L-6 Neuropeptides: Targets for antidepressants?

L.ectures

St-3

If the therapeutic effect of 5HT-acting drugs, is to produce an increase in synaptic 5-HT throughput then depletion of brain 5-HT function should reverse this action. Early forward-looking studies by Hopsin and colleagues used PCPA to prevent 5-HT biosynthesis and showed this eliminated the effects of antidepressants. More recently Charney and his group have used a less toxic paradigm to reduce brain 5-HT function. They deplete 5-HT production by treating patients with a low tryptophan diet plus a mixture of amino acids that block the entry of plasm tryptophan into the brain. This markedly decreases brain 5-HT release in animals and in patients treated by 5-HT-acting antidepressants produced a short lived relapse of their depression. In some cases there was a recurrence of the specific delusional ideas that were present prior to treatment. Depression was not induced in those patients maintained on the noradrenergic antidepressant desiprarnine. These data clearly demonstrate that continued throughput of 5-HT is necessary for the antidepressant action of the SSRls and the tricyclics that have some 5HT uptake blocking properties. In this regard depression differs from OCD where similar acute depletion of 5-HT does not bring back the symptoms. It seems likely therefore that the mechanisms of antidepressant drug action in depression are predominantly presynaptic, to increase synaptic levels of 5-HT, whereas in OCD postsynaptic or downstream receptor changes may be more important.

References Blier

P, de Montigny C (1994) Current advances and trends in the treatment of depression. Trends Phanacol Sci 15: 220.226. Coppen A, Prange AJ. Whybrow PC, Noguera R (1972) Abnormalities of lndoleamines in Affective Disorders. Arch Gen Psychiatiy 26: 474-476. Delgado PL, Chamey (1990) Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psvch 47: 41 l-416. Glue P, Cowen-PJ. Nutt DJ. Kolakowska T , Gtahame-Smith DG (1966) The effect of lithium on 5-HT-mediated neuroendocrtne responses and platelet 5-HT receptors. Psychopharmacol 90: 396.402.

IL-5

Critical progress of mood disorders

J. Vetulani. Academy

Departmenf of Sciences,

Keywords:

MAO, Reversible

in MAO

inhibition

in the treatment

of Biochemistry, institute of Pharmacology, Smetna 12, 31-343 Krakdw, Poland inhibitors,

Subtype

specificity,

Polish

RIMA

MAO inhibitors (MAOI) were the first effective antidepressant drugs introduced into clinic about 40 years ago, but because of their adverse side effects they rapidly fell to disrepute and were substituted by safer tricyclic antidepressants. However, as 30-40% of depressions are treatment-resistant, and ECT is now used only as the last resource, MAOI aroused some interest as an alternative therapy for nonresponders. During the last years the MAO-inhibitors reached a progressive importance in clinical practice because of the discovery that MAO exists as two distinct isozymes, MAO-A and MAO-B, which differ in their substrate and inhibitor specificities. MAO-A is mainly involved in the metabolism of 5 HT and noradrenaline, whereas P-phenylethylamine and probably dopamine are predominantly deaminated by MAO-B. The discovery was followed by synthesis of isozyme-specific MAOI, such as clorgyline (MAO-A) and deprenyl (NIAO-B inhibitor). While clorgyline was found an effective antidepressant drug, the antidepressant potential of deprenyl was low, but because of specific inhibition of dopamine metabolism the drug was found useful in treatment of Parkinson’s disease. In contrast to nonspecific MAOI, MAO-A inhibitors carry little or no risk of inducing severe hypertensive crises, because by inhibiting selectively of MOA-A, they still allow the metabolism of tyraznine by MAO-B. The second step in re-introduction of MAOI into clinic was the synthesis of reversible inhibitors. Classical MAOI bind irreversibly to the FAD-containing active site of MAO by hydrazine (phenelzine, isocarboxazid), cyctopropylamine (tranylcypromine), or acetylenic (pargyline, clorgyline, deprenyl) group. Because MAO has a half life of approx. 12 days, the effects of compounds are long-lasting. This makes difficult titration of dosage, renders level monitoring useless and makes difficulties if toxicity occurs. The discovery of reversible, short-lasting MAOI (their average half life in patients is 4-5 h) allowed for better control of degree of MAO inhibition. The introduction of selective and reversible inhibitors of MAO-A (RIMA) has led to the reexamination of the position of MAOI in psychiatry. RIMA seem to have about the same clinical activity as other types of antidepressants, including tricyclics and related compounds and also classical MAOI.

