The dopamine hypothesis of schizophrenia revisited

Ps¥choneuroendocrinology,Vol.4, pp. 37 to 46. © Pergamon Preu Ltd. 1979.Printedin GreatBritain.

THE

DOPAMINE

0306-4530/79/0101-0037502.00/0

HYPOTHESIS

OF

SCHIZOPHRENIA

REVISITED DANIEL P. VAN KAMMEN Unit Chief, Section on Neuropsychopharmacology, Biological Psychiatry Branch, NIMH, 9000 Rockville Pike, Bldg 10, Rm 4N214 Bethesda, MD 20014, U.S.A. (Received 31 August 1978)

SUMMARY (1) The effects of antipsychotic agents in blocking dopamine (DA) receptors and the similarity between paranoid schizophrenia and amphetamine-induced psychosis have opened new research areas in schizophrenia. (2) This paper reviews studies on the hypothesized role for DA in schizophrenia, specifically defects in the DA system including receptor supersensitivity and other dysfunctions. (3) While clinical studies seem to support the DA hypothesis, evidence from the evaluation of spinal fluid homovanillic acid (HVA), dopamine~13-hydroxylasc(DBH) and plasma prolactin has been inconclusive. (4) Schizophrenic symptoms fluctuate with central DA activity and some positive brain autopsies appear to support the notion of dysfunctional DA systems. (5) Increasing evidence suggests that other neurotransmitters or modulators of DA activity, such as amino acids (e.g. GABA), amines (norepinephrine) or peptides (endorphins), may be involved in the regulation of psychosis. (6) The author suggests that more specific presynaptic DA agonists and agents that specifically affect mesolimbic DA systems should be developed to test the DA hypothesis further. The mechanism of hgw DA activity affects schizophrenia has not yet been elucidated. Key Words--dopamine; schizophrenia; prolactin; CSF-homovanillic acid; dopamino-[~hydroxylase (DBH).

INTRODUCTION ALTHOUGH it was 25 yr ago that Delay & Deniker (1952) introduced chlorpromazine as the first effective pharmacological treatment of schizophrenia, the cause of schizophrenia still escapes us. However, the role of dopamine (DA) in the antipsychotic effects of neuroleptics has been well established (Carlsson & Lindqvist, 1963; Anden, Butcher, Corrodi, Fuxe & Ungerstedt, 1970). The classic report by Connell (1958) and the studies by Bell (1973); Griffith, Cavanaugh, Held & Oates (1972) and Angrist, Sathananthan, Wilk & Gershon (1974b) have shown that high doses of drugs that increase D A and norepinephrine (NE) activity, such as amphetamine, can induce a psychosis that is hard to differentiate from paranoid schizophrenia. The assumed role of D A i n these drug effects has led to theformulation of the D A hypothesis and to a systematic approach in the study of schizophrenia. The D A hypothesis postulates an increased D A activity in the brain of schizophrenic patients. Because this hypothesis has been reviewed extensively (Meltzer & Stahl, 1976; Carlsson, 1978; Hartmann, 1976; Snyder, 1977), this paper will focus, instead, on recent attempts to test the D A hypothesis. The author will examine some of the negative and positive findings. In its most simple format, the hypothesis states that there is too much D A in the brain, either through an increased synthesis or a faulty feedback regulation (e.g. GABA) (van Kammen, 1977). Another formulation is that the D A receptors are supersensitive (Iversen, 37

