Neurotransmitter functions in depression

Frog. Neurc-Psychophormacol & BioL Psychint. 1982. Vol. 6, pp. 639-644 Printed in Great Britain. All rights reserved.

0278-58461821060639-07503.5010 Copyright © 1982 Pergamon Press Ltd.

NEUROTRANSMI'ITER FUNCTIONS IN DEPRESSION YVON D. LAPIERRE

Director of Research, Royal Ottawa Hospital Ottawa, Canada

(Final form, August 1982)

Abstract

Lapierre, Yvon D.. Neurotransmltter functions in depression. & Biol. Psychiat. 1982, 6(4-6) : 639-644.

Pro~.Neuro.Psychopharamcoi.

&

The understanding and management of depression has now progressed beyond the limitations imposed by clinical exmnlnation. Biochemical and pharmacological studies based on the biogenic amine hypothesis t~ve investigated neurotransmltter mechanisms to varying degrees. I. Subgroups of depressions may be identified and treated based on MHPG execution. 2. HVA correlates more with activity than with mood. 3. CSF-5HIAA may be helpful in categorising some depressions. 4. Acetylcholine has some effect on mood most probably through indirect action on other neurotransmitters. 5. GABA is still not adequately investigated. 6. Desensitization of presynaptic adrenerglc autoreceptors may explain some of the mechanisms of antidepressant action of drugs. 7. Decreased post-synaptic adrenergic activity is a common effect of most antidepressants and of ECT.

Keywords:

Biogenic ~ i n e s

r=ceptors,

depression.

Methods The perspective of biological psychiatry and psychopharmacology on depression is that the clinical syndrome results from a combination of psychological and physiological variables. The illness has a biological substratum upon which are grafted a number of psychological factors. The confluence of both lead to a clinically defined syndrome. The study of depressLon is Limited by the lack of specificity of clinical definitions and must be complemented by biological criteria which go beyond the scope of the clinical examination.

A precise diagnosis is essential to define the clinical sy~drolae, its prognosis without modality and the prognosis witi~ treatment.

the characteristics and pathophysiology of treatment, the most efficient treatment

The biological measurements contribute quantifiable variables which then serve as measurements of change. An ideal method should separate depression from normal, define subgroups of depression, separate the state of depression from the depressive trait and serve as reference of state change from the acutely depressed to recovery. 639

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Y,D. Lapierre

The biochemical and pnarmacological approaches are closely interlinked in most investigations, The cateeholamine hypothesis proposed by Scnildkraut (1967) has been the basis of investigations which nave set the groundwork of subsequent research. Schildkraut's proposal that depression may be due to a relative or absolute functional deficiency of catecholamlnes in the brain of depressed patients was quickly followed by a similar hypothesis on the role of indolamines in depression (Coppen, 1972). The limitations of these hypotheses are now generally accepted but their heuristic value remains (Mendels 1974). The scope of the hypothesis is limited for a number of reasons, one being ttmt the depressive syndrome obviously involves a number of other systems. If limited to the depletion of amines, these depletions would have to be extreme and sharply localized. Secondly, as depression covers many other areas of psychopathology, the specificity of amine depletion would embrace many other psychiatric conditions and could De an epiphenomenon. Finally, if this were the sine qua non mechanism of depression, amine depleting drugs would of necessity cause depression but this is not the case (Sourkes, 1977).

Studies of neurotransmitter functions in depression have investigated the basic stages of metabolism of neurotransmitters from synthesis to storage, release, reuptake and inactivation. The two catechoiamines of main interest in the investigations of depression are norepinephrine and dopamine.

Metabolic

Figure I Cycle of Noradrenaline

and Dopamine

MHPG (3-methoxy-4-hydroxyphenylglycoi) is an easily accessible urinary metabolite of CNS norepinephrine and has been widely studied in depression. In depressives it has been observed to be decreased and to return to normal levels a~ter treatment (Pickar, 1978), with a more pronounced returu in recovered patients. In bipolars, especially in males, the urinary MHPG was found to be lower than for unipolar depressives (Beckman & Goodwin, 1980).

Therapeutic implications of the MH~G studies helped further the understanding of depression. Maas (1975) subclassified depression according to the level of pre-treatment MHPG and response to medication. A first group (Group A) was found to have a low pretreatment MHPG, an elevation of mood after a trial on amphetamine and subsequently a favourable antidepressant response wzth imipramine and desmethylimipramine. A second sub-group (Group B) were those patients with a normal or elevated pre-treatment MHFG. These patients had no improvement in mood with amphetamine. Their therapeutic response to imipramine and desmethylimipramine was unsatisfactory but they did respond to amitriptyline and nortriptyline.

Homovaniilic acid (HVA), a metabolite of dopamine, is lowered in the CSF of patients with psychotic depression suggesting that there may be a decrease in dopamine turnover

Neurotransmitters

in depression

641

during depression. This lowering of the HVA did not correlate well with tile depressive symptoms out rather with activity. Treatment with L-Dopa resulted in increased motor activity without consistent improvement in the depressive syndrome (McClure, 1973). CSF-HVA is generally lower in depression when compared to schizophrenics and normal. It was also observed that Probenicid concentrates more in the CSF of depressives and a distinct correlation between its concentration and those of Dopac, HVA, MHPG and 5HIAA exist suggesting a change in transport mechanisms in depression (Berger et al., 1980) and another avenue of investigation.

