Antidepressants chronic administration

NEUROBIOLOGICAL CHANGES INDUCED BY CHRONIC ADMINISTRATION OE ANTIDEPRESSANTS... 

More importantly for this discussion is the finding that chronic administration of an antidepressant produces a similar increase in the concentration of extracellular 5-HT in the terminal field together with recovery of neuronal firing. Presumably this is because the prolonged elevation of extracellular 5-HT around the neurons in the Raphe causes progressive desensitisation of the somatodendritic 5-HTia receptors. At this point, inhibition of their firing does not occur and so more 5-HT is released in the cortex (see Hervas et al. 1999). 

Table 20.7 Neurochemical changes generally found after chronic administration of antidepressant drugs or repeated electroconvulsive shock...

Studies in mice have shown a hypericum extract to increase exploration in an unfamiliar environment, prolong sedative sleep time, and antagonize the effects of reserpine. Other antidepressant-like effects are found on the water-wheel test, and chronic administration decreased aggression in socially isolated male mice (Okpanyi and Weischer 1987). 

Jones RS, OIpe HR. (1984). An increase in sensitivity of rat cingulate cortical neurones to substance P occurs following withdrawal of chronic administration of antidepressant drugs. Br J Pharmacol. 81(4) 659-64. 

Bonson KR, Buckholtz JW, Murphy DL. (1996). Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans. Neuropsychopharmacology. 14(6) 425-36, Bonson KR, Murphy DL. (1996). Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors, or lithium. Behav Brain Res. 73(1-2) 229-33. 

In SUMMARY, it would appear that a detailed knowledge of the pharmacokinetics of the main groups of psychotropic drugs is only of very limited clinical use. This is due to limitations in the methods for the detection of some drugs (e.g. the neuroleptics), the presence of active metabolites which make an important contribution to the therapeutic effect, particularly after chronic administration (e.g. many antidepressants, neuroleptics and anxiolytics), and the lack of a direct correlation between the plasma concentration of the drug and its therapeutic effect. Perhaps the only real advances will be made in this area with the development of brain imaging techniques whereby the concentrations of the active drug in the... 

Figure 6.8. Changes that occur following the chronic administration of antidepressants. SSRIs and MAOIs desensitize the inhibitory S-HT a somato dendritic receptors. SSRIs and MAOIs desensitize the inhibitory S-HT b/S-HTid inhibitory auto receptor on the presynaptic terminal. After acute administration, the TCAs and the SSRIs inhibit the uptake of 5-HT into the nerve terminal by binding to the...

Eollowing chronic administration to rats, there is evidence that most antidepressants cause adaptive changes in S-HT a/ 5-HT2a alpha-1, alpha-2 and beta adrenoceptors, GABA-B receptors and possibly the NMDA-glutamate receptors. 

There is experimental evidence that the chronic administration of antidepressants or ECT enhances the inhibitory effect of micro-iontophoretically applied 5-HT. This effect is blocked by lesions of the noradrenergic projections to the frontal cortex. 

Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OA, Charney DS, Krystal JH (2001) Reductions in occipital cortex GABA levels in panic disorder detected with Ih-magnetic resonance spectroscopy. Arch Gen Psychiatry 58 556-561 Grant MM, Weiss JM (2001) Effects of chronic antidepressant drug administration electroconvulsive shock on locus coeruleus electrophysiologic activity. Biol Psychiatry 49 117-129... 

The significance of the effects of the TCAs on receptor sensitivity and subsequent antidepressant effects remains unclear. Other agents that possess similar receptor interactions to TCAs (such as cocaine and the tti receptor) are devoid of antidepressant activity. In addition, receptor blockade is seen with initial doses of medication, while changes in mood symptoms have considerable lag time. The lag phase of clinical effectiveness appears to be due to changes in receptor density and postsynaptic activity associated with chronic administration of TCAs (Sugrue, 1983). 

Nalepa I, Vetulani J Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram. J Neurochem 60 2029-2035, 1993 Nalepa I, Vetulani J The responsiveness of cerebral cortical adrenergic receptors after chronic administration of atypical antidepressant mianserin. J Psychiatry Neurosci 19 (2) 120, 1994... 

Bonson KR, Murphy DL. Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium. Behav Brain Res 1996 73(l-2) 229-33. 

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