Recent pharmacologic advances in antidepressant therapy

Recent Pharmacologic Advances in Antidepressant Therapy CLINTON

D. KILTS,

Ph.D.,

Atlanta, Georgia

The serotonergic properties of newer generation antidepressants underscore the role of 5-hydroxytryptamine (S-HT, serotonin) in both the pathophysiology and the pharmacotherapy of major depression. Clinical differences between selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are attributed to the greater potency and selectivity for 5-HT transporter inhibition by the SSRIs and the comparatively weak interaction of the SSRIs with nonserotonin neurotransmitter receptors. The SSRIs, monoamine oxidase inhibitors (MAOIs), and TCAs share a common adaptive regulation of noradrenergic, 5-HT, and glutamate neurotransmission, suggesting possible unifying mechanisms of action underlying their antidepressant effects. In vivo neuroimaging techniques, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) have yielded a functional neuroanatomy of compromised neurocircuitry in major depression and promise to be invaluable in mapping the in vivo effects of future novel antidepressant drugs.

From Emory University School of Medicine, Atlanta, Georgia. Requests for reprints should be addressed to Clinton D. Kilts, Ph.D., P.O. Drawer AF, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322.

December

D

epression causes immense personal suffering and disability associated with social and occupational impairment [1,2]. The annual cost of depression in the United States has been estimated to be $43.7 billion, which includes direct treatment costs and the indirect costs of suicide and workplace losses [3]. Fortunately, depression is now successfully treated in a majority of patients who are accurately diagnosed. This advance in the treatment of depression is due in large part to the availability of a new generation of antidepressant drugs. In addition to psychotherapy, the early-generation antidepressant treatment modalities include the tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and electroconvulsive therapy (ECT) (Table I).

Early-generation treatment modalities for depression, although effective, are associated with substantial adverse effects. The TCAs are associated with cardiovascular toxicity and anticholinergic side effects including blurred vision, dry mouth, urinary retention, and constipation. The MAOIs are associated with numerous unfavorable and, at times, life-threatening side effects, with the most notable limitation to their use being a hypertensive syndrome resulting from the interaction with dietary tyramine. The use of ECT is becoming more common, especially for refractory depression. However, memory loss and social stigma remain obstacles to widespread use of ECT. The later generation antidepressants (Table II) have demonstrated efficacy with a greatly improved side-effect profile. The selective serotonin reuptake inhibitors (SSRIs) are the major antidepressants of this generation, which has a decided serotonergic mechanism of action. The clinical success of the SSRIs has refocused the putative mechanisms of depression and antidepressants from a generalized involvement of monoamine neurotransmitters to a more central role of serotonin (i.e., 5-hydroxytryptamine [5-HT]). This article will interpret recent advances in the understanding of neural substrates of depression and antidepressants. The dual roles of 5-HT as both a portal for depression and a mechanism of antidepressant therapy will be presented, and the recent contributions of molecular neurobiology and in vivo functional brain imaging will be examined. 19, 1994

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Decreased Concentrations of Cerebrospinal Fluid 5HT and 5-HIAA in Depression

TABLEI Early Generation Antidepressant Treatment Modalities

The balance of evidence obtained from mechanistic studies indicates that depression is associated with a deficit in 5-HT neurotransmission. One of the earliest and most compelling findings was the observation of a bimodal distribution of 5-HIAA concentrations in the cerebrospinal fluid (CSF) of patients with depression [5,6]. The CSF 5-HIAA concentration in approximately 33% of the patients examined was significantly decreased relative to that of normal controls. Abnormally low concentrations of CSF 5-HIAA of ~15 ng/mL (range in normal subjects: 18-44 ng/mL) were associated with suicide attempts [6], a finding consistent with the recurring link between suicide and depression. The relationship between suicide, depression, and decreased CSF 5-HIAA has more recently been demonstrated in a longitudinal study [7]. These observations lead to the proposal for a biologic subgrouping of depression expressed as a reduction in 5-HT neuronal activity. The findings of decreased 5-HT concentrations in the brain and limbic system of postmortem tissue from patients with depression [8] or suicide victims [9,10] is consistent with this hypothesis.

a Tncyclic antidepressantsITCAsT -Amitriptyine -1mrpramine -Nortriptyline -Desipramse -Doxepin * MonoamineoxidaseinhibitorsIMAGfsl -Phenelzrne -1socarboxazid -Tranylcypromine * ElectroconwlsivetherapyIECT)

TABLEII Later-Generation Antidepressants * Selectrveserotoninreuptakeinhibitors(SSAls) -Paroxetine -Fluoxetine -Serbaline -Fluvoxamine -Citalopram * SerotoninandnoreptnephrineuptakeInhibition -Venlafaxine * Serotoninuptakeand5HTe receptorinhibiiion -Trazodone -Nefazodone * Serotoninreuptakeenhancers -Tianeptine 0 5HTrA receptorpartialagonists -Busprrone -Ipsaptrone -Gepirone

Blunted Prolactin Response to Tryptophan in Depression

YT = 5.hydroxytryptamine fserotonrnl.

