Brain dysfunction depression

Nemeroff CB, Krishnan KRR, Reed D, et al Adrenal gland enlargement in major depression a computed tomographic study. Arch Gen Psychiatry 49 384-387, 1992 Nestler EJ, Terwilliger RZ, Duman RS Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem 53 1644-1647, 1989 Nestor PC, Parasuraman R, Haxby JV, et al Divided attention and metabolic brain dysfunction in mild dementia of the Alzheimer s type. Neuropsychologia 29(5) 379-387, 1991... 

S100B Developmental brain dysfunction, learning and memory deficits Alzheimer s disease, blood brain barrier dysfunction Down syndromebrain trauma and ischemia, schizophrenia, depression... 

Depression is a separate issue from cognitive impairment, but often when people are depressed they also struggle with memory, attention, and concentration problems. Clearly, the symptoms of post-chemo brain and depression overlap. We know from our studies at UCLA that specific brain changes correlate with the severity of depression, just as specific brain changes correlate with the severity of short-term memory impairment. Depression is rooted in biology. So are memory problems. Both are forms of neurologic dysfunction. 

Evidence cited to support 5-HT dysfunction in depression includes 1) decreased levels of 5-HT and 5-HIAA in the brains of depressed patients who commit suicide,62 2) sub-normal concentrations of 5-HT metabolites in the cerebrospinal fluid (CSF) of depresslves,63 and 3) diminished rates of 5-HT turnover, manifested as deficient 5-HIM accumulation in the CSF following treatment with the efflux blocker, probenecid.64... 

The most commonly used therapies for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin noradrenaline reuptake inhibitors (SNRIs). SSRIs, which constitute 60% of the worldwide antidepressant and antianxiety market, are frequently associated with sexual dysfunction, appetite disturbances and sleep disorders. Because SSRIs and SNRIs increase 5-HT levels in the brain, they can indirectly stimulate all 14 serotonergic receptor subtypes [2,3], some of which are believed to lead to adverse side effects associated with these drugs. Common drugs for short-term relief of GAD are benzodiazepines. These sedating agents are controlled substances with addictive properties and can be lethal when used in combination with alcohol. The use of benzodiazepines is associated with addiction, dependency and cognitive impairment. 

Traditionally, most affective disorders have been treated with compounds that resemble the neurotransmitters that are deficient or in excess in specific brain regions. The aberrant levels of neurotransmitters (or their receptors), such as norepinephrine, dopamine, acetylcholine, and serotonin, have correlated with behavioral symptoms of schizophrenia, depression, anxiety, sleep disorders, motor dysfunctions, attention difficulties, and cognitive disorders. Most drugs discovered for these disorders resulted from screening compounds directly in rodent behavioral models that mimic the behavior of the disease. In these cases, the molecular target" or mechanism of action was assumed to be the deficiency or excess of a neurotransmitter. 

The selectivity of the SSRIs does not mean that they are totally without side effects. First, serotonin-secreting nerve cells are distributed throughout the brain and control a wide array of nervous system activities. As a result, increasing serotonin not only relieves depression, it can also produce many side effects such as abdominal discomfort, sexual dysfunction, and anxiety. Second, the selectivity of the SSRIs is not absolute but relative. Although the main action of the SSRIs is the same, they do have differences. For patients, this means that the drug interactions and side effects of the SSRIs vary somewhat. It also means that a patient who does not respond to one SSRI may respond to another. 

Hopefully the combination of TMS with fMRI will enable the more precise location of the regional dysfunction in depression to be located and thereby enable the neuronal pathways concerned to be identified. To date, the early studies of TMS with fMRI have shown that the effects of TMS occur in brain regions distant from the site of stimulation, including the caudate, orbitofrontal cortex and the cerebellum. 

Indicative of serotonergic dysfunction, abused children with depression were shown to exhibit increased prolactin, but normal cortisol responses to the injection of E-5-hydroxytryptophan, a precursor of 5-HT, as compared to nonabused depressed children and controls (Kaufman et ah, 1998). Likewise, increased prolactin responses to fenfluramine were observed in boys with adverse rearing environment (Pine et ah, 1997). Since prolactin, but not cortisol release, is mediated via 5-HTia receptors, these findings suggest sensitization of these receptors due to early-life stress. Another study recently reported that children with traumatic brain injury (TBl) who had experienced abuse have dramatic increases in CSE concentrations of glutamate, compared to nonabused TBI children (Ruppel et ah, 2001). 

Barkai et al. (1978) reported that cerebrospinal fluid levels of inositol were lower in patients with depression than in psychiatrically healthy subjects. We hypothesized that inositol may be deficient in some brain systems in depression. This does not contradict the concept that Li reduces inositol levels and that Li" is an antidepressant, because the PI cycle serves as a second messenger for several balancing and mutually interactive neurotransmitters. Li+ could alleviate depression by reducing inositol and a primary hyperactivity of one hypothetical brain system low inositol levels in another system could cause second messenger dysfunction and thereby depression. 

Tariot PN, Cohen RM, Welkowitz JA, et al Multiple-dose arecohne infusions in Alzheimer s disease. Arch Gen Psychiatry 45 901-905, 1988 Taylor AE, Saint-Cyr JA, Lang AE Frontal lobe dysfunction in Parkinson s disease the cortical focus of neostriatal outflow. Brain 109 845-883, 1986 Taylor DP, Smith DW, Hyslop DK, et al Receptor binding and atypical antidepressant drug discovery, in Receptor Binding in Drug Research. Edited by O Brien RA. New York, Marcel Dekker, 1986, pp 151-165 Tejedor-Real P, Mico JA, Maldonado R, et al Effect of mixed (RB 38A) and selective (RB 38B) inhibitors of enkephalin degrading enzymes on a model of depression in the rat. Biol Psychiatry 34 100-107, 1993... 

The co-3 fatty acids have numerous important functions, especially in the brain. Accordingly, a deficiency of DHA and EPA may cause dysfunction of the central nervous system and probably also the retina, thereby resulting in impaired vision. In addition, there is a variety of neurological and psychiatric disorders that have been associated with decreased levels of especially DHA and AA, such as, for example, schizophrenia and depression [3], post-traumatic stress syndrome, autism and attention deficit hyperactivity disorder. Since no primary inherited defect of essential fatty acid interconversion has yet been described, no specific explanations for the essential fatty acid concentration changes are readily available. 

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