However, they are lacking hepatotoxicity and have only a slight potentiating effect on the hypertensive action of tyramine. They are also significantly better tolerated than tricyclics and only slightly less well tolerated than placebo. Animal studies have demonstrated that RIMA increase dopamine outflow from the striatum, the biochemical action regarded as important for the action of antidepressants. The first reversible MAO-A inhibitor, extensively investigated and presently widely marketed is moclobemide. Another effective drug of this group is brofaromine. Several other compounds of this group, such as CGPI 1305A, cimoxatone, amiflamine, BW 13701187, toloxatone, are presently investigated. Undoubtedly, introduction of MAOI of new generation may lead to improvement of treatment of many forms of depression, including those resistant to tricyclic antidepressants.

0L-6

Neuropeptides:

targets

J.M. van University,

Ree. Rudolf Magnus Institute Universiteitsweg 100, 3584

Keywords:

Neuropeptides;

Antidepressants;

for antidepressants? for Neurosciences, Utrecht CG Utrecbt, The Netherlands Depression

Different approaches can be followed to develop new pharmacological treatment strategies for depression i.e. (patho)physiological, pharmacological and pathological approaches. The physiological approach includes the investigation of physiological processes in the brain that are disturbed in depression. Knowledge about substances and mechanisms implicated in the regulation of these processes may eventually lead to entities with antidepressant action. The pharmacological approach involves first the characterization of the action in animals of drugs known to be effective in treating depressive patients, and second, the comparison of the effects of new entities with those of antidepressants. The pathological approach includes the induction of the similar pathology in animals as is present in patients. Characteristic svmotoms of deoression are. amona others. mood changes and a decrease of the ability to experience ple&ure. An animal model dealing with so called pleasure centers is intracranial selfstimulation, investigating brain systems which mediate reward. A number of theories of depression focuses on the postulate that depression results from a reduction in the activity of reward systems. One of the brain systems implicated in the brain reward circuitry is the dopaminergic pathway with cell bodies in the ventral tegmental area (VTA) and terminals in the nucleus accumbens among others. Some peptide studies have been performed with intracranial selfstimulation in animals implanted with electrodes in the VTA. Evidence has been presented that endogenous opioids modulate the threshold for selfstimulation, suggesting that a decreased activity of these peptides may result in anhedonia and mood changes. Selfstimulation behavior is also modulated by peptides related to neurohypophyseal hormones i.c. the vasopressin fragment DGAVP and the C-terminal fragment of oxytocin, prolyl-leucyl-glycinamide, and by peptides related to (p-endorphin ic. the u-type and y-type endorphins. Cognitive dysfunctions may accompany the mood disturbances in depression. Thus, entities with a cognition-enhancing action may at least be useful in treating those dysfunctions Among the peptides that have been implicated in certain cognitive processes are those related to adrenocorticotropic hormone (ACTH) and vasopressin. The number of studies comparing the effects of neuropeptides with those of antidepressants is limited. One series of experiments have concentrated on the links between melatonin and the mesolimbic dopamine system. Melatonin, injected into the nucleus accumbens, induces distinct behavioral changes. These behavioral responses were completely inhibited by local treatment with small doses of various antidepressant drugs (Gaffori et al., 1985). A similar inhibition of the melatonin-induced behavioral changes was found with the peptide p-endorphin-(lo-18) (PE(lO-18)) after intra-accumbal or after subcutaneous administration. Also subcutaneous administration of the other peptides with possible antidepressant activity i.c. prolyl-leucylglycinamide (PLG) and thyrotropin-releasing hormone (TRH), dose dependently counteracted the melatonin-induced behavioral responses (Hatta et al., 1995). Chronic systemic treatment with different antidepressants i.c. desipramine, fluvoxamine and mianserin still blocked the behavioral changes induced by intra-accumbal injection with melatonin (DurfachMisteli and Van Ree, 1992). This effect of the antidepressants was mimicked after chronic systemic treatment with PE-(10-18). Thus, according to the pharmacological isomorphism principle, the peptides PE-(IO-18) PLG and TRH may be potential antidepressantlike peptides. The pathological approach has hardly been applied in studies on