ROLEOF 5-HT IN THE PATHOPHYSIOLOGY OF DEPRESSION Synaptic transmission for 5-HT neurons represents a concert of functions modulated by cell bodyand nerve terminal-localized 5-HT autoreceptors. Transmission is mediated by postsynaptic 5-HT receptors, the 5-HT uptake transporter complex, and the ionotropic and metabotropic second messenger systems that transduce, amplify, and integrate 5-HT receptor signals. Serotonergic neurotransmission is terminated by the 5-HT transporter complex that mediates the uptake of 5-HT from the synaptic cleft. The enzymology of 5-HT synthesis is relatively simple and is rate-limited by the availability of tryptophan and its carrier-mediated brain uptake. 5-HT is metabolized in the central nervous system (CNS) by monoamine oxidase to 5hydroxyindoleacetic acid (5-HIAA) [4].

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Additional evidence is derived from results of the challenge of 5-HT-regulated neuroendocrine fimction in depression. Intravenous administration of Ltryptophan (a 5-HT precursor) increases plasma prolactin concentrations in normal subjects. Tryptophan-induced increases in plasma prolactin are enhanced by 5-HT uptake inhibitors and abolished by pretreatment with 5-HT receptor antagonists [ll]. These results indicate that the prolactin response to tryptophan is mediated by an increase in brain 5-HT neurotransmission. The prolactin response to intravenous tryptophan administration is significantly blunted in patients with depression relative to normal controls [El. These results are consistent with a reduction in 5-HT function in depression. Reversal of Antidepressant Effect by Ttyptophan Depletion

The clinical consequences associated with tryptophan depletion in depressed patients further underscore the role of 5-HT in depression and the mechanism of action of antidepressants. Depletion of plasma, and presumably CSF, tryptophan by a diet low in tryptophan and high in neutral amino acids that compete with available tryptophan for CNS uptake, precipitated a rapid relapse in remitted

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The platelet shares a large number of common properties with 5-HT neurons, including embryological ancestry, 5-HTa receptors, and vesicular monoamine and membrane 5-HT transporters, in addition to [3H]imipramine binding sites [221. Human platelets therefore represent readily available, though incomplete, models of brain 5-HT neurons. Comparison of platelet [3H]imipramine binding in Increased Density of Postsynaptic 5-HT2 Receptors >150 patients with major depression and 100 norAn additional finding consistent with a reduction mal controls indicated that the reduction in [3H]imipramine binding site density in major dein 5-HT neuronal activity and release in depression pression is robust and not a function of age or genis provided by the demonstration of an increased density of postsynaptic 5-HTa receptors in the fronder (Figure 1) [23]. Moreover, reductions in platetal cortex of drug-free patients with depression [ 141 let [3H]imipramine binding were specific for major and depressed victims of suicide [9,101. 5-HTa re- depression in that binding was not reduced comceptor binding was decreased in depressed patients pared to control subjects in patients with mania, who were euthymic at death as compared with nor- Alzheimer’s disease, atypical depression, or panic mal controls [14]. These observations suggest that disorder. The decrease in platelet binding of increased 5-HTz receptor density represents an [3H]imipramine relative to normal controls is also upregulatory response to decreased synaptic 5-HT observed in depressed patients who have never received antidepressant treatment, a finding arguing concentrations and is related to the depressive state. A similar alteration in the density of platelet against the possibility that reductions are second5-HTz receptors (i.e., a peripheral model of the se- ary to antidepressant administration [24]. rotonergic neuron; see below) in depression has also Correlated markers of depression often bear a relation to the symptoms of depression. A traitbeen reported [15-171. dependent marker signifies an enduring correlated The 5-HT Transporter phenomenon of the diagnosis of depression that The specific involvement of the 5-HT transporter bears no obvious relation to the severity of sympcomplex in depression is suggested by the antidetoms. A state-dependent marker signifies a phepressant activity of all 5-HT transport inhibitors. nomenon correlated with the severity of depressive The decrease in [3H]imipramine binding to the symptoms and thus exhibiting an episodic relation platelet 5-HT transporter of drug-free depressed to the diagnosis. The question as to whether a depatients represents arguably one of the most reprocreased density of platelet 5-HT transporters repducible biological findings in depression [l&21]. resents a state- or trait-dependent marker of dedepressed patients who were being treated with antidepressants. Relapse occurred within hours of ingestion of the diet and was itself rapidly reversed by a tryptophan-supplemented diet [131. An important role for 5-HT in the regulation of mood and as a substrate for the therapeutic effects of antidepressants is strongly indicated by these findings.

1750

1

8 8.

1500 1250 (f %%g Protein) Figure 1. Scatterplot

of individual E,,, values for 13Hlimipramine in platelets from depressed and normal subjects; bars alongside show mean 2 SEM. There are no significant differences between males (0, A) and females (0, A); however, results for depressed subjects in both age groups are significantly lower than those from normal controls (p
1000 750

