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Possible withdrawal from endogenous opiates in schizophrenia
... We excluded studies if they contained any of the following criteria: single-patient case reports [31][32][33][34][35], lack of placebo control [36][37][38][39][40][41][42][43][44][45], failure to specify direction of effect [38,[46][47][48][49][50][51][52][53][54][55][56][57], administration of mixed novel therapeutic drugs other than opioid antagonists (not including baseline antipsychotic treatments) [58], change in design midway through the study [59], inclusion of patients with mental illnesses other than schizophrenia, schizoaffective disorder, and schizophreniform disorder, and lack of stratification by diagnosis [60,61] (however, if a study did include patients with other mental illnesses but published the individual patient level data, we included the data only from patients who only carried a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, and excluded data from the patients with other diagnoses), and no English translation available for the full text [62]. Finally, if identical results from a single trial were published twice in two separate journals, we included only the results from the publication with the larger dataset in our analysis. ...
Current treatments for the symptoms of schizophrenia are only effective for positive symptoms in some individuals, and have considerable side effects that impact compliance. Thus, there is a need to investigate the efficacy of other compounds in treating both positive and negative symptoms. We conducted a meta-analysis of English language placebo-controlled clinical trials of naloxone, naltrexone, nalmefene, and buprenorphine in patients with schizophrenia to determine whether opioid antagonists have therapeutic efficacy on positive, negative, total, or general symptoms. We searched online databases Ovid Medline and PsychINFO, PubMed, EMBASE, Scopus, Cochrane library/CENTRAL, Web of Science, and Google Scholar from 1970 through February 2019. Following PRISMA guidelines, Hedges g was calculated for each study. Primary study outcomes were the within-subject change on any symptom assessment scale for positive, negative, total, or general symptoms of schizophrenia between active drug and placebo conditions. Thirty studies were included with 434 total patients. We found a significant effect of all drugs on all scales combined with both a standard random effects model: (g = 0.26; P = 0.02; k = 22; CI = 0.03–0.49) and a more inclusive bootstrap model: (g = 0.26; P = 0.0002; k = 30; CI = 0.11–0.51) and a significant effect on total scales with the bootstrap model (g = 0.25288; P = 0.015; k = 19; CI = 0.04–0.35). We also observed a significant effect of all drugs on all positive scales combined with both the random effects (g = 0.33; P = 0.015; k = 17; CI = 0.07–0.60) and bootstrap models (g = 0.32; P < 0.0001; k = 21; CI = 0.13–1.38). This evidence provides support for further testing in randomized clinical trials of a new class of non-D2-receptor drugs, based on opioid mechanisms, for the treatment of positive and negative symptoms of schizophrenia.
... On the other hand, the lack of a morphine effect in NALOXONE AND DRINKING 239 these experiments (i.e., a failure to find a bipolar effect) leaves open the possibility that decreases in consumption are due to a nonspecific effect such as nausea or general malaise following naloxone administration. Previous studies indicate that naloxone can produce a conditioned taste aversion (LeBlanc & Cappell , 1975 ;Stolerman, Pilcher, & D'Mello, 1978;Van der Kooy & Phillips, 1977), and there have been reports of nausea and dysphoria in humans given narcotic antagonists (Gitlin & Rosenblatt, 1978). It is possible that decreases in feeding, drinking, and self-stimulation all stem from a mild, nonspecific illness produced by naloxone, and this hypothesis cannot be ruled out on the basis of the data presently available. ...
Naloxone hydrochloride, in doses of.5 to 10 mg/kg intraperitoneally, reduced water consumption by rats fluid deprived for 24 h. Administered intracerebroventricularly, 100 micrograms of naloxone produced similar effects while doses of 50 micrograms or less had no effect. Naloxone (10 mg/kg) also reduced consumption of a palatable solution (10% sucrose, weight/volume) by nondeprived rats. Morphine sulfate (.5 to 2 mg/kg) failed to increase consumption.
... Similarly, an endogenous ligand of a putative LSD-serotonin receptor has been described in the cerebrospinal fluid of unmedicated psychotic patients (Mehl et al., 1977). Naloxone has been reported to reduce the auditory hallucinations in some schizophrenic patients (Gunne et al., 1977;Terenius et al., 1977;Watson et al., 1978) but has also been ineffective in other cases (Gitlin and Rosenblatt, 1978;Janowsky et al., 1977a, b;Davis et al., 1977). These and other reports of enhanced opiate-like material in the cerebrospinal fluid have raised speculations regarding an abnormal endogenous opiate associated with mental disease. ...