Sl-4

Lectures

neuropeptides and depression. A patho(physio)logical example is the effect of short-term isolation on social behavior of rats. An isolation period of 7 days results in increased social behaviors, when rats are tested in dyadic encounters. A single treatment with various antidepressant drugs normalized the increased social interactions of the isolated rats to the level of the group-housed rats. Some neuropeptides induced a similar effect as the antidepressants. The effective peptides were PLG, TRH and the ACTH-(6 9) analog ORG 2766 (Niesink and Van Ree, 1984). The learned helplessness phenomenon -performance deficit in a learning task after exposure to uncontrollable stress - is one of the models frequently used to detect antidepressant activity in animals (Willner, 1964). Endogenous vasopressin has been implicated in the performance deficit. Another more or less related procedure, the so called ‘behavioral despair’, deals with the onset of immobility, when animals are forced to swim without the possibility to escape. The onset of immobility in the second test is more rapid than in the first test, and is delayed by pretreatment with a wide variety of antidepressants. The action of these drugs is mimicked by PLG and TRH. Another test procedure with potential consistent validity for depression is chronic unpredictable stress. The induced behavioral disturbances are at least partly counteracted by chronic antidepressant treatment. A similar effect has been reported with PLG. Some peptides have been used to treat depressed patients. Most studies have been perfoned with TRH. This peptide was ineffective in most double-blind studies using oral administration. However, after intravenous administration, a short lasting antidepressant effect was observed in about half of the studies. PLG has been given orally to depressed patients in 4 studies. In most of them an antidepressant effect was reported which occurred rapidly. In conclusion, although the research so far is limited, detailed animal and human research may eventually disclose neuropeptides or related entities with therapeutic action in depression.

References Duffach-Misteli, C. and Van Ree, J.M. (1992) Dopamine and melaionin in the nucleus accumbens may be implicated in the mode of action of antidepressant drugs. Eur. J. Pharmacol. 217. 15-21. Gaffori, 0. and Van Flee, J.M. (1965) Serotonin and antidepressant drugs antagonize melatonin-induced behavioural changes after injection into the nucleus accumbens of rats. Neuropharmacoiogy 24, 237-244. Hatta, K., Wolterink, G. and Van Ree, J.M. (1995) Prolyl-leucyl-glycinamide, thyrotropinreleasing hormone and (3-endorphin-(lo-16), like antidepressants, antagonize melatonin-induced behavioural changes in rats. Eur. J. Pharmacol. 264, 327-330. Niesink, R.J.M. and Van Rec. J.M. (1964) Neuropepiides and social behavior of rats tested in dyadii encounters. Neuropeptides 4, 463-496. Willner, P. (1964) The validity of animal models of depression. Psychophanacology 63, l-16.

CRH

in affective

E. Holsboer-Trachsler.

disorders

Rsychiafric

CH-4025

Base/, Switzerland

Keywords:

CRH;

HPA-axis;

University

Hospital,

Depression

Unit,

Depression

Normal controls, when exposed to a stressor, respond with elevated ACTH and cortisol as part of their internal mechanisms of adaptation, established to match external demands. Amona healthv individuals termination of stress exposure is always followed by a return of stress hormone levels to baseline. Hospitalized patients with depression hypersecrete ACTH and cortisol throughout the 24h cycle, in the absence of any external stimuli. Furthermore, they present a blunted ACTH response but a normal cortisol response to a CRH probe, and nonsuppressed ACTH and cortisol concentrations after a test dose of dexamenthasone. The main driving force behind HPA activation is the hypothalamic corticotropin-releasing hormone (CRH) acting in synergy with arginine-vasopressin, produced in the neurons of the paraventricular nucleus, to enhance the release of ACTH and subsequently cortisol (Holsboer 1992). A key role of increased secretion of CRH in the development of depression is indicated by clinical and preclinical studies. This hypothesis is supported by the observed elevation of CRH in the cerebrospinal fluid of depressives, decreased CRH binding in the frontal cortex of depressed individuals who committed suicide, and reduced ACTH secretion in response to CRH infusion in depressives. These findinas are believed to reflect desensitized CRH re&ptors at corticotrophic cells or restricted secretory response of ACTH to CRH, or both, caused by increased basal levels of cortisol. These clinical findings were amplified by studies in control