0 500

0

250 40 Normal Controls

Years

Old Major Depression

a60 Years Old

I I Normal Controls

Major Depression

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pression remains unresolved. However, the results of a recent study [25] indicate that decreases in platelet [3H]imipramine binding at baseline may be predictive of response to antidepressant therapy and that clinical recovery is associated with the normalization in the number of binding sites. [3H]Imipramine binds with high affinity to sites not associated with the 5-HT transporter and to domains of the 5-HT transporter that are distinct from those labeled by the SSRIs [26]. The question as to whether major depression is associated with a similar decrease in the density of platelet binding sites radiolabeled by more specific, high-affinity 5-HT uptake inhibitors (e.g., paroxetine or citalopram) remains unresolved. Although several investigations did not find a decrease in platelet [‘Hlparoxetine binding in depression [27,28], a decrease in the density of platelet binding sites for both r3H]paroxetine and [“Hlimipramine has been reported in major depression [231. The results of binding site analyses conducted in postmortem human brain tissue support the contention that platelet binding studies accurately model the influence of major depression on 5-HT transporters in the CNS. Perry and coworkers [81 reported a decrease in [3H]imipramine binding sites in the occipital cortex and hippocampus of patients with depression relative to normal control subjects. A similar decrease in brain 5-HT transporters in major depression was demonstrated using the more specific high-affinity ligand [3H]citalopram [29]. Studies examining diverse measures of 5-HT neuronal function demonstrate that brain 5-HT systems are markedly altered by depression. Collectively, these findings support the contention that 5-HT neurotransmission is diminished in depression and that reductions in 5-HT may be causally related to the etiology of depression. Other neurotransmitters, including corticotropin releasing factor (CRF) and norepinephrine, have been convincingly implicated in the pathophysiology of depression [30,31]. It is therefore highly probable that major depression represents a defect in the interrelationship of multiple neurotransmitter systems in the CNS.

THE ROLEOF 5HT IN ANTIDEPRESSANT THERAPY There can now be little argument that the SSRIs represent significant improvements over the TCAs in the treatment of depression. The mechanisms underlying this advance are attributed to differences between the TCAs and SSRIs in terms of transporter mechanisms, receptor pharmacology, and adaptive response of the CNS to chronic antidepressant administration. 6A-6S

Transporter Pharmacalogy of TCAs and SSRls The 5-HT transporter is thought to represent the molecular site of action of the TCAs and SSRIs. The field of molecular neurobiology has recently provided an extensive understanding of the structure, function, and regulation of the 5-HT transporter. The cloning and sequencing of the gene encoding the human 5-HT transporter have elucidated its gene and protein structure [32]. The expression in cell lines of the cDNA encoding the human 5-HT transporter has provided a greatly improved understanding of 5-HT transporter function, including its ion dependency and pharmacologic regulation. Sequence analysis of the expressed human 5-HT transporter indicated a primary sequence of 630 amino acids and a high degree of sequence homology to other neurotransmitter transporters, including the norepinephrine, dopamine, and gammaaminobutyric acid (GABA) transporters. The structural relationship between transporters is consistent with the 5-HT transporter’s being a member of a large family of genes encoding transporters [33] and with the biogenic amine transporters’ representing a small subfamily within a larger family. The putative membrane topology of the human 5-HT transporter consists of 12 hydrophobic membrane spanning regions with both the amino and car-boxy1 termini localized in the cytoplasm [32]. Chromosomal in situ hybridization experiments suggest that the human 5-HT transporter is encoded by a single gene localized to chromosome 17 [32,34]. However, the presence of multiple distinct human 5-HT transporters is suggested by the multiple hybridizing mRNAs in human placenta and lung, possibly resulting from alternative gene processing [32]. Functional expression of a cDNA encoding the human 5-HT transporter in HeLa cells demonstrated its Na+ and Cl- dependency and the inhibition of 5-HT uptake by SSRIs, TCAs, and cocaine [32]. The TCAs are structurally similar antagonists of the 5-HT and norepinephrine transporters. Amitriptyline and imipramine are the most 5-HT transporter-selective TCAs, with inhibition constants (Ki) of approximately 100 nM and 5-HT/norepinephrine transporter inhibition ratios of approximately 1.0 [35]. In contrast, the SSRIs are structurally distinct agents (Figure 2) that are weakly basic, halogenated, nonpolar compounds, with discrete pharmacokinetic and pharmacodynamic properties. As their name implies, the SSRIs are highpotency (Ki values of l-25 nM> 5-HT transporter inhibitors with large ratios (20-320) of selectivity for 5-HT versus norepinephrine uptake inhibition [35-371 (Figure 3). Paroxetine is the most selective 5-HT transporter inhibitor of the Food and Drug

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Administration (FDA)-approved SSRIs, with a 31%fold selectivity for the 5-HT transporter versus the norepinephrine transporter [3’7] (Table III>. In general, the SSRIs and TCAs exhibit negligible intrinsic activity as inhibitors of in vitro dopamine uptake. For example, paroxetine is approximately 1,800 times more potent as an inhibitor of the 5-HT transporter than the dopamine transporter (Figure 4). In contrast, sertraline inhibits [3H]dopamine uptake (Ki = 230 nJ4) and is approximately as potent as cocaine, which is a nonselective dopamine uptake inhibitor. Sertraline possesses a dopamine/5-HT transporter inhibition ratio of approximately 32 [37]. Clinical evidence of dopamine uptake inhibition by sertraline is lacking. However, in vitro evidence of inhibition of brain dopamine transporter activity by sertraline suggests that it should be used cautiously in the treatment of psychotic depression, for which dopamine agonists are generally thought to be deleterious. The selectivity of the SSRIs for 5-HT transporter inhibition that has been demonstrated in rodent synaptosomal preparations and transfected cell lines reflects a similar in vivo human pharmacology. Young, healthy volunteers received escalating oral doses of paroxetine (lo-40 mg daily) for 28 days. Plasma samples from these subjects gradually exhibited selective inhibition of [3H]5-HT uptake in rat cortical synaptosomal preparations [381. Inhibition of 5-HT uptake by plasma samples was negligible on day 1 and highly significant on day ‘7 and day 28 of paroxetine administration. Negligible [3H]5HT uptake inhibition was observed in plasma samples obtained at the end of a 2-week drug-washout period. Paroxetine administration did not affect [3H]norepinephrine uptake at any of the time points studied. These results demonstrate that chronic administration of paroxetine, at clinically relevant doses, results in a selective inhibition of the 5-HT transporter in humans.

hypertension, dizziness, and tachycardia are due to inhibition of ai-noradrenergic receptors. 5-HT receptor antagonism by the TCAs may contribute to the weight gain and sleep disturbances associated with their use. In striking contrast, the SSRIs exhibit very few significant interactions with neurotransmitter receptors, as assessed by in vitro radioligand binding

0-CCH-(CH$,-NH-W,

CH-CHpi,CH,-OCH, F3c

Figure 2. Structures

of selective

serotonin

:-OCH

reuptake

2 CH 2 NH 2

inhibitors (SSRls).

