Tag Archives: major depressive disorder

Exercise scores as well as Zoloft for major depression

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Another outcome study to add to the massive body of evidence that the psychopharmaceutical model for treating depression is seriously flawed was published in the journal Psychosomatic Medicine. The authors pitted sertraline (Zoloft, an SSRI) against exercise and placebo as they set out to…

“…assess whether patients receiving aerobic exercise training performed either at home or in a supervised group setting achieve reductions in depression comparable to standard antidepressant medication (sertraline) and greater reductions in depression compared to placebo controls.”

They randomly assigned 202 adults diagnosed with major depression were to either supervised exercise in a group setting; home-based exercise; antidepressant medication (sertraline, 50–200 mg daily); or placebo pill for 16 weeks. This was followed by a structured clinical interview for depression and completed the Hamilton Depression Rating Scale (HAM-D). Typically, the data showed little difference between the placebo and Zoloft, and virtually no difference between the medication and exercise:

“After 4 months of treatment, 41% of the participants achieved remission, defined as no longer meeting the criteria for major depressive disorder (MDD) and a HAM-D score of <8. Patients receiving active treatments tended to have higher remission rates than the placebo controls: supervised exercise = 45%; home-based exercise = 40%; medication = 47%; placebo = 31%. All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group.”

There is an enormous amount of science showing that this class of medications profoundly perturbs the brain in such a way that attempting to stop taking them after 6 weeks or continuing them long-term can result in the dismal trap of a brain sensitized to depression. This study would have been even more striking had they compared the unmedicated exercise group to those who were medicated after attempting to stop. As it is, the authors conclude:

“The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response is determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors.”

Historically, before the age of psychopharmaceuticals most cases of major depression tended to be self-limiting. For an objective, meticulous, articulate and gripping scientific and historical narrative on how anti-depressants, tranquilizers and anti-psychotic medications have promoted the skyrocketing levels of mental disability, I suggest Anatomy of an Epidemic by Robert Whitaker. Anyone considering taking or prescribing these medications should be aware of the science reviewed comprehensively in this text.

Nutritional and metabolic requirements for pediatric brain health

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Numerous micro and macronutrients are required to grow and sustain a human brain in both structure and function. A paper published in the Journal of Nutrition, Health & Aging presents evidence for some of the key micronutrients:

“…most micronutrients (vitamins and trace-elements) have been directly evaluated in the setting of cerebral functioning. For instance, to produce energy, the use of glucose by nervous tissue implies the presence of vitamin B1; this vitamin modulates cognitive performance…Vitamins B6 and B12, among others, are directly involved in the synthesis of some neurotransmitters…Supplementation with cobalamin…frequently improves the functioning of factors related to the frontal lobe, as well as the language function of those with cognitive disorders. Adolescents who have a borderline level of vitamin B12 develop signs of cognitive changes.“

Revisiting the importance of iron for the brain:

“Iron is necessary to ensure oxygenation and to produce energy in the cerebral parenchyma (via cytochrome oxidase), and for the synthesis of neurotransmitters and myelin; iron deficiency is found in children with attention-deficit/hyperactivity disorder. Iron concentrations in the umbilical artery are critical during the development of the foetus, and in relation with the IQ in the child; infantile anaemia with its associated iron deficiency is linked to perturbation of the development of cognitive functions.“

Moreover, even subclinical deficiencies of micronutrients can have profound effects:

“…the full genetic potential of the child for physical growth and mental development may be compromised due to deficiency (even subclinical) of micronutrients.”

Macronutrients for the brain are addressed by the same author in an accompanying paper, starting with another look at fats:

“DHA (docosahexaenoic acid) is one for the major building structures of membrane phospholipids of brain and absolutely necessary for neuronal function…ALA acid deficiency alters the course of brain development…the nature of polyunsaturated fatty acids (in particular omega-3, ALA and DHA) present in formula milks for infants (premature and term) conditions the visual, neurological and cerebral abilities, including intellectual…Low fat diet may have adverse effects on mood.“

Regarding protein:

“The nature of the amino acid composition of dietary proteins contributes to cerebral function; taking into account that tryptophan plays a special role. In fact, some indispensable amino acids present in dietary proteins participate to elaborate neurotransmitters (and neuromodulators).”