The narcotic antagonist naloxone was tested to determine its possible interaction with N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) in adult male Holtzman rats trained to press a bar on a fixed-ratio four schedule (FR 4 ), i.e., every fourth press earned a reward of 0.01 ml sugar sweetened milk. LSD (0.1 mg/kg) or increasing doses of DMT (1.0, 3.2, and 10.0 mg/kg) were administered i.p. to disrupt food-rewarded fixed ratio bar pressing in a dose related fashion. Pretreatment (5–10 min) with behaviorally ineffective doses of naloxone (1.0–5.6 mg/kg) dramatically enhanced the effects of DMT and LSD. The content of DMT in the brain and liver of rats injected with DMT alone (10 mg/kg) and with a 5 min pretreatment of naloxone (3.2 mg/kg) was determined by radiochemical analysis at 30 and 90 min after 14 C-DMT injection. There was no significant difference for either brain or liver 14 C-DMT levels when control DMT rats were compared with the naloxone pretreated rats. These results seem to rule out interference by naloxone with the metabolism of DMT as a mechanism of the observed behavioral potentiation. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/46408/1/213_2004_Article_BF00431949.pdf
It has been suggested that the endogenous opioid peptides, the enkephalins and endorphins, may play a part in the development of certain psychiatric diseases. If shown to be true this would represent a major breakthrough in academic psychiatry, opening the way to alternative therapy.
Hormones from the anterior and posterior lobes of the pituitary gland are essential for the regulation of peripheral endocrine organs, water metabolism, and other processes of importance in the maintenance of homeostasis. The release of anterior pituitary hormones is controlled by both releasing and release-inhibiting factors, produced in the hypothalamus and transported to the pituitary gland via the bloodstream (portal vascular system between hypothalamus and pituitary gland). Neurohypophyseal hormones produced in the hypothalamus are transported via neurons to the posterior pituitary lobe where they are stored.
The existence of specific opiate receptors in primate brain and pituitary (Kuhar et al., 1973) and of endogenous peptide ligands for these receptors (Goldstein, 1976; Wilkes et al., 1980) suggests that these endogenous opiates (endorphins) may have a role in regulating human behavior. In addition to possible involvement in nociception (Hosobuchi and Li, 1978; Oyama et al., 1980; von Knörring et al., 1979), a role of the endorphins in mental illness has been a focus of scientific interest. There are several reasons that suggest such a role: (1) endorphins and opiate receptors are found in brain areas thought to be important in regulating behavior (Watson et al., 1979); (2) there is an interaction of endorphins with neurotransmitter systems, especially dopamine (Van Loon and Kim, 1978; Watson et al., 1979), thought to be important in mental illness; (3) preliminary animal research has indicated a neurolepticlike effect of endorphins, based on alteration of conditioned avoidance behavior (de Wied et al., 1978a) and production of catalepsy (Bloom et al., 1976; Jacquet and Marks, 1976); and (4) the common exogenous opiate alkaloids (e.g., morphine, heroin) have psychoactive properties that include production of psychoticlike states or euphoria, as well as a reduction of symptoms in some psychopathologic states (Verebey et al., 1978).
Opiate receptor antagonists of the “pure” type include the parenterally administered naloxone and the orally effective naltrexone (Martin et al., 1973; Resnick et al., 1974). An early report suggested that the former decreased hallucinations in schizophrenic patients (Gunne et al., 1977). The latter is the subject of this review since it, like naloxone, competes with endorphins for opioid receptor sites (Greenstein et al., 1978). Naltrexone acts for approximately 72 hr (Martin et al., 1973) and seems to be particularly free of side effects and toxicity (Greenstein et al., 1976, 1978; Bradford and Kaim, 1977). This drug is rapidly and completely absorbed with peak plasma levels of parent compound in 1 hr and of active metabolite (β-naltrexol) in 2 hr without accumulation (Verebey et al., 1976). The use of naltrexone in schizophrenic patients was primarily an attempt to evaluate the role of endorphins and opiate cells in mental illness.
The discovery of opiate receptors in the human brain sparked the search for their endogenous ligands. Independently, Terenius and Wahlström (1975) and Hughes (1975) isolated the endogenous ligands. The important ligands are the two pentapeptides Met- and Leu-enkephalin (Hughes et al.,1975) as well as β-endorphin (β-lipotropin61–91). There is overwhelming evidence that the glycoprotein pro-opiocortin is the parent substance for both adrenocorticotropic hormone (ACTH) and β-endorphin (Mains et al., 1977). Enkephalins, on the other hand, may have a different precursor and may share a common precursor with growth hormone (Weber et al., 1978, 1979). Kangawa et al. (1979) have identified a new 15-residue peptide containing Leu-enkephalin in pig hypothalamus, termed α-neoendorphin. Thus, it appears that α-neoendorphin may be the parent substance of Leu-enkephalin. Recently, it has been reported that the adrenal gland contains a precursor polypeptide for enkephalins (Kimura et al., 1980). Shine and colleagues (1980), by employing gene cloning techniques, have manipulated bacteria to produce β-endorphins. This will provide in the future enough β-endorphins for clinical evaluations as well as toxicity studies inexpensively. As enkephalins are metabolized by a rapid cleavage of the tyrosine-glycine bond, attempts to protect against this cleavage have led to long-acting and more potent analogs. In addition, receptor binding affinity, an important factor for determining the activity of these molecules, can be increased by enhancing lipophilicity around the C-terminal amino acid.