I

Receptor Pharmacology of SSRls and TCAs The use of the TCAs in the treatment of major depression is best characterized by clinical efficacy associated with an unfavorable side-effect profile and risks in overdose. The low therapeutic index of the TCAs is generally attributed to a complex receptor pharmacology [35,39,40] rather than their nonselectivity for inhibition of neurotransmitter transporters. The blurred vision, urinary retention, constipation, dry mouth, and memory disturbances associated with TCA therapy are mediated, in large part, by antagonism of muscarinic-cholinergic receptors. Similarly, the antagonism of H-l histamine receptors underlies the hypertension, sedation, and drowsiness associated with the TCAs. Orthostatic December

J

Figure 3. Selectivity for serotonin versus norepinephrine

reuptake.

(Reprinted

from 13’],w’thpermissionJ

‘SelectlW exPressed BLratm Of~“hw.m CcmStants ,K,)Larger valuer denote g,eater 58,Ed,“,lY to,JelDtM,” Flgure 4. SelectWy for serotonin versus dopamine reuptake. (Reprinted from 1371, with permIssIon.)

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TABLEIII In Viio Differences Between SSRlsand TCAsin Potency and Selectivity for MT Uptake Inhibition

1.1 7.3 6.2 25 100 87

Paroxetine Sertraline Fluvoxamine Fluoxetine lmipramine Amtiptyline

318 192 177 20 0.65 0.91

Adapted from [35,37l. K, = inhibitionconstant; NE = norepinephrine;SSRI= selectii serotonin reuptake inhibitor; TCA = bicyclic antide pressant.

TABLEIV Effect of Chronic Antidepressant Treatment Modalities on Norepinephrine, 5-HT, and Glutamate Neurotransmission TWbMltS

N&MT NeWhllhSSl~

&Adremeptor

DwityorFuncti0n

Tricyclic antipressants

I

t

-paroxetine

No effect

t

-citalopram

Noeffecf

t

-Ruoxetine

Noeffect

t

(amtiiptyiine, desipramine,imipramine) Selectiveserotoninreuptake inhibitors

Electroccwlsiie shock

4

t

Monoamineoxidaseinhibitors

1

t

na = not assayed; NMDA = Nmethybaspartate. Data from I44-461.

site competition [35,39]. A receptor interaction of moderate affinity exists with paroxetine for radiolabeled muscarinic-cholinergic receptors. However, the in vitro affinity of paroxetine for muscarinic-cholinergic receptors is approximately 17 times less than that of amitriptyline [35] and, to date, no clinically significant anticholinergic effects of paroxetine have been noted [41]. Adaptive Response of the CNS to Repeated Antidepressant Treatments

The clinical efficacy of antidepressant therapy is not a simple result of the inhibition of 5-HT uptake or direct effects on neurotransmitter receptors. A therapeutic response to SSRIs and TCAs typically requires 3-6 weeks of repeated drug administration [42,43], despite in vitro and in vivo [38] observations that maximal 5-HT uptake inhibition occurs in days. Studies of antidepressant mechanism of action have, therefore, focused on the adaptive responses of neurotransmitter systems in the CNS to chronic antidepressant administration. Three major candidate responses have been proposed and include: (a) downregulation of the padrenergic re6A-N

ceptor, (b) enhancement of 5-HT neurotransmission, and (c) adaptation of the N-methyl-n-aspartate (NMDA) subtype of glutamate receptors. BETA-ADRENOCEPTOR

DOWNREGULATION:

ChrOIliC

administration of pharmacologic and nonpharmacologic antidepressant therapies in animal models results in a reduction in the density of cerebrocortical P-adrenoceptors and/or a decrease in the coupling of P-adrenoceptors with the adenylate cyclase second messenger system (Table IV) [47-491. Betaadrenoceptor downregulation occurred following chronic, but not acute, administration of a wide range of clinically efficacious antidepressant therapies, including TCAs, ECT, and rapid eye movement sleep deprivation. Demonstration of treatment-induced Padrenoceptor downregulation was dependent on the integrity of brain 5-HT neurons

r501. This link between brain 5-HT and norepinephrine systems and a role for Padrenoceptor downregulation as the “final common pathway” of antidepressant mechanism of action remained a viable scheme until the SSRIs were studied [461. Chronic administration of paroxetine [3’7,51] or citalopram [52] did

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not alter the density or function of brain padrenoceptors in animal studies. Moreover, fluoxetine [53,54], sertraline [55], and fluvoxamine [56,57] do not downregulate Padrenoceptors (or only weakly down-regulate these receptors) after repeated administration to rats. Perhaps mediated by their lack of effect on central noradrenergic receptors and transporters, the lack of effect of the repeated administration of SSRIs weakens the hypothesis that P-adrenoceptor downregulation represents a common mechanism of action for antidepressant therapies. ENHANCEMENT