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DANIEL P. VAN I(AMIVIEN

1974), i.e. that the number of DA postsynaptic receptors is increased. It is also conceivable that other substances in the brain affect DA receptor activity (regulatory systems) or the postsynaptic neuron (e.g. peptides). Most research has focused upon the first two formulations of the hypothesis. The different DA systems that have been identified in the brain are: (a) the nigro-striatal pathway, the largest DA system that regulates extrapyramidal motor behavior. This pathway has been identified as the anatomical site of Parkinson's disease and of the extrapyramidal side-effects of antipsychotic agents; (b) the meso-corticol and the meso-limbic pathways originating next to the substantia nigra. These pathways presumably regulate emotional behavior and are postulated to be the DA systems involved with psychosis; and (c) the tubero-infundibular pathway that regulates release in a tonic inhibitory way of anterior pituitary hormones such as prolactin. BIOCHEMICAL EVALUATION At the present time direct access to the meso=limbic and meso-corticol pathways is not possible. Therefore, assessing homovanillic acid (HVA), the major DA metabolite in the cerebrospinal fluid (CSF), is the most direct measurement of DA activity in the brain (Meltzer & Stahl, 1976; Bowers, 1974; Post, Fink, Carpenter & Goodwin, 1975; Post & Goodwin, 1975). It can be assumed that the measured HVA in spinal fluid comes mainly from the nigro=striatal pathway. Homovanillic acid could reflect DA activity in the mesocorticol and meso=limbic pathways because these pathways are closely connected with the nigro-striatal pathway. Other measures include determination of serum prolactin levels that are raised by DA blockade and decreased by DA stimulation. Furthermore, a deficiency in central dopamine-~-hydroxylase (DBH), the enzyme which converts DA into NE, has been hypothesized to result in a relative increase in DA (Hartmann, 1976). This enzyme also can be measured in the CSF. Additional information from these indirect parameters of DA activity can be obtained by using pharmacological agents known to affect DA activity and, subsequently, used to relate the biochemical effects of these agents to clinical states, diagnostic subgroups or similar variables. SPINAL FLUID HVA Almost all reports indicate that baseline levels of HVA in patients with a variety of schizophrenic diagnoses do not differ from those of comparison groups. Bowers (1974) found the lowest HVA accumulation after probenecid in drug-free patients who were positive for first-rank Schneiderian symptoms and who had a poor prognosis. Post et al. (1975) reported that the HVA values of acutely psychotic patients after probenecid declined in good prognosis patients after remission. These findings of Bowers (1974) and Post et aL (1975) may be interpreted as an increased DA receptor activity in schizophrenia and decreased dopamine release in remitted and chronic patients--i.e, during remission normal regulatory mechanisms are restored with subsequent decreased DA turnover. This explanation, of course, needs to be tested but is consistent with Davis' (1974) formulation of the two-factor hypothesis. HVA is raised during the first two weeks by neuroleptics and then returns to baseline levels with chronic treatment. This rise of HVA indicates DA receptor blockade and

DOPAM~eH~rrI-ir~m or SCmZOPX-IRE~_A

39

coincides with the development and disappearance of extrapyramidal side-effects. Acute haloperidol greatly lowered GABA levels in animals during the same time that HVA was raised; as with GABA levels HVA returned to baseline on chronic treatment (Lloyd & Hornykiewicz, 1977). Van Praag (1977) reported that during the first week of neuroleptic treatment, as a result of DA receptor blockade, the percent increase in HVA after probenecid correlated significantly with global improvement. He also reported that patients who had delusions and hallucinations when drug-free had higher baseline HVA levels than other patient groups. It is conceivable that compensatory mechanisms normalize HVA and GABA levels during chronic neuroleptic treatment and that these compensatory mechanisms are involved in the sustained improvement (van Kammen, 1977). However, extensive longitudinal evaluation of HVA, before and after different doses and at different timepoints of neuroleptic treatment in treatment-responsive and unresponsive patients, has not been reported. POSTMORTEM STUDIES Postmortem brain studies have produced conflicting results. Seeman, Tedesco, Lee, Chau-Wong, Muller, Bowles, Whitaker, McManus, Tittler, Weinreich, Friend & Brown, 1978 and Crow, Johnstone, Longdon & Owen, 1978, reported data in support of DA postsynaptic (neuroleptic) receptor supersensitivity and normal "apomorphine" receptors in the limbic and striatal areas of schizophrenic autopsy brains compared to controls. Dopamine was found to be increased in the nucleus accumbens by Bird, Barnes, Iversen, Spokes, Mackay & Shepherd (1977) but not by Crow et al. (1978). Whether the DA receptor increase is drug-induced needs to be clarified, although some patients were off neuroleptics for 1 yr or more or had not received neuroleptics at all. Other areas like the amygdal nuclei need to be studied. Unfortunately, not all authors agree on the size and location of the nucleus accumbens for study. PROLACTIN RELEASE Prolactin release is under tonic inhibitory control of DA and can be increased by several other mechanisms including serotonin. No abnormalities in prolactin levels have been observed in drug-free psychotic or nonpsychotic schizophrenic patients (Meltzer & Stahl, 1976; Langer, Sachar & Gruen, 1978; Meltzer & Fang, 1976; Meltzer, Fang & Goode, 1978; Siris, van Kammen, DeFraites, Siris, Alexander, Docherty, Heykants & Bunney, 1978), suggesting that prolactin regulation is not disturbed in schizophrenic patients compared to normal controls. It is possible that the DA system that inhibits prolactin release is regulated in the same way as the mechanism that regulates psychotic behavior (Kolakowska, Wiles & McNeilly, 1975; Sedvall, Alfredsson, Bjerkenstedt, Eneroth, Fyro, Harnryd & WodeHelgodt, 1976; Siris et aL, 1978). Prolactin levels increase after the first dose of neuroleptic while it may take several weeks of treatment before the full antipsychotic effect takes place. After discontinuation of neuroleptics, prolactin levels decline to baseline within three days (Meltzer & Stahl, 1976; Kolakowska, et al., 1975), in contrast to changes in clinical state: e.g. relapse or exacerbation of psychosis can occur anywhere from a few weeks to many months after withdrawal.