The involvement of endogenous opioid peptides in the nurture of mental diseases is suggested by the following observations: 1.
β-Endorphin (β-EP) and enkephalins may act as neurotransmitters in the central nervous system (CNS) in a mediatory process that involves the inhibition of postsynaptic adenylate cyclase and the activation of guanylate cyclase (Gispen et al., 1977; Minneman and Iversen, 1976), or in a modulatory function that alters the response of neurons to the stimulatory effects of classical nonpeptide neurotransmitters. This last effect could be obtained by en-dorphin-induced modifications of the neuronal membranes, resulting in altered activity of specific enzymes involved in neuronal function. In this context β-EP could interfere with the activity of classical neurotransmitters, and therefore changes in the levels of these natural opioids could be responsible for the appearance and development of mental diseases. Enkephalins have been shown to inhibit the release of acetylcholine (ACh) in the hippocampus, of nora-drenalin (NE), dopamine (DA) and adenylate cyclase in the entire brain and especially in the striatum of rats (Kosterlitz and Hughes, 1975).
2.
A specific behavioral effect has been demonstrated in animals injected intracerebrally with β-EP, represented by a catatonialike condition with motor retardation and muscular rigidity, which is considered to be an anologue of human catatonia or of the extrapyramidal rigidity elicited in schizophrenics by neuroleptics (Bloom et al., 1976; Jacquet and Marks, 1976).
Tics are sudden, recurrent and stereotyped motor movements or vocalizations. Dopamine blockers are the main pharmacological agents used in the management of tics. Opioid antagonists have been reported to have been effective in the management of tics. In this article, two patients with chronic motor tic disorder are reported, whose symptoms were disappeared by using opioid substances.
Clinical endorphin research in schizophrenia has so far fanned out in the following directions: (a) studies of endorphin concentration in body fluids, and (b) studies of the effects in schizophrenic patients of opiate (endorphin) antagonists, and of endorphins and endorphin derivatives. The main results are reviewed in this paper. The conclusions drawn are:
(1)
Body fluid research has so far yielded no conclusive evidence of disrupted endorphin metabolism in schizophrenia. Technology for the measurement of small quantities of endorphins is, however, still deficient.
(2)
The opiate antagonist issue is controversial. One of the major problems is that the studies undertaken differ considerably from each other in patient selection, dose and route of administration, making comparisons difficult. Furthermore, only single dose studies have been reported; the results of repeated administrations may be different.
(3)
To date only β-endorphin, DTγE (a fragment of γ-endorphin) and FK33-824 (a synthetic met-enkephalin derivative) have been studied therapeutically. Of these, DTγE is the most interesting in scientific terms, firstly because, pharmacologically, it seems to be related to the ‘true’ neuroleptics, and secondly because its lacks morphinomimetic properties. The therapeutic potential of this substance, if confirmed, would therefore not be related to morphine-like activity but to a ‘genuine’ opiate-receptor-independent anti-psychotic action.
Synopsis Naltrexone is a long acting competitive antagonist at opioid receptors which blocks the subjective and objective responses produced by intravenous opioid challenge. It is suitable for oral administration, and has been studied as an adjunct for use in opioid addiction management programmes. In non-comparative clinical trials involving detoxified patients, oral naltrexone reduced heroin craving and between 23 and 62% of patients remained in treatment after 3 to 4 weeks. However, in two studies 32 to 58% of patients who continued in treatment were opioid-free between 6 and 12 months after stopping naltrexone. As might be expected studies involving highly motivated patients have shown this type of patient group to achieve greater treatment success rates during naltrexone therapy, and remain opioid-free longer than other groups of apprently less motivated patients. In addition, when naltrexone is combined with family support, psychotherapy and counselling, patients are more likely to remain opioid-free. Naltrexone produces a low incidence of side effects, with gastrointestinal effects being the most commonly reported symptoms. Thus, despite the overall high attrition rates from trials, in selected patient groups and in combination with appropriate support mechanisms and psychotherapy, naltrexone represents a useful adjunct for the maintenance of abstinence in the detoxified opioid addict. Pharmacodynamic Properties Naltrexone produces negligible opioid agonist properties, with no analgesic activity in the mouse and limited or no activity in rat writhing tests. In human studies there have been only isolated reports of agonist effects such as pupillary miosis, dysphoria and unpleasant sensations following naltrexone administration. In the rhesus monkey, intravenous naltrexone suppressed morphine self-administration and in the drug-dependent animal precipitated opioid withdrawal with a potency at least 12 times that of nalorphine and 2.5 times that of naloxone or cyclazocine. In post-addict volunteers, oral naltrexone 100mg produced 90% blockade of subjective and objective responses, including euphoria and reinforcement produced by intravenous heroin challenge at 24 hours, with the naltrexone antagonism of subsequent heroin challenges decreasing over 72 hours. In morphine-dependent subjects naltrexone was approximately 17 times more potent than nalorphine and twice as potent as naloxone, respectively, in precipitating an abstinence syndrome. Following daily oral administration, naltrexone 50mg attenuated the development of abstinence and dependence with a potency similar to that produced by cyclazocine 4mg orally in subjects dependent on 240mg of morphine per day. In