OF

5-HT

NEUROTRANSMISSION:

Considerable evidence for an increase in 5-HT neurotransmission as a unifying mechanism of antidepressant action for pharmacologic and nonpharmacologic therapies has been generated by the study of an electrophysiologic animal model of 5-HT function. Treatment effects were assessed on presynaptic and postsynaptic 5-HT function using the 5-HT innervation of the dorsal hippocampus of the rat as a model 5-HT neuronal system. De Montigny and Aghajanian [58] first noted that the long-term, but not acute, administration of TCAs enhanced the response to 5-HT of forebrain 5-HT terminal fields. The ability to enhance the efficacy of 5-HT synaptic transmission was subsequently demonstrated following the long-term treatment with electroconvulsive shock [44,59], MAOIs [44,60], SSRIs [44,61,621, lithium [63], and the 5-HTiA receptor agonist gepirone [641 (Table IV). The effects of treatments on 5-HT synaptic transmission were not observed following acute treatments. Moreover, the enhanced responsivity of forebrain 5-HT neurons to the long-term administration of TCAs was demonstrated to be a generalized property of cortical and subcortical 5-HT projection fields and, therefore, not unique to the hippocampus [44]. Accumulated evidence further indicated that the mechanisms underlying the enhanced 5-HT neurotransmission differed according to the type of antidepressant treatment examined. Specifically, an examination in this electrophysiologic model of the effects of treatment on 5-HT autoreceptors localized either at somatodendritic or terminal sites, or the 5-HT postsynaptic receptor in the hippocampus, indicated qualitatively different effects of treatments on the function of these receptor subpopulations. Chronic administration of femoxetine, citalopram, fluoxetine [62], or paroxetine [44] potentiate 5-HT synaptic transmission by reducing the function of somatodendritic and nerve terminallocalized 5-HT autoreceptors. These treatments were without effect on the responsivity of the postsynaptic 5-HT receptor. The SSRIs as a group, therefore, appear to enhance 5-HT neurotransmis-

sion by the selective attenuation of the inhibitory influence of 5HT autoreceptors on 5HT neuronal activity and release. In contrast, chronic administration of TCAs and electroconvulsive shock increased the responsiveness of postsynaptic 5-HT receptors in the absence of an observable effect on the function of 5-HT autoreceptors [44]. Repeated administration of an MAO1 or a 5-HT1~ receptor agonist enhanced 5-HT neurotransmission by yet a third distinct mechanism of action. Chronic administration of the MAO1 clorgyline [62] or the 5-HTiA agonist gepirone [64] induces a desensitization of the somatodendritic, but not terminal, 5HT autoreceptor. These results indicate that chronic administration of diverse antidepressant therapies enhances the effectiveness of 5-HT synaptic transmission in the rat hippocampus by distinct mechanisms. This adaptive response parallels the gradually developing therapeutic benefit associated with these therapies and provides a plausible mechanism underlying the enhanced therapeutic response to combination therapy. ALTERATIONS

IN

THE

NMDA

RECEPTOR

COMPLEX:

Recent evidence supports the contention that the NMDA receptor complex represents a “final common pathway” of antidepressant action. The NMDA subtype of glutamate receptor represents a ligand-gated ion channel and supramolecular complex possessing multiple allosterically coupled recognition sites for glutamate, glycine, polyamines, and use-dependent channel blockers (e.g., MK-801) 1651. Glutamate-mediated excitatory neurotransmission via the NMDA receptor is dependent on the binding of the neurotransmitter glycine to a strychnine-insensitive receptor [66]. The results of recent radioligand binding site analyses indicate that chronic administration of imipramine to mice results in an adaptive impairment in the operation of the NMDA receptor complex at multiple recognition sites of the complex [67]. Imipramine treatment resulted in a reduction in the potency of glytine to inhibit ligand binding to the strychnineinsensitive glycine receptor, a decrease in the proportion of high-affinity glycine sites associated with the NMDA receptor, and a decrease in the basal binding of f3H]MK-801 to the NMDA receptorcoupled channel. The effects of imipramine on the NMDA receptor complex were not observed following acute drug administration and were selective for the cerebral cortex, as similar effects of longterm imipramine administration were not observed in the hippocampus, striatum, or basal forebrain. A subsequent study [45] demonstrated that the long-term treatment with pharmacologic and nonpharmacologic antidepressant therapies resulted in a similar reduction in the apparent affinity of gly-

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tine at a strychnine-insensitive binding site. Significant reductions in glycine receptor affinity were noted following the administration of tricyclic antidepressants, MAOIs, SSRIs, and electroconvulsive shock (Table IV). Effects persisted for lo-15 days after cessation of treatment and were not observed following acute treatments. The effect of long-term treatments on glycine receptor affinity reliably predicted the antidepressant efficacy of 22 of the 23 treatments examined; the effect also appeared to be specific for antidepressant therapies, as a number of psychoactive drugs lacking clinical efficacy in the treatment of depression were without effect on the apparent affinity of glycine for its receptor site. Although the effects of treatments on the NMDA receptor complex on CNS function are currently unknown, it has been proposed [67] that these results, taken with findings from in vitro and in vivo animal models and from clinical pharmacology and neurochemistry, suggest a role for alterations in calcium homeostasis in the mechanism of action of antidepressants and the pathophysiology of major depression. Overall, the study of the adaptive response of the CNS to long-term antidepressant treatments supports the presence of unifying mechanisms of action of available antidepressant therapies. The case for a common mechanism of action could probably best be made for the enhancement of 5-HT neurotransmission or changes in the NMDA receptor complex, compared with treatment-induced p-adrenoceptor downregulation. It should, however, be stressed that the existence of a final common pathway for the mechanism of action of diverse antidepressant therapies is dubious in light of the probability that no single pathway exists for the pathophysiology of major depression. Biologic and pharmacologic observations continue to stress the heterogeneity of major depression. It is highly plausible that the response to a TCA in a patient who is resistant to SSRI therapy may have an associated distinct pathophysiology and related requirement for a padrenoceptor downregulation in the attainment of an optimal drug response.