40

DANIELP. VANKAZAN

This delay in the re-emergence of psychotic symptomatology is inconsistent with rebound supersensitivity of DA receptors but consistent with acute withdrawal dyskinesias (Tarsy & Baldessarini, 1974). The dissociation of late relapse and the early decrease in prolactin levels after neuroleptic withdrawal remain major challenges for the DA hypothesis. In studying a small group of patients, Meltzer et al. (1978) found a correlation between a decrease in psychosis and an increase in prolactin during the first 2 weeks of neuroleptic administration of up to 800 mg CPZ units. This correlation between change in psychosis and change in prolactin at different time-points of antipsychotic treatment has also been observed by Kolakowska et al. (1975), Sedvall et al. (1976) and Siris et al. (1978). Siris et al. (1978) reported that in a small group of male and female schizophrenic patients a decrease in psychosis and an increase in prolactin correlated after 4 weeks of pimozide treatment. However, this correlation was not found by Langer et al. (1978) and could not be repeated by Siris et al. (1978) in 5 additional male patients. One can question whether either the dose of neuroleptic, method of neuroleptic administration, time of blood sampling for prolactin, or the fact that there are different subgroups of schizophrenic patients played a role in the discrepancies. Sedvall et al. (1976) measured spinal fluid prolactin levels and suggested that the dose of neuroleptic need only be increased up to a maximum rise in prolactin--i.e. maximum DA receptor blockage--to achieve a later optimal therapeutic effect of neuroleptic treatment. In other words, maximal DA blockade can occur after a single dose of neuroleptic but chronic treatment is needed before this dose will lead to optimal therapeutic effects, suggesting that neuroleptic-induced symptomatic improvement is a secondary effect of DA blockade. At present, elevated prolactin levels after neuroleptic use may indicate only that the patient is complying with taking his drugs. DOPAMINE-I3-HYDROXYLASE IN CSF Further support for a DA disregulation disorder in schizophrenia comes from the hypothesis concerning low DBH in schizophrenia. Low DBH could lead to a relative excess of DA and a decrease in NE. This hypothesis is based upon animal studies and unconfirmed brain autopsy studies as formulated by Wise & Stein, (1975) and Hartmann, (1976). The role of low DBH in psychosis is supported by clinical studies done with DBH inhibitors in manic patients (Sack & Goodwin, 1974) and observations that alcoholic patients may become psychotic with disulfiram (Antabuse). Hartmann (1976) reported that he experienced perceptual disturbances when he took a combination of a DBH inhibitor and L-DOPA. We did not find DBH in the CSF of schizophrenics to be different from values of normals, depressed or alcoholic patients (Lerner, Goodwin, van Kammen, Post, Major, Ballenger & Lovenberg, 1978), nor did we observe an increased DA turnover in those schizophrenic patients with low DBH. A relative DBH deficiency is probably not of primary importance in schizophrenia; the presence of a subgroup of low DBH cannot be excluded at this time. This would be true only if our measurement of DBH in the CSF is indicative of the relative DBH activity in the brain. It is conceivable that central NE activity might have a secondary effect upon course, chronicity or symptomatology (Carlsson, 1978; Hartmann, 1976; Snyder, 1977), because "reactive" patients tended to have lower DBH activity. BEHAVIORAL STUDIES It is well established that DA receptor blockers have antipsychotic effects, although not

DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

41

every schizophrenic patient becomes completely symptom-free with neuroleptic drugs (Meltzer & Stahl, 1976). Individual differences in drug metabolism, duration of illness, extent of the hypothesized defect in DA activity regulation, or a different etiology, all could be responsible for lack of response in some patients. Blood level studies have not provided the clinician with the tools needed to determine the optimal therapeutic neuroleptic dose for each individual patient, presumably because of pharmacokinetic differences and because metabolites of these agents also have DA receptor blocking properties (Creese, Burt & Snyder, 1976; Seeman, Lee, Chau-wong & Wong, 1976). Recently, in two separate studies, Creese et al. (1976) and Seeman et al. (1976) reported a significant correlation between the clinical potencies of antipsychotic agents and their ability to replace 3H-haloperidol from its specific membrane-binding sites--i.e. DA receptors in antagonist formation. This correlation underscores the importance of DA receptor blockade in the antipsychotic effects of neuroleptics. This important observation is being extended into a radioreceptor assay measuring total levels of DA blockade in the blood of patients, which could lead to regulation of antipsychotic doses similar in significance to the lithium blood level determination for manic-depressive patients. After many years of uncontrolled clinical observations, Janowsky & Davis (1976), Angrist, Lee & Gershon (1974a), Angrist, Sathananthan, Shopsin & Gershon (1977), van Kammen, Bunney, Docherty, Jimmerson, Post, Siris, Ebert & Gillin (1977), Cesarec, Eberhard & Nordgren (1974) and Small, Kellams & Milstein (1977) have shown, in doubleblind studies, that direct and indirect DA agonists, such as amphetamine, methylphenidate, L-DOPA, ET-495 and lergotrile, considerably increase or induce psychotic symptoms in schizophrenic patients in doses thought to be too low to induce psychosis in nonschizophrenic subjects. Acute administration of neuroleptics has been shown to reverse the psychotogenic effects of DA agonists. On the other hand, we have confirmed the work of others that indirect or direct DA agonists actually may reverse the clinical effects of chronic neuroleptic treatment (Janowsky & Davis, 1976; Angrist et aL, 1976). The DA agonistinduced worsening of psychosis can be interpreted as a result of DA receptor supersensitivity or dysfunctional DA regulatory systems. Davis (1974) expanded the DA hypothesis into a two-factor hypothesis. Janowsky & Davis (1976) had observed no increase in psychosis after DA stimulation in some schizophrenic patients who were in stable remission. Davis noted that patients were more vulnerable to DA stimulation and subsequent symptom provocation during psychosis than during remission, indicating that DA stimulation, by itself, probably is not enough to induce psychosis, or that DA receptor supersensitivity only occurs during psychosis. DA receptor supersensitivity has been found after chronic neuroleptic treatment in the corpus striatum in animals. In man neuroleptic withdrawal does not lead to immediate re-emergence of psychosis in most cases. In our double-blind studies of amphetamine given 7 days after pimozide withdrawal--the time of postulated rebound DA receptor supersensitivity--we did not observe increased behavioral response to the amphetamine infusion compared to the amphetamine effects after much longer drug-free periods or during chronic pimozide treatment. The lack of increased response in psychosis after DA antagonist withdrawal suggests that there is no supersensitivity in the meso-corticol and meso-limbic pathways, unless slowly decreasing levels reverse this receptor supersensitivity. Sokoloff suggested

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DANIEL P. VAN KAMMEN

recently that D-amphetamine may not affect this meso-limbic DA system (Sokoloff, personal communication, 1978). Support for DA involvement is further enhanced by the work of Carlsson (1978) who reported that alpha-methyl-para-tyrosine (aMPT), an inhibitor of DA and NE synthesis, restored the optimal antipsychotic effects of thioridazine in patients who had become psychotic when therapeutic doses of this neuroleptic had been lowered. Nasrallah, Donnelly, Bigelow, Rivera-Calimlim, Rogol, Potkin, Rauscher, Wyatt & Gillin (1977) were unable to repeat these findings but they used different antipsychotic agents in a different clinical paradigm. Previous single-blind studies have shown that of 30 patients, 8 improved, 12 worsened and 10 did not change (Gershon, Hekimian & Floyd, 1967; Charalampous & Brown, 1967). However, aMPT induces DA receptor supersensitivity, which could explain the worsening and the lack of change. It is suggested that the potential therapeutic effects of ctMPT in schizophrenia should be studied further. In a previous report we reviewed the role of ~,-aminobutyric acid (GABA) in the feedback regulation of DA activity in the brain (van Kammen, 1977). GABA agonists depress DAinduced motor activity but facilitate DA-induced stereotypy in animals (Scheel-Kriiger, Cools & van Wel, 1977). If increased DA activity is present in schizophrenia, changes in GABA activity should change psychotic behavior. Clinical studies of drugs that increase GABA activity, such as D-cycloserine (Simeon, Fink, Itil & Ponce, 1970; Papeschi & Pugliese, 1965), muscimol, tested by us and others (Tamminga, Crayton & Chase, 1978a), lioresal (Simpson, Branchey & Shrivastava, 1976; Frederiksen, 1975) and GHB (Tanaka, Mukai & Takayanagi, 1966) usually have shown a worsening of psychotic symptoms in schizophrenic patients. These drugs do not induce a psychosis in nonschizophrenic subjects. Some chronic patients supposedly improve following the administration of these GABAergic drugs (Frederiksen, 1975; Tanaka, et al., 1966). Psychotic symptom changes by GABA agonists support the role for DA in schizophrenia. However, according to Lichstein, Dobkin, Ebstein, Biederman, Rimon & Belmaker (1978), Zimmer, Teelken, Zander & Ackenheil (1978) and our own unpublished data, GABA levels in the CSF of schizophrenic patients are not different from those of control groups. Zimmer et al. (1978) found an increase in levels by chronic antipsychotic treatment. Evaluation of GABA levels after acute neuroleptic treatment has not been reported. According to Snyder and Wyatt (personal communication, 1978) GABA receptors are not supersensitive in autopsy brains of schizophrenic patients. The GABA-DA connection is not yet fully understood (van Kammen, 1977). Not all behavioral studies of DA agonists have indicated a worsening in psychosis. Apomorphine and bromocryptine, both DA agonists, do not seem to induce psychosis (Angrist, Thompson & Shopsin, 1975; Corsini, Del Zompo, Manconi, Cianchetti, Manconi & Gessa, 1977). Some patients improved during acute or chronic treatment with amphetamine (van Kammen et al., 1977; Cesarec et al., 1974; Kiloh, Neilson & Andrews, 1974), L-DOPA (Inanaga, Nakazawa, Inoue, Tanaka & Ogawa, 1975; Gerlach & Luhdorf, 1975) or apomorphine (Corsini et al., 1977; Tamminga, Schaffer, Smith & Davis, 1978b). This has been explained (Corsini et al., 1977; Tamminga et al., 1978b) as being a result of a relative stimulation of presynaptic over postsynaptic DA receptors that leads to decreased DA synthesis and release and subsequently to less postsynaptic DA receptor stimulation.

