.31). Those who stayed on micronutrients through to follow-up or stopped all treatment reported better psychological functioning than those who switched to other treatments including medications. About 10% of the sample continued to have post-traumatic stress disorder symptoms. CONCLUSIONS: Disaster survivors improve psychologically over time regardless of receiving intervention; however, those taking micronutrients during the acute phase following a disaster show better outcomes, identifying micronutrients as a viable treatment for acute stress following a natural disaster with maintenance of benefits 1 year later. PMID: 24554519

Learn more about Anxiety Disorders »