FUTUREDIRECTIONSFORADVANCESIN ANTIDEPRESSANTTHERAPY Advancement of antidepressant therapy will involve an improved understanding of the neural substrates of depressive disorders and the response of such substrates to treatment. Functional brain imaging techniques-including positron emission tomography (PET) and single photon emission computed tomography (SPECT)-have proven to be unique, powerful methods of mapping neural circuits involved in visual, motor, and complex cogni6A-10s

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tive operations [68-701. The application of these imaging technologies to psychiatry has provided invaluable insights into the functional neuroanatomy of neuropsychiatric disorders and drug abuse that have far exceeded the functional predictions made from structural imaging studies. The emerging picture of depression is that of a biologic disorder associated with abnormal functioning of the frontal and temporal lobes and perhaps in their interaction [71]. A final direction for the future of targeted antidepressant therapies that cannot be overlooked is the unexpectedly large number of distinct 5-HT receptors that have been recently identified by molecular neurobiology techniques [72]. At this time, there are 13 5-HT receptors that have been cloned, sequenced, and functionally expressed in cell systems. These 5-HT receptor subtypes have distinct gene and protein structures and differing brain regional localizations and mechanisms of receptor signal transduction. This new knowledge has the potential to be translated by the medicinal chemist into drugs that have regionally selective effects on 5-HT receptors and autoreceptors. The potential of these drugs, given alone or in combination with existing 5-HT uptake inhibitors, to alter dramatically the efficacy and side-effect liability of antidepressant therapies may evolve into an entirely new class of antidepressant drug therapies.

ACKNOWLEDGMENT The author gratefully acknowledges the invaluable contributions of Barbara House to the preparation of this manuscript.

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SYMPOSIUM ON THE MANAGEMENT OF DEPRESSION/ KILTS 11. Cowen PJ. PsychotropIc drugs and 5-HT neuroendocrlnology. Trends Pharmacol Sci 1987; 8: 105-8. 12. Heninger GR, Charney DS, Sternberg DE. Serotonergic function in depression: prolactin response to intravenous tryptophan In depressed patients and healthy sub jects. Arch Gen Psychiatry 1984; 41: 398-402. 13. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Henlnger GR. Serotonin function and the mechanism of antidepressant action: reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 47: 411-8. 14. Yates M, Leake A, Candy JM, Fairbairn AF, McKeith IG, Ferrier IN. 5-HT2 receptor changes in major depression. Biol Psychiatry 1990; 27: 489-96. 15. Biegon A, Essar N, Israeli M, Elizur A, Bruch S, Bar-Nathan AA. Serotonin 5.HTz receptor binding on blood platelets as a state dependent marker in major affective disorder. Psychopharmacology 1990; 102: 73-5. 16. Arora RC, Meltzer HY. Increased serotoninz (5.HTz) receptor binding as measured by ‘H-lysergic acid diethylamide (%LSD) in the blood platelets of depressed patients. Ltfe Sci 1989; 44: 725-34. 17. Pandey GN, Pandey SC, Janlcak PG, Marks RC, Davis JM. Platelet serotonin2 receptor binding sites in depression and suicide. BIOI Psychiatry 1990; 28: 215-22. 18. Briley MS, Langer SZ, Raisman R, Sechter D, Aarifian E. 3H lmipramine binding sites are decreased in platelets of untreated depressed pabents. Science 1980; 209: 303-5. 19. Langer SZ, Zariflan E, Briley M, Raisman R, Sechter D. High-affinity binding of 3H-imipramine in brain and platelets and Its relevance to the biochemistry of affective disorders. Life Sci 1981; 29: 211-20. 20. Nemeroff CB, Knight DL, Krishnan KR, et al. Marked reduction in the number of platelet 13Hlimipramine binding sites in geriatric depression. Arch Gen Psychiatry 1988; 45: 919-23. 21. Paul SM, Rehavi M, Skolnick P, Ballenger JC, Goodwin FK. Depressed patients have decreased binding of 3H-imipramine to platelet serotonin “transporter.” Arch Gen Psychiatry 1981; 38: 1315-7. 22. DaPrada M, Cesura AM, Launay JM, Richards JG. Platelets as models for neurones? Experientia 1988; 44: 115-26. 23. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depresslon: focus on the serotonin transporter. Clin Chem 1994; 40: 288-95. 24. Nemeroff CB, Knight DL, Knshnan KR. Reduced platelet i3Hlparoxetine and L3Hlimipramine blnding in major depression. L4bstr.l Sot Neurosci Abstr 1991; 17: 586. 25. Freeman AM, Stankovlc SMI, Bradley R, Zhang GZ, Libb W, Nemeroff CB. Tritiated platelet imlpramine binding and treatment response in depressed outpatients. Depression 1993; 1: 20-3. 26. Hrdina PD, Foy B, Hepner A, Summers RJ. Antidepressant binding sites in brain: autoradiographic comparison of [3Hlparoxetine and 13H]imipramine localization and relationship to serotonln transporter. J Pharmacol Exp Ther 1990; 252: 410-8. 27. D’Haenen H, De Waele M, Leysen JE. Platelet 3H-paroxetine binding in depressed patients. Psychiatry Res 1988; 26: 11-7. 28. Lawrence KM, Falkowski J, Jacobson RR, Horton RW. Platelet 5-HT uptake sites in depression: three concurrent measures using ?H]imipramine and [3H]paroxetlne. Psychopharmacology 1993; 110: 235-9. 29. Leake A, Fairbairn AF, McKelth IG, Ferrier IN. Studies on the serotonin uptake binding site in major depressive disorder and control postmortem brain: neurochemical and clinical correlates. Psychiatry Res 1991; 39: 155-65. 30. Hartley PR, Nemeroff CB, Owens MJ. The corticotrophin releasing factor In depression. Directions in Psychiatry 1993; 13: 1-8. 31. Price LH, Charney DS, Rubln AL, Heninger GR. Az-adrenergic receptor function in depresslon. The cortisol response to yohimbine. Arch Gen Psychiatry 1986; 43: 849-58. 32. Ramamoorthy S, Bauman AL, Moore KR, et al. Antidepressant- and cocalnesensitive human serotonln transporter: molecular cloning, expression, and chrom@ somal localization. Proc Nat1 Acad Sci USA 1993; 90: 2542-6. 33. Kilty JE, Amara SG. Families of twelve transmembrane domain transporters. Curr Opin Biotechnol 1992; 3: 675-82. 34. Lesch KP, Wolozln BL, Estler HC, Murchy DL, Riederer P. Isolation of a cDNA encodlng the human brain serotonin transporter. J Neural Transm 1993; 91: 67-72. 35. Thomas DR, Nelson DR, Johnson AM. Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor. Psychopharmacology 1987; 93: 193-200. 36. Bolden-Watson C, Rlchelson E. Blockade by newly developed antidepressants of blogenlc amine uptake into rat brain synaptosomes. Life SCI 1993; 52: 1023-g. 37. Tulloch IF, Johnson AM. The pharmacologic profile of paroxetlne, a new selective serotonin reuptake inhibltor. J Clin Psychiatry 1992; 53 (Suppl): 7-12.