opioid-dependent or detoxified patients and healthy volunteers, oral administration of naltrexone 25 to 100mg daily produced significant increases in plasma concentrations of β-endorphin, cortisol and luteinising hormone, equivocal changes in prolactin and testosterone concentrations, non-significant increases in adrenocorticotrophic hormone and no effect on follicle-stimulating hormone concentrations. Naltrexone is a competitive antagonist at opioid receptor sites. Following long term naltrexone administration to animals, marked increases in the numbers of putative brain opioid receptors, but not the σ subclass, were detected but these observations have not been reported in humans. In morphine-dependent animals, naltrexone produced supersensitivity to morphine in the locus coeruleus which is the central nervous system site believed to be involved in the genesis of opioid dependence. Pharmacokinetic Properties Oral administration of naltrexone results in rapid absorption with peak plasma concentrations of 19 to 44 μg/L being reached within 1 hour. Oral bioavailability was reported to range between 5 and 60%. Linear increases in the area under the plasma concentration-time curve (AUC) were observed for naltrexone and β-naltrexol (a metabolite of naltrexone) following oral administration of naltrexone 50, 100 and 200mg. There was no evidence of accumulation of naltrexone after multiple dosing in healthy subjects Naltrexone is 20% bound to plasma proteins and has an apparent volume of distribution of 16.1 L/kg after single doses and 14.2 L/kg after repeated administration. Metabolism of naltrexone is predominantly through reduction to 6β-naltrexol, which in common with other minor metabolites undergoes extensive glucuronide conjugation in the liver. Up to an estimated 60% of an oral dose reaches the systemic circulation, with 24-hour urinary recovery reported as conjugated naltrexone 18% and conjugated β-naltrexol 21%. The elimination half-life of orally administered naltrexone derived from urinary excretion data varied from 1.1 to 10.3 hours; the differences could be due to variations in enterohepatic recycling between subjects. The plasma concentration and elimination half-life of naltrexone, and to a lesser extent that of the main metabolite β-naltrexol, correlate with the degree of opioid antagonism as evidenced by the objective and subjective withdrawal signs produced following intravenous heroin administration. Therapeutic Trials In open and blinded dose-ranging studies oral naltrexone 20 to 200mg daily attenuated the responses to heroin challenge between 24 and 72 hour after naltrexone administration in most patients. Furthermore, it produced a reduction in craving and up to 85% of urine samples were found to be opioid-free. In non-comparative trials in patients detoxified from opioids, naltrexone 350 mg/week was administered in divided doses. Between 23 and 62% of patients remained in treatment after 3 to 4 weeks; when this group was followed up at 12 months 64% of naltrexone-treated patients were opioid-free compared to 39% in the control group. In 2 non-comparative studies 32 and 58% of patients who continued in treatment were opioid-free between 6 and 12 months after stopping naltrexone, 11 to 33% of urine samples were opioid-positive during naltrexone maintenance, and heroin use and craving was generally reduced, and in some patients eliminated. In non-comparative studies involving particularly motivated patients, such as those at risk of losing employment or liberty, only 18% were readdicted at 6 months after commencing naltrexone. Other non-comparative studies in which naltrexone was used in conjunction with behaviour and family therapy reported improved retention times and success rates, with 52% of these patients continuing in treatment programmes after stopping naltrexone compared with 12.5% of patients receiving naltrexone alone. Double-blind studies have demonstrated the effectiveness of naltrexone in reducing heroin self-administration and craving compared with placebo. Thus, patients receiving naltrexone injected 2 to 7.5% of available heroin whereas patients on placebo injected 57.5 to 100% of that available, which correlated with the number of urine samples positive for opioids. In a double-blind tolerability study, naltrexone produced 67 drug-related side effects compared with 298 for cyclazocine. From currently available preliminary clinical data there is no evidence to suggest that naltrexone 5 to 100mg daily improves the symptoms of Alzheimer’s disease, Parkinsonism, Huntington’s disease or schizophrenia. In addition, the effects of naltrexone on food intake and bodyweight are equivocal with further studies required to determine any potential of naltrexone as an anorectic. Side Effects Gastrointestinal symptoms, particularly nausea and vomiting, have been the most frequently reported side effects. Other reported effects include headaches, skin rashes, decreased mental acuity, depression, anxiety, and loss of energy. However, such symptoms are also observed in opioid naive subjects and during opioid withdrawal, and thus could be attributed to naltrexone inducing mild abstinence syndrome in certain patients. In obese patients naltrexone in doses up to 300mg produced elevations in serum transaminase enzymes 3 to 19 times greater than baseline values. However, following cessation of naltrexone treatment, values returned to baseline or below. Dosage and Administration Administration of naltrexone should not be initiated until the patient has been opioid-free for 7 to 10 days and the naloxone challenge test for opioid withdrawal is negative. If no abstinence signs are observed, following a preliminary dose of naltrexone 25mg, the rest of the daily dose is administered. Maintenance treatment regimen with naltrexone can be flexible where patients may receive naltrexone 50mg on weekdays and 100mg on Saturday or 100mg every other day, or 150mg every third day. Naltrexone is contraindicated in patients with acute hepatitis or liver failure and should not be used in patients receiving opioid analgesics.