The importance of blood sugar stability cannot be overstated:

“The regulation of glycaemia (thanks to the ingestion of food with a low glycaemic index ensuring a low insulin level) improves the quality and duration of intellectual performance, if only because at rest the brain consumes more than 50% of dietary carbohydrates, approximately 80% of which are used only for energy purpose. In infants, adults and aged, as well as in diabetes, poorer glycaemic control is associated with lower performances, for instance on tests of memory. At all ages…some cognitive functions appear sensitive to short term variations in glucose availability.”

The author concludes:

“[A] number of findings show that dietary factors play major roles in determining whether the brain ages successfully or experiences neurodegenerative disorders.”

Research recently presented in Psychosomatic Medicine (Journal of Biobehavioral Medicine) investigates:

“……the association between dietary folate, riboflavin, vitamin B-6, and vitamin B-12 and depressive symptoms in a group of adolescents.“

The authors correlated data on dietary intake with scores for depressive symptoms in 3,067 boys and 3,450 girls aged 12 to 15 years as defined by the Center of Epidemiologic Studies Depression Scale. What were the results?

“The prevalence of depressive symptoms was 22.5% for boys and 31.2% for girls. Folate intake was inversely associated with depressive symptoms in both boys and girls. Vitamin B-6 intake was inversely associated with depressive symptoms in both boys and girls. Riboflavin intake was inversely associated with depressive symptoms in girls, but not in boys. No clear association was seen between vitamin B-12 intake and depressive symptoms in either sex.”

Other studies have show an association between low vitamin B12 and depression in adults. We can speculate that this may be due to declining gastric digestive and absorptive capacity with age.

The authors conclude:

“This study suggests that higher intake of dietary B vitamins, particularly folate and vitamin B-6, is independently associated with a lower prevalence of depressive symptoms in early adolescence.“

There is interesting evidence for the importance of zinc in the clinical management of ADHD in a paper published in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry. The authors state:

“Some studies suggest that deficiency of zinc play a substantial role in the aetiopathogenesis of ADHD. Therefore, to assess the efficacy of zinc sulfate we conducted treatment trial.”

They examined the effect of double-blind treatment with zinc sulfate or placebo on 72 girls and 328 boys with a diagnosis of ADHD. Efficacy was assessed with a triad of rating scales. What did the data show?

“Zinc sulfate was statistically superior to placebo in reducing both hyperactive, impulsive and impaired socialization symptoms, but not in reducing attention deficiency symptoms, as assessed by ADHDS. However, full therapeutic response rates of the zinc and placebo groups remained 28.7% and 20%, respectively. It was determined that the hyperactivity, impulsivity and socialization scores displayed significant decrease in patients of older age and high BMI score with low zinc and free fatty acids (FFA) levels.“

The benefit of carnitine has been investigated for ADHD in boys and presented in a paper published in the journal Prostaglandins, Leukotrienes and Essential Fatty Acids:

“The ADHD behavior was observed by parents completing the Child Behavior Checklist (CBCL) and by teachers completing the Conners teacher-rating score, in a randomized, double-blind, placebo-controlled double-crossover trial.”

Significant improvements in behavior at home and at school were documented:

“Before treatment, the CBCL total and sub-scores were significantly different from those of normal Dutch boys. Responders showed a significant improvement of the CBCL total scores compared to baseline…responders showed higher levels of plasma-free carnitine and acetylcarnitine.“

The authors state in their conclusion:

“Treatment with carnitine significantly decreased the attention problems and aggressive behavior in boys with ADHD.“

An important paper also published in Progress in Neuro-Psychopharmacology and Biological Psychiatry disruption of the metabolism of tryptophan by inflammation can contribute to major depressive disorder (MDD) in adolescents. For background the authors state:

“Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins…The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho…”

The authors employed high resolution proton magnetic resonance spectroscopic imaging to examine fourteen adolescents with MDD, seven of whom had melancholic features, and six healthy controls.

“Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate and the left putamen, respectively…These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD.“

In other words, the authors’ evidence shows that for the melancholic subset of adolescents with major depressive disorder, pro-inflammatory cytokines are disrupting the metabolism of tryptophan into serotonin. This brings into focus special considerations for the management of diet and nutritional precursor supplementation.

Environmental toxins also place a burden on brain metabolism that can disrupt neurodevelopment. A paper published in the journal Neurotoxicology describes the importance of the redox/methylation pathways in the brain. The authors state:

“Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase.”

Methionine synthase activity is required for the dopamine metabolic activity and dopamine receptor function that promotes neuronal synchronization and attention (synchrony is impaired in autism).

“Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects…oxidative stress, initiated by environment factors in genetically vulnerable individuals, [can lead] to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.”

Here we see the possibility of environment conditions demanding extraordinary metabolic support to prevent disruption of developing neural networks.

None of the research presented here implies that a specific nutritional or metabolic intervention is correct for any given individual. In all cases the parents and clinician should keep in mind the possibility that any of these factors may play a role. However, a “try this, try that” approach should be avoided in favor of objectively determining the needs of the individual with the appropriate laboratory tests. While the experienced clinician will have an abundant toolbox, the urinary assessment of organic acids is an indispensable resource.

Inflammation, mitochondrial dysfunction and neurodegeneration in major depression

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Is depression mainly a disorder of serotonin regulation? A paper just published in Progress in Neuro-Psychopharmacology and Biological Psychiatry reminds us that, of course, it is not. The authors state:

“For many years, a deficiency of monoamines including serotonin has been the prevailing hypothesis on depression, yet research has failed to confirm consistent relations between brain serotonin and depression.“

They observe that there is a relationship between depression a number of other conditions with a common set of underlying causes:

“…depression is one of a family of related conditions sometimes referred to as the “affective spectrum disorders”, and variably including migraine, irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia and generalized anxiety disorder, among many others.”

What do these disorders have in common?

“…we present data from many different experimental modalities that strongly suggest components of mitochondrial dysfunction and inflammation in the pathogenesis of depression and other affective spectrum disorders. The three concepts of monoamines, energy metabolism and inflammatory pathways are inter-related in many complex manners. For example, the major categories of drugs used to treat depression have been demonstrated to exert effects on mitochondria and inflammation, as well as on monoamines. Furthermore, commonly-used mitochondrial-targeted treatments exert effects on mitochondria and inflammation, and are increasingly being shown to demonstrate efficacy in the affective spectrum disorders.”

In the functional approach, the evaluation and treatment of depression is not complete without addressing the factors that contribute to neuroinflammation, neurodegeneration and mitochondrial dysfunction with the appropriate tests and physiological interventions.

Neurotransmitter GABA important for major depression

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Biological PsychiatryThis paper just published in the journal Biological Psychiatry reports on valuable finding that is important for anyone suffering from or treating major depression needs to know: the neurotransmitter GABA can play a significant role in the biological component of major depression. GABA is the most abundant inhibitory neurotransmitter in our bodies. The authors note that

“Several lines of evidence suggest that major depressive disorder is associated with deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission.”

In their study they used transcranial magnetic stimulation to measure the integrity of GABA function in

“medicated patients with treatment resistant major depressive disorder (TRD), unmedicated patients with major depressive disorder, and medicated euthymic [normal mood] patients with a history of major depressive disorder and compare them with healthy subjects.”

Their compelling findings were that

“All major depressive disorder patient groups demonstrated significant cortical silent period deficits [GABA(B) receptor-mediated inhibitory neurotransmission] compared with healthy subjects.” Interestingly, “only TRD [treatment resistant depression] patients demonstrated significant deficits in short-interval cortical inhibition [GABA(A) receptor-mediated inhibitory neurotransmission] compared with healthy subjects, medicated euthymic major depressive disorder patients, and unmedicated major depressive disorder patients.”

I’m sure readers know that there is much more to the story of major depression than one neurotransmitter. But this is a welcome study for functional medicine practitioners who have seen empirically positive results since we have excellent resources for physiologically supporting improved GABA function. They also noted another finding important for functional medicine doctors and neurotherapists who treat additional biological causes of depression (metabolic, inflammatory, electrical, etc):

“TRD patients also demonstrated a significantly greater resting motor threshold compared with all other clinical subgroups and healthy subjects, suggesting that TRD was also associated with hypoexcitability of the frontal cortex.”

The authors state in conclusion:

“Our findings suggest that GABA(B) neurophysiological deficits are closely related to pathophysiology of major depressive disorder. Our findings also suggest that more severe illness is selectively associated with GABA(A) receptor-mediated inhibitory deficits.”

By the way, four years earlier to the day there was a paper published in the same journal that concluded:

“This study provides evidence of reduced GABAergic [GABA function] tone and motor threshold asymmetry in patients with major depression.”

For an easy reading description on how this investigative approach can help personalize the treatment of depression and more on why GABA is important see this article.