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38. Nelson DR, Palmer KJ, Tasker TCG, Tulloch IF. Neurochemlcal evidence that the antidepressant paroxetine is a selective serotonin reuptake inhibitor in man. Depression 1993; 1: 263-7. 39. Cusack B, Nelson A, Richelson E. Binding of anbdepressants to human brain receptors: focus on newer generabon compounds. Psychopharmacology 1994; 114: 559-65. 40. Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter re ceptors of normal human brain in vitro. J Pharmacol Exp Ther 1984; 230: 94-102. 41. Boyer WF, Blumhardt CL. The safety profile of paroxetine. J Clan Psychiatry 1992; 53 (SuppI): 61-6. 42. Kletn DF, Davis JM. Diagnosis and Treatment of Psychiatric Disorders. Baltimore, MD: Williams and Wilkins, 1969. 43. Aberg-Wistedt A. The antidepressant effects of 5-HT uptake inhibitors. Br J Psychiatry 1989; 8 (SuppI): 32-40. 44. Chaput Y, de Montigny C, Blier P. Presynaptic and postsynaptlc modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 1991; 5: 21929. 45. Paul IA, Nowak G, Layer RT, Popik P, Skolnick P. Adaptation of the N-methyl-daspartate receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther 1994; 269: 95-102. 46. Vetulani J. The development of our understanding of the mechanism of acbon of antidepressant drugs. Pol J Pharmacol Pharm 1991; 43: 323-38. 47. Sarai K, Frazer A, Brunswick D, Mendels J. Desmethyllmipramineinduced decrease in beta-adrenergic receptor binding In rat cerebral cortex. Biochem Pharmacol 1978; 27: 2179-81. 48. Wolfe BB, Harden TK, Sporn JR, Moknoff PB. Presynaptic modulation of beta adrenergic receptors in rat cerebral cortex after treatment with antidepressants. J Pharmacol Exp Ther 1978; 207: 446-457. 49. Sulser F. Mode of action of antidepressant drugs. J Clin Psychiatry 1983; 44: 14-20. 50. Gravel P, de Montigny C. Noradrenergic denervation prevents sensitization of rat forebrain neurons to serotonin by tricyclic antidepressant treatment. Synapse 1987; 1: 233-9. 51. Nelson DR, Thomas DR, Johnson AM. Pharmacological effects of paroxebne after repeated administration to animals. Acta Psychiatr Stand 1989; 350 (Suppl): 21-3. 52. Hyttel J, Overo KF, Arnt J. Biochemical effects and drug levels in rats after long-term treatment with the specific 5HT-uptake Inhibitor, citalopram. Psychopharmacology 1984; 83: 20-7. 53. Beasley CM, Masica DN, Potvin JH. Fluoxetine: a review of receptor and functtonal effects and their clinical implications. Psychopharmacology 1992; 107: l-10. 54. Byerley WF, McConnell EJ, McCabe RT, Dawson TM, Grosser BI, Wamsley JK. Decreased beta-adrenergic receptors In rat brain after chronic administration of the selective serotonin uptake inhibitor fluoxetine. Psychopharmacology 1988; 94: 1413. 55. Koe BK. Preclinical pharmacology of sertraline: a potent and specific inhibitor of serotonln reuptake. J Clin Psychiatry 1990; 51 (Suppl b): 13-7. 56. Brunello N, Riva M, Volterro A, Racagni G. Biochemical changes in rat braln after acute and chronic admlnistration of fluvoxamine, a selective 5-HT uptake blocker, comparison with desmethyllmipramine. In: Advances in Pharmacotherapy, vol. 2. Basel, Switzerland: S Karger AG, 1986: 189-96. 57. Hrdlna PD. Pharmacology of serotonin uptake inhibitors: focus on fluvoxamlne. J Psychiatr Neuroscl 1991; 16 (Suppl 1): 10-8. 58. de Montigny C, Aghajanian GK. Tncyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science 1978; 202: 1303-6. 59. de Montigny C. Electroconvulsive shock treatments enhance responsiveness of forebrain neurons to serotonin. J Pharmacol Exp Ther 1984; 228: 230-4. 60. Blier P, de Montigny C, Azzaro AJ. Modification of serotonergic and noradrenergic neurotransmissions by repeated administration of monoamine oxldase inhibitors: electrophysiological studies in the rat central nervous system. J Pharmacol Exp Ther 1986; 237: 987-94. 61. Chaput Y, de Montigny C, Blier P. Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: electrophysiological studies in the rat braln. Naunyn-Schmiedebergs Arch Pharmacol 1986; 333: 342-8. 62. Blier P, Chaput Y, de Montigny C. Long-term 5-HT reuptake blockade, but not monoamlne oxidase inhibition, reduces the function of terminal 5-HT autoreceptors: an electrophyslological study in the rat brain. Naunyn-Schmiedebergs Arch Pharmacol 1988; 337: 246-54. 63. Bluer P, de Montigny C. Short-term lithium admInIstration enhances serotonerglc