Naloxone and naltrexone were compared neuropharmacologically, especially in several rodent models considered to be predictive of antipsychotic activity, since narcotic antagonists have been reported to be effective in the treatment of schizophrenia. Naltrexone was found to be a potent antagonist of amphetamine-induced aggregate toxicity in mice; this was in marked contrast to naloxone, which enhanced amphetamine's toxicity. Both naloxone and naltrexone exhibited an unusual profile of activity in the apomorphine-induced stereotypy test in mice in that they antagonized the chewing behavior but failed to antagonize the rearing; this is in contrast to the activity of standard neurolepitcs (e.g., haloperidol, clozapine) which antagonize both behaviors induced by apomorphine. Neither of the narcotic antagonists exhibited any activity in several other tests predictive of antipsychotic activity. Naltrexone was a potent inhibitor of spontaneous locomotor activity in mice; naloxone, although much weaker, also antagonized motor activity. Thus, endorphins may play a role in the modulation of exploratory or locomotor activity. The marked difference in activity between the two antagonists in the amphetamine aggregate toxicity study may indicate a significant neuropharmacological difference between these agents; i.e., naltrexone may be much more than merely a more potent naloxone. Furthermore, naltrexone's potent activity as an antagonist of amphetamine-induced aggregate toxicity in mice may be predictive of a better therapeutic effect in schizophrenia than has been observed with naloxone.
The response of plasma β-endorphin (ir) to infusions of randomly assigned d-amphetamine (20 mg) and placebo was studied in eight schizophrenic patients. Although there was no statistically significant difference between the response to d-amphetamine and placebo, significant increases in plasma β-endorphin (ir) levels were observed following each infusion. Although heterogeneity in β-endorphin (ir) response was observed, individual differences did not relate to clinical variables such as abnormalities on computed tomography or “process-reactive” distinctions. An excessive β-endorphin response to placebo in schizophrenia is discussed.
The field of opioid research took a large step forward with the development of technology that permitted the demonstration of opiate receptors in the brain in the early 1970s. This then led rapidly to the discovery of endogenous biologic peptides with opiate activity. Simon1 has coined the term “endorphin” to designate this new and exciting group of brain substances, and today there is much speculation that the endorphins may have a significant role to play in clinical psychiatry of the future.Early interest had been alerted by several striking findings from studies in opioid pharmacology that suggested that this group of compounds exerted their pharmacologic activities via specific receptors:2 namely, (1) astonishingly low doses of opiates put forth detectable pharmacologic action and etorphine, a morphinomimetic agent, (2) can exert a 5,000-to-10,000-times more potent action than morphine; (3) only the levoisomer of morphine is pharmacologically active indicating stereospecificity;3 and (4) pure opium antagonists that produce neither euphoria nor analgesia are available. By 1973, workers4–7 from several major centers around the world demonstrated the existence of specific opiate receptor binding sites on cell membranes, and a competitive race had begun to find those substances now called the endorphins.
Many experimental approaches have been devised to study the functions of endorphins. A strategy which has been used very widely consists in the administration of an opiate antagonist. It is assumed that the antagonists displace endorphins from their receptors; once this happens, any function for which endorphins are needed should be altered. It has been hypothesized that endorphins play a role in endocrine functions (see below), pain perception (BUCHSBAUM, DAVIS & BUNNEY, 1977; EL-SOBKY, DOSTROVSKY & WALL, 1976; GREVERT & GOLDSTEIN, 1978; HOSOBUCHI, ADAMS & LINCHITZ, 1977), modulation of mood (JONES, 1978), sexual functioning (GOLDSTEIN & HANSTEEN, 1977), mental health (WATSON et al., 1978; VEREBEY, VOLAVKA & CLOUET, 1978) and other areas. These hypotheses were tested by the administration of the opiate antagonist naloxone. Another opiate antagonist, naltrexone, has also been used for similar experiments: it was administered to rats in order to study the function of endorphins in prolactin release (GUIDOTTI & GRANDISON, 1978); it was also used in therapeutic experiments in psychotic patients (SIMPSON, BRANCHEY & LEE, 1977; GUNNE & TERENIUS, 1978; GITLIN & ROSENBLATT, 1978).
