Norepinephrine in depression

What then, is the current evidence to support a role of norepinephrine in depression, such that manipulation of noradrenergic activity bears particular relevance to the successful treatment of mood disorders Interpretation of studies depends on the continually evolving conceptualizations of the roles of brain noradrenergic systems. A potentially useful way of thinking about the function of the norepinephrine in the brain can be derived from examining the neuroanatomy of the noradrenergic system. A summary of findings [primarily from rodents and primates) is as follows. 

Bunney WE Jr, Davis JM Norepinephrine in depressive reactions a review. Arch Gen Psychiatry 13 483-494, 1965... 

Nutt DJ. The role of dopamine and norepinephrine in depression and antidepressant treatment. J. Clin. Psychiatry 2006 67(suppl 7) 3-8. 

The pressor (increased blood pressure) responses to tyramine and noradrenaline (norepinephrine) in depressed patients remained virtually unchanged after 14 days of treatment with mianserin 60 mg daily.In 5 healthy subjects taking maprotiline the pressor response to tyramine was reduced threefold while the noradrenaline response remained unchanged. ... 

Both norepinephrine (NE) and serotonin play important roles in depression, with increased levels of NE and its metabolites commonly found in the plasma, cerebrospinal fluid, and urine of patients with MDD (Lake, Pickar, Ziegler etal., 1982 ... 

Roy, A., Pickar, D., Dejong, J., Karoum, F. Linnoila, M. (1998). Norepinephrine and its metabolites in cerebrospinal fluid, plasma and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression. Arch. Gen. Psychiatry, 45, 849-57. 

Iproniazid and imipramine seemed to work as antidepressants, but how did they achieve their effects It would be another decade before the chemical-imbalance theory was launched. In 1965, Joseph Schildkraut at the National Institute of Mental Health in Washington, DC, published a groundbreaking paper in which he argued that depression was caused by a deficiency of the neurotransmitter norepinephrine in the gaps between neurons in the brain.8 Two years later Alec Coppen, a physician at West Park Hospital in Surrey, published another version of the chemical-imbalance theory. His version differed from Schildkraut s in that it put most of the blame on a different neurotransmitter, emphasizing serotonin rather than norepinephrine as the neurotransmitter that was lacking.9... 

Numerous reports of altered neurotransmitter and hormone functions which have been associated with the affective disorders are reviewed by Levell [142]. It was originally proposed that one or more of the neurotransmitter amines in the brain (norepinephrine, dopamine, serotonin) may be functionally elevated in manic patients and reduced in depressed patients [143]. For instance, an increase in the production of dopamine, observed in a number of case reports, is thought to be the cause of the switch into the manic phase in bipolar patients. For example, Bunney et al. reported an increase in the level of homovanillic acid (HVA), a... 

Pharmacology Bretylium tosylate inhibits norepinephrine release by depressing adrenergic nerve terminal excitability, inducing a chemical sympathectomy-like state. Bretylium blocks the release of norepinephrine in response to neuron stimulation. Peripheral adrenergic blockade causes orthostatic hypotension but has less effect on supine blood pressure. It has a positive inotropic effect on the myocardium. Pharmacokinetics Peak plasma concentration and peak hypotensive effects are seen within 1 hour of IM administration. However, suppression of premature ventricular beats is not maximal until 6 to 9 hours after dosing, when mean plasma concentration declines to less than 50% of peak level. Antifibrillatory effects occur within minutes of an IV injection. Suppression of ventricular tachycardia and other ventricular arrhythmias develops more slowly, usually 20 minutes to 2 hours after parenteral administration. 

Side effects, mainly due to serotonin reuptake inhibition include G1 upset, nervousness, and sexual dysfunction. SSRls are associated with an increased risk of falls. Hyponatraemia due to SIADH is an uncommon, but important side effect in elderly patients. Selective serotonin and norepinephrine reuptake inhibitors (S SNRls) such as venlafaxine and duloxetine are also useful in older patients. Other heterocyclic antidepressants of importance in older patients because of relative safety include bupro-prion and mirtazepine. They are reserved for patients with resistance to or intolerance of SSRls. Currently, trazodone is used mostly for sleep disturbance in depression in doses of 50-100 mg at bedtime. The monoamine oxidase inhibitors phenelzine. 

Anand, A. and Charney, D.S. (2000) Norepinephrine dysfunction in depression. / Clin Psychiatry 61 16-24. 

Biochemical lesions that induce depressive syndromes include such classic examples as Parkinson s and Huntington s diseases, especially early in their courses. These disorders involve derangements of central amine systems (i.e., in Parkinson s, there is a disturbance in both dopamine and norepinephrine in Huntington s, dopamine is affected, as well as other nonbiogenic amine neural circuits). Furthermore, antidepressants and ECT, which potentiate central neurotransmission, have effectively relieved depression associated with Parkinson s disease. 

Studies of depressed patients have sometimes shown an alteration in monoamine function. For example, some studies have found evidence of alteration in serotonin receptor numbers (5-HT1A and 5-HT2c) or norepinephrine (k2) receptors in depressed and suicidal patients, but these findings have not been consistent. A reduction in the primary serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid is associated with violent and impulsive behavior, including violent suicide attempts. However, this finding is not specific to major depression and is associated more generally with violent and impulsive behavior. 

In summary, SSRIs undoubtedly improve symptoms in OCD, just as they improve symptoms in depression. However, as compared to the use of SSRIs in depression, OCD responses to SSRIs specifically require 5HT and not norepinephrine reuptake inhibition, the OCD responses are generally slower, less robust, more likely to relapse after SSRI discontinuation, and not as immediately dependent on synaptic 5HT availability. 

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