The intermediate metabolites of catecholamines have been studied through COMT, an extraneuronal enzyme. There is an elevation of RBC COMT activity in agitated depressed males (Davidson et al., 1979) and a decrease in retarded depressives (Shulman et al., 1978). Treatment with imipramine resulted in a linear correlation between RBC COMT and therapeutLc response, the best results occurring with low pre-treatment COMT levels (Davidson et al., 1976). Artificial inhibition of COMT does not influence the course of depression (~Igrist et al., 1973). It thus does not appear that COMT has a direct relationship to depression per se but may be an enzyme related to associated phenomena such as motor activity.

Studies on the precursors of catec holamine neurotransmitters have focused on tyrosine. Although levels of tyrosine do not vary in depression, loading with tyrosine has resulted in a few case reports of improvement (Goldberg, 1980 and Gelenberg, 1980). A tyrosine precursor, D-phenylalanine, has not produced any change in blood levels of phenylalanine nor of tyrosine. Furthermore, this precursor has not been demonstrated as modifying the course of depression in any way (Mann, 1980). Treatment wLth L-Dopa up to 7 grams daily has not produced improvement either (Mendels, 1974).

Another strategy has been the potentiation of catecholamines at the receptor level. Salbutamol stimulates beta adrenergic receptors and has been observed to be antidepressant in some patient. Norepinephrlne an activator of dopamine receptors is possibly helpful in depressed patients with low HVA response to probeneeid (van Praag, 1980). It also increases basal levels of plasma norepinephrine proportlonai to the improvement in depression (Reus et al., 1980).

Serotonin, an indoleamine, has been implicated in depression for sometime (Coppen, 1972).

~o

5.Hu~

Insert Figure 2 here Metabolic Cycle of Serotonin

Studies of 5-HIAA in serum and urine have been confounded by the presence of serotonin from the periphery. These have not been successful in demonstrating differences between depressed and non-depressed patients. Pre-treatment with L-Tryptophan does not modify urinary 5-HIAA (Fraser et al., 1973). 5-HIAA concentrations in the CSF of depressed patients has a blmodal distribution. In those patients with lower levels there is a significant correlation between concentration of 5-HIAA and degree of depression. This

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Y.D. Lapierre

does not occur in patients with higher levels (Asber~, 1976). L-Tryptophan admlnistrat[on results in a slight increase of CSF 5-HIAA but there is no change in depression (Dunner et al., 1972). 5-HT uptake in the platelets of depressives is reduced. This may be due to a decreased diffusion of 5-HT into the platelets in affective disorders (Giret et al., 1980).

Studies of serotonin presursors ~mve yielded interesting but controversial results. Mendels (1974) was mlable to demonstrate any antidepressant activity of L-Tryptophan at doses of 7 grams whereas van Praag 41980) demonstrated a potentiation of Ciomipramine, a serotonin reuptake inhibitor with L-Tryptophan. Studies on L-Tryptophan transport mechanisms suggest that t|~re is a difference in clearance to the brain in patients who respond to treatment with L-Tryptophan.

The MAO enzyme has been of considerable interest in depression because of the proven antidepressant effect of some MAO inhibitors. This enzyme has been studied primarily in platelets where MAO activity ~ms not consistently varied in depressives compared to manics and controls (Coper e t a l . , 1979). There have been slight subgroup differences suggesting that there may be sex-related differences with females having greater MAO activity than males (White et al., i980). There is also evidence that MAO activity increases with age thus explaining toe increased incidence of depression with advancing age.

Acetyicholine has been ~mplicated in affective disorders via an indirect route. The inhibition of acetylcholine esterase by physostigmine produces increased levels of acetylcholine and is associated with symptoms of depression in normais (Risch et al., 198A). Further support comes from the observations that physostigmine administration results ~n a transient decrease in manic symptoms (Janowski e t a l . , 1973). However there is no clear relationsnip established between acetylcholine activity and depression. There is some suggestive evidence that this neurotransmitter is acting in equilibrium with catecholamines (Mendels, 1976).

Gabaaminobutyric acid (GABA) was found to be lower in the CSF of depressed patients compared to normals, schizophrenics, manics and patients with anorexia nervosa (Garner et al., i~81). These findings are still preliminary and must be explored further. The importance of GABA is supported further by the recent observations of some antidepressant activity of alprazolam, a new triazolo-benzodiazepine.

RECEPTOR CHANGES IN DEPRESSION

Presynaptically, the alpha-2 adrenergic receptor is modified by tricyclic antidepressants. These lead to desensitization of the autoreceptor to norepinephrine and serotonin. This is hypothesized to act on feedback mechanisms and lead to greater production of the neurotransmitters and an improvement in depression (Slaver et al., 1981; Charney e t a l . , 1981).

The postsynaptic amine receptors are modified by antidepressants. Treatment leads to decreased beta adrenerglc activity and enchanted responsiveness to serotonln and to alpha adrenergic stimulation. Interestingly, these change in beta adrenergic activity occur with tricyclic antidepressants, atypical antidepressants and ECT (Charney et al., 1981; Sulser et al., 1979). Depression may have as biological substrate a decreased norepinephrinergic activity which leads to compensatory postsynaptic supersensitivity. Instead of being a condition of hypoarousal, depression may be a state of neuropharmacological hyperarousal (Friedman, 1978).

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Conclusion The initial biogenic amine hypothesis is not rejected. There is ample evidence for involvement of amine neurotransmltter systems in depression. The mechanisms by which this may occur are not completely elucidated and explorations continuing in the postsynaptic neuronal systems may produce further insights into this complex syndrome.

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Inquiries aud reprint requests should be addresseo Dr. Y.D. Lapierre Royal Ottawa Hospital 1145 Carling Avenue Ottawa, Ontario KIZ 7K4

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