A factor in the urine of schizophrenic patients has been investigated for its effects on uptake of monoamines in crude synaptosomal preparations and on behaviour in rats. Urine from seven schizophrenic patients was precipitated with benzoic acid and fractionated on Sephadex G 25, P 2 gels and Fractogel, and characteristic patterns of peptide and protein-associated peptide complexes were found. One factor which showed marked biological activity (factor 3b2) was further studied. This factor strongly inhibited uptake of [3H]dopamine into hypothalamic and striatal synaptosomes, and slightly reduced this uptake in hippocampal synaptosomes, uptake of [14C]5-hydroxytryptamine was also some-what reduced in synaptosomes from these three structures.When injected intracerebroventricularly in rats factor 3b2 produced a characteristic behavioural syndrome, including transient ‘explosive motor behaviour’, autonomic changes, long-lasting (at least 3 weeks) ‘catalepsy’, rigidity and loss of righting reflexes. Pain sensitivity was greatly reduced, and body temperature initially rose and then it was reduced for several days. Rats with unilateral 6-hydroxydopa-mine-induced lesions of the nigrostriatal dopamine pathway showed turning ipsilateral to the lesion after injections of factor 3b2. Behavioural effects (except the autonomic effects) were partly or completely blocked by pretreatment with the opiate receptor blocker naloxone, and several of the behavioural effects were also blocked by the dopamine receptor blocker haloperidol. Repeated injections of factor 3b2 resulted in the development of tolerance, as well as cross tolerance with morphine.It was concluded that schizophrenic patients excrete in the urine peptides or peptide-like factors which have strong opiate receptor stimulating effects, and which also result in dopaminergic stimulation. The possibility that this factor is of importance in the pathogenesis of schizophrenia is discussed.
Naltrexone is a long acting competitive antagonist at opioid receptors which blocks the subjective and objective responses produced by intravenous opioid challenge. It is suitable for oral administration, and has been studied as an adjunct for use in opioid addiction management programmes. In non-comparative clinical trials involving detoxified patients, oral naltrexone reduced heroin craving and between 23 and 62% of patients remained in treatment after 3 to 4 weeks. However, in two studies 32 to 58% of patients who continued in treatment were opioid-free between 6 and 12 months after stopping naltrexone. As might be expected studies involving highly motivated patients have shown this type of patient group to achieve greater treatment success rates during naltrexone therapy, and remain opioid-free longer than other groups of apparently less motivated patients. In addition, when naltrexone is combined with family support, psychotherapy and counselling, patients are more likely to remain opioid-free. Naltrexone produces a low incidence of side effects, with gastrointestinal effects being the most commonly reported symptoms. Thus, despite the overall high attrition rates from trials, in selected patient groups and in combination with appropriate support mechanisms and psychotherapy, naltrexone represents a useful adjunct for the maintenance of abstinence in the detoxified opioid addict.
We utilized a naloxone challenge strategy to investigate the functioning of the endogenous opioid system (EOS) in schizophrenia. Patients with schizophrenia, who were on neuroleptic medication or drug-free, demonstrated a significantly larger serum cortisol response to opioid blockade by naloxone than did age- and sex-matched normal controls. Patients, but not normal controls, also demonstrated an inverse relationship between baseline cortisol and the magnitude of the response. This enhanced cortisol response is consistent with tonic hyperactivity of the EOS in schizophrenia.
Naloxone and related opioid antagonists have been shown to have therapeutic utility in a variety of conditions. The effects of opioid antagonists in either physiological or pathological processes are most clearly seen when there is excessive occupancy of opioid receptors, as in opiate overdose. Opioid antagonists are also able to reverse several types of cardiovascular shock, conditions in which endogenous opioids appear to be mobilised, resulting in increased opioid receptor occupation. There are also more controversial circumstances in which excessive occupation of opioid receptors may assume pathological significance, such as hypercapnia. Opioid antagonists could be useful in such a situation by re-sensitising the respiratory centres to carbon dioxide.
There is some evidence that opioid antagonists may benefit some schizophrenic and manic-depressive patients, suggesting that an endogenous opioid ligand might cause disturbances in mental functioning. The diversity and complexity of opioid mechanisms in the central nervous system suggest that more specific opioid antagonists could be more selective in altering physiological or pathological functioning.