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SYMF’OSIUMON THE MANAGEMENTOF DEPRESSION/KILTS neurotransmission: electrophysiological evidence in the rat CNS. Eur J Pharmacol 1985; 113: 69-77. 64. Eilier P, de Montigny C. Modificabon of 5-HT neuron properties by sustained administration of the 5-HTr, agonist gepirone: electro-physiological studies in the rat brain. Synapse 1987; 1: 470-80. 65. Carter A. Glycrne antagonists: regulahon of the NMDA receptorchannel complex by the strychnineinsensrtive glycine site. Drugs Future 1992; 17: 595-613. 66. Kleckner NW, Dingledine R. Requirement for glycine in activation of NMDA-recep tors expressed in Xenopus oocytes. Science 1988; 241: 835-7. 67. Nowak G, Trullas R, Layer RT, Skolnick P, Paul IA. Adaptive changes in the N-methyl-daspartate receptor complex after chronic treatment with imipramine and l-aminocyclopropanecarboxylic acid. J Pharmacol Exp Ther 1993; 265: 1380-6. 68. Colebatch JG, Deiber MP, Passingham RE, Fnston KJ, Frackowiak RSJ. Regronal cerebral blood flow durmg voluntary arm and hand movements in human subjects. J Neurophysiol 1991; 65: 1392-401. 69. Zeki S, Watson JD, Lueck CJ, Friston KJ, Kennard C, Frackowiak RS. A direct demonstration of functional specialization in human visual cortex. J Neurosci 1991; 11: 641-9. 70. Squire LR, Ojemann JG, Miezin FM, Petersen SE, Videen TO, Raichle ME. Activation of the hippocampus in normal humans: a functional anatomical study of memory. Proc Natl Acad Sci USA 1992; 89: 1837-41. 71. George MS, Ketter TA, Post RM. SPECT and PET imaging In mood disorders. J Clin Psychiatry 1993; 54 (SuppI): 6-13. 72. Teitler M, Herrick-Davis K. Multiple serotonin receptor subtypes: molecular cloning and funchonal expression. Crit Rev Neurobiol 1994; 8: 175-88.

DISCUSSION Participant: What is the role of dopaminergic effects during treatment with the SSRIs? Dr. Kilts: Sertraline is unique among the SSRIs because of its effect on the dopamine neurotransporter in the central nervous system (CNS). The effects of sertraline on dopamine reup-

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take are similar to cocaine. Because of these potential dopaminergic effects with sertraline, alternative therapy should be sought when treating patients with psychotic depression. Participant: Why are selective monoamine oxidase inhibitors (MAOIs), such as moclobemide or clorgyline, not better developed and nearer market in the United States? Dr. Kilts: This is a supply-and-demand issue; the availability of better antidepressant drugs has discouraged manufacturers from pursuing the development of more MAOIs. The MAOIs clearly have a place in the treatment of special patient subpopulations, such as treatment-refractory depression, but even improving on the original MAOIs by developing selective agents does not provide therapy as well tolerated as other currently available agents. Participant: Why do some patients who fail therapy with an SSRI respond to a TCA? Is this differential response related to better enhancement of serotonergic neurotransmission with the TCAs? Dr. Kilts: No. The differential response of antidepressants in the clinical setting must be viewed from a perspective of chronic adaptation of the CNS to drug therapy. There is much that is not known about long-term adaptation and the etiology of depression in individual patients. Because there is no common biochemistry of depression, there are many pathways toward effective treatment.

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