DOPAMINE HYPOTHF~SOFSCHIZOPHRENIA

43

Other explanations include induction of subsensitive postsynaptic DA receptors (Friedhoff, Bonnet & Rosengarten, 1977) and activation of different types of DA receptor systems modulated by GABA as suggested by Cools & van Rossum (1976), Tye, Horsman, Wright, Large & Pullar (1977) and Scheel-Kruger et al. (1977). The behavioral effects of DA agonists and antagonists are consistent with the role of DA in maintaining psychotic symptoms. Because most DA agonists and antagonists also affect NE activity, an additive role for NE in schizophrenia certainly cannot be excluded at this time either (Carlsson, 1978; Hartman, 1976; Snyder, 1977; van Kammen et al., 1977). GABAergic drugs appear to be able to induce psychosis in stable, remitted schizophrenic patients, thus supporting the concept of disturbed DA activity regulation in schizophrenia. CONCLUSIONS Some of the biochemical evaluations in pharmacological studies have established an important role for D A in schizophrenia. Indirect measurements of D A activityin the brain, such as spinal fluidH V A , serum prolactin levelsand D B H in the CSF, have not indicated an increased DA activity in schizophrenic patients compared to controls. These measurements may not necessarily reflect DA activity in the limbic and cortical structures. There is some indication that fluctuations in certain parameters of central DA activity correlate with changes in mental states of schizophrenic patients. A monolithic DA hypothesis formulating that increased DA activity leads to schizophrenia appears to be too simplistic a notion. Furthermore, acute onset and continued frank psychosis with good initial neuroleptic response would suggest a DA receptor supersensitivity. Chronic schizophrenia may be related more to DA supersensitivity. Schizophrenia is, quite likely, a heterogenous disorder. The available biochemical approaches have not confirmed a DA disturbance as the primary etiology in schizophrenia. Pharmacological studies are still the major support for the hypothesis but do not necessarily indicate the primary locus of the defect. Because almost all DA active pharmacological agents also affect other systems, the relationships between regulatory systems such as NE, serotonin, GABA, substance P (Carlsson, 1977), endorphins (Biggio, Casu, Corda, Di Bello & Gessa, 1978) etc. and DA activity in schizophrenia await further evaluation. Paradoxical findings like improvement in schizophrenic symptoms following apomorphine, amphetamine or L-DOPA may be explained by presynaptic receptor stimulation or induction of subsensitivity of postsynaptic receptors. It is suggested that DA agonists that specifically stimulate presynaptic receptors other than apomorphine that cannot be used chronically (nephrotoxicity) should be developed. A role for different types of DA receptors cannot be excluded either (Cools & van Rossum, 1976). Better understanding of how the activity of DA systems in the brain is regulated is needed before we can accept fully the concept that schizophrenia is a disorder caused solely by increased dopamine activity.

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