Since the discovery of endorphins, a number of hypotheses relating these substances to mental illness have been formulated; these hypotheses are discussed in other on the in this volume. The administration of opioid antagnoists has been used as a tool to test some of these hypotheses. This strategy is based onthe displacement of endorphins from the receptors; the functions that are affected by endorphins are thus altered. Unfortunately, opioid antagonists have many other effects besides the displacement of endorphins. These confounding effects will be discussed later. The naloxone effect alone cannot automatically be accepted as a proof of endorphin involvement. Naloxone has psychological, neurophysiological, and endocrinological effects in normal man. We should expand our knowledge of naloxone effects in normal subjects if we want to understand its action in mental illness.
Naltrexone, a long acting opiate antagonist, and placebo were administered to eight schizophrenics in doses of 200 mg per day for 1 week in a double-blind, crossover design. No improvement was noted, and no side effects resembling the opiate withdrawal syndrome with naltrexone were found. Naltrexone does not appear to alter schizophrenic symptomatology.
In the past 20 years, research into biochemical determinants of disturbed behavior has focused mainly on the central monoamines (MA). Other central transmitters either did not fulfill these criteria, or did so only to a partial extent. An example is acetylcholine. The discovery of the neuropeptides was of importance to biological psychiatry for two reasons. The first is a general reason: neuropeptides represent a new principle in neurobiology, that of hormone-like compounds produced in the brain, whose target is the brain. The second is a specific biological psychiatric reason: the neuropeptides have added a new dimension to human brain and behavior research, supplementary to the MA dimension. This chapter discusses the relation between neuropeptide and MA systems.
Considerable progress has been made in increasing the formal correctness of outcome research in schizophrenia by employing strict methodologic standards. However, based on a recent review of the literature, the authors note that insufficient attention has been directed toward the meaningfulness of such research. The interest of a particular study derives from its application beyond the specific patients treated; lack of attention to meaningfulness encourages the researcher to posit unjustified or overly generalized conclusions, resulting in the widespread adoption of questionable treatment strategies or the dismissal of potentially useful ones. Increased attention to meaningfulness will make the conclusions of this type of research more valuable, both from pragmatic and theoretical standpoints.
Since 1975, different morphinomimetic peptides have been isolated from hypophyseal-hypothalamic extracts: the pentapeptides methionine-enkephalin and leucine-enkephalin, and the longer peptides alpha-, beta- and gamma-endorphin. The primary structure of most of these peptides is also present in that of beta-lipotropin. The morphinomimetic properties of endorphins can be blocked with opiate-antagonists. In rats, moreover, the endorphins influence behavior which cannot be blocked with opiate antagonists. On the basis of the hypothesis that hyperactivity of endorphin systems may be involved in the pathogenesis of schizophrenia and manic syndromes, the effect of opiate antagonists on psychotic and manic symptoms has been examined in a number of clinical studies in the past few years. A transient therapeutic effect has been demonstrated in about 30% of the patients so treated. Our own double-blind controlled study of 5 schizophrenic and 5 manic patients in the context of a World Health Organization project failed to reveal any therapeutic effect after subcutaneous injection of 20 mg naloxone. The possible reasons of the negative results are discussed.
Proper diagnosis of comorbid disorders is crucial in treatment planning for the dually diagnosed. Since psychoactive substance use can obfuscate the diagnosis, special care must be taken to exclude organically based syndromes. Adequate periods of abstinence should first be achieved and subsequently the patient re-examined for residual symptoms compatible with a nonaddictive, nonsubstance-induced psychiatric disorder. The integration of concurrent treatment of both the mental and the addictive disorders appears to be the best approach for treatment of comorbid psychiatric and addictive disorders. An abstinence-based model that typically utilizes a 12-step group therapy is often employed for the addictive illnesses. Other forms of psychosocial therapies such as case managers are being used as well. Presently, physicians' prescribing practices for comorbid addicted patients are based on traditional approaches to use of medications in psychiatric patients, and their attitudes towards addictive disorders may play a significant role in determining the overall success of treatment.
This study was conducted to determine whether the addition of naltrexone to ongoing neuroleptic treatment would facilitate the reduction in positive or negative symptoms in patients with schizophrenia. Twenty-one patients meeting DSM-III criteria for schizophrenia were enrolled; all patients had been stabilized for at least 2 weeks on their dosage of neuroleptic medicine before entering the study. Patients were randomized to receive either placebo or naltrexone 200 mg/day for 3 weeks in addition to their neuroleptic. Patients randomized initially into the placebo arm were crossed over to receive naltrexone in a single-blind fashion for 3 additional weeks. All patients were rated weekly with the Brief Psychiatric Rating Scale (BPRS). Fifteen patients received placebo and six received naltrexone in the first 3 weeks. No significant effects of naltrexone on total BPRS scores or BPRS subscale scores were observed. Patients who received naltrexone on a single-blind basis at the end of the placebo-controlled trial demonstrated a transient exacerbation in negative symptoms as reflected by the total BPRS score and the BPRS Withdrawal-Retardation subscale score. Repeated-measures analysis of variance (ANOVA) on the BPRS total score of the subsequent treatment with naltrexone showed a trend for a significance in the drug by time effect. Repeated-measures ANOVA on the BPRS Withdrawal-Retardation subscale of the subsequent treatment with naltrexone showed a significant drug by time effect. The current data failed to indicate a clinical benefit when naltrexone was added to the neuroleptic regimen. Other potential applications of naltrexone in schizophrenia are addressed.