subjects which showed that several of the changes seen during sleep in depression (e.g. decrease in slow-wave sleep and growth hormone release) can be induced by pulsatile CRH administration. Furthermore, in animal experiments central administration of CRH produced effects reminiscent of the symptoms of patients with severe depression, including autonomic nervous system activation, altered locomotor activity, decreased sexual drive, diminished appetite, increased anxiety, disturbed sleep and several indications of a weakened immune response (Holsboer 1995). In clinical psychiatry, the dexamethasone suppression test (DST) became one of the most frequently used neuroendocrine tests to assess HPA-system function in depression, although one major drawback of the DST for clinical purposes is its low sensitivity, ranging between 20-50%, depending on e.g. age, severity of depression and dexamethasone dose. The availability of human CRH allowed to extend and refine the assessment of HPA regulation by combining the DST with the CRH test. This combined DEX-CRH test allows us to unravel changes in neuroendocrine feedback capacity of the hypothalamic-pituitary-adrenocortical(HPA)-systern among depressives (Holsboer-Trachsler 1994). We used the combined DEX-CRH test as a state marker and applied it longitudinally to follow up treatment response in depressive illness (Holsboer-Trachsler et al. 1991). Depressed patients, in contrast to sedentary control subjects, showed a substantial activation of the HPA system after administration of the combined DEX-CRH test. The abnormal activation disappeared in parallel with clinical remission and thus proved to be a state-dependent characteristic of major depression. Subsequent studies corraborated these findings indicating that the DEX-CRH test might be a useful tool in monitoring treatment response (Holsboer-Trachsler et al. 1994). It appeared that in most cases the normalization of the HPA system developed before clinical improvement. In addition, a less severe HPA dysregulation turned out to be predictive for beneficial treatment response. The observed interrelationship between changes in HPA function and depressive psychopathology is of considerable theoretical interest in connection with the antidepressant action of drugs. The changes in glucocorticoid interaction with brain corticosteroid receptors may account for at least some of the observed abnormalities in HPA functioning in depression. The activity of the HPA system is largely controlled by two corticosteroid receptors in the brain, which are distinguishable as the mineralcorticoid receptors (MR) and the glucocorticoid receptors (GR). Both MR and GR mRNA levels and hormone-binding activities are found to be increased following treatment of different cell lines or animals with antidepressants (Reul et al. 1993). On the basis of this work, it is hypothesized that a primary action of antidepressants could be the stimulation of corticosteroid receptor gene expression which improves negative feedback capacity resulting in decreased HPA-system activity. Notably corticosteroids reduce expression of CRH, through nuclear corticosteroid (MR and GR) receptors (Sarden et al. 1995). Since the time course of antideoressant actions on corticosteroid receptors follows more closely that of ciinical improvement of depression, antidepressants might elevate mood in depression through their long-term effects on HPA-regulation. If additional evidence that neuroendocrine alterations are causally involved in affective disorders can be accumulated, this would provide a lead for a completely new insight into antidepressant action and subsequent development of new drugs by focusing on this action.

References Barden, N., Reul, J.M.H.M. and Holsboer. F. (1995) Do antidepressants stabilize mood through actions on the hypothalamic-pituitary-adrenocortical system? Trends Neurosd. 16, 6-11. Holsboer, F. (1992) The hypothalamo-pituitaty adrenocottical system. In ES Paykel (Ed.) Handbook of affective disorders, Churchill Livingston, U.K. Holsboer. F. (1995) Neuroendocrinolwv of affective disorder. In: F.E. Bloom. D.J. Kupfe; (Ed&.) Psychopharmacology:“?he Fourth Generation of Progress. Raven Press, New York, pp 957-969. Holsboer-Trachsler, E., Stohler, R. and Hatxinger, M. (1991) Repeated Administration of the Combined Dexamethasone-Human Corticotropin Releasing Hormone Stimulation Test During Treatment of Depression. Psychiatty Research 36. 163-171. Holsboer-Trachsler. E., Hemmeter, U., Hatzinger, M., Seifritz, E., Gerhard, U. and H&i, V (1994) Sleep deprivation and bright light as potential augmenters of antidepressant drug treatment - neurobiological and psychomentdc assessment of course. J psychiatr. Res. 28 (4), 361-399. Holsboer-Trachsler, E. (1994) Neurobiologische und psychopathologische Verlaufsmessungen bei Depressionstherapie. Bibliotheca Psychiatrica, No.166, Karger Verlag m-.-a ease” Reul, J.M.H.M., Stec, I., Sdder. M.. Holsboer, F. (1993) Chronic treatment of rats with the antidepressant taryadrenocortical

amitriptyline attenuates the activity system. Endocrinology 133, 312-320.

of the hypothalamic-pitui-