Diagnostic criteria for 14 psychiatric illnesses (and for secondary depression) along with the validating evidence for these diagnostic categories comes from workers outside our group as well as from those within; it consists of studies of both outpatients and inpatients, of family studies, and of follow-up studies. These criteria are the most efficient currently available; however, it is expected that the criteria be tested and not be considered a final, closed system. It is expected that the criteria will change as various illnesses are studied by different groups. Such criteria provide a framework for comparison of data gathered in different centers, and serve to promote communication between investigators.
Naltrexone (EN-1639A) is approximately 17 times more potent than nalorphine as an antagonist in man. It is virtually devoid of agonistic activity, including the ability to induce nalorphine-like dysphoric effects. Its duration of action is longer than that of naloxone, but shorter than that of cyclazocine. It is effective orally. When administered in a dose level of 50 mg/day, it produces a degree of blockade of the effects of morphine and heroin that is comparable to that obtained with 4 mg of cyclazocine per day orally. Naltrexone, thus, appears to be a relatively pure potent narcotic antagonist which is effective orally and which may have utility in the treatment of heroin and narcotic dependence.
The endogenous morphinomimetic brain peptides Met5-enkephalin and alpha-, beta-, and gamma-endorphins have been evaluated in rats after intracerebrospinal fluid injection. beta-Endorphin produces marked, prolonged muscular rigidity and immobility similar to a catatonic state, counteracted by the opiate antagonist naloxone; this effect occurs at molar doses 1/100 to 1/400 that at which the other peptides or morphine block the response to painful stimuli. All peptides evoked dose-related, naloxone-reversible, wet-dog shakes in rats that had not been exposed to drugs. beta-Endorphin produced hypothermia, whereas gamma-endorphin produced hyperthermia. Such potent and divergent responses to naturally occurring subtances suggest that alterations in their homeostatic regulation could have etiological significance in mental illness.
In a single-blind pilot study 0.4 mg naloxone i.v. was found temporarily to reduce or abolish auditory hallucinations in four cases of chronic schizophrenia whereas saline was without effect. In one of these patients there was a similar reversal also of her visual hallucinations. Two additional cases who denied hearing voices before the injections, reported no subjective effects.
An ascending series of single doses of the narcotic antagonist naltrexone, ranging from 20 to 160 mg, was administered to 8 abstinent former addicts in order to assess agonistic activity and any toxic side effects. There was little alteration of normal body function. Significant, but small, changes in sublingual temperature (0.4 degrees F decrease), and diastolic blood pressure (1.7 mm Hg increase) were induced. Among the battery of tests assessing behavioral or mood-feeling variables, only 2 showed significant between-condition effects: facilitated performance on the Cross-out Test (attention and perception), and a dose-related decrease in Morphine-Benzedrine Group (MBG) scores of the Addiction Research Center Inventory (ARCI) (mild euphoria). On the whole, subjects had few subjective reactions or unpleasant side effects. Naltrexone appears to be a safe, nontoxic medication in the dosage range examined.
The specific narcotic antagonist naloxone (0.4 milligram) was given intravenously to seven chronic schizophrenics who reported that they had very frequent auditory hallucinations. Saline solution was used as a placebo. The coded study did not reveal any effect of naloxone on hallucinations or on global psychopathology.
We have not been able to confirm the report of Gunne and associates that naloxone has antihallucinogenic properties. It is significant that our patients, like those of Gunne and associates, were receiving neuroleptics and were severely and chronically ill. Thus in our eight subjects naloxone does not seem to have immediate antipsychotic and antihallucinatory effects when administered in I.V. doses of 1.2 mg.
The narcotic antagonist EN 1639A (naltrexone) was studied in 37 heroin addicts and found to be clinically useful, with a low incidence of side effects, a lack of toxicity, a high degree of acceptability to the patient, and the capacity to antagonize the euphoric effects of heroin for up to 72 hr after a single oral dose. These findings provide a basis for expanding studies of the clinical efficacy of naltrexone in the treatment of opiate dependence.
SYNOPSIS
At least for heuristic purposes, certain operationally definable concepts of conditioning theory can serve as a framework for research on ‘drug dependence’ both in man and in animals: primary and secondary pharmacological reinforcement, either of which may be direct (‘psychic’) or indirect (‘physical’); and social reinforcement (‘cultural’).