[Show abstract][Hide abstract] ABSTRACT: Background and Objective: Because increased dopamine neurotransmission occurs with most antidepressants, and because antipsychotics cause behavioural supersensitivity to dopamine, short-term low-dose antipsychotic treatment was tested on depressed patients with an expectation of clinical improvement in the supersensitive phase following drug withdrawal.
Method: This was a randomized, double-blind, placebo-controlled study of 48 patients who met criteria for DSM-IV® Major Depressive Disorder, were in a Major Depressive Episode, and had a Hamilton Depression Rating Scale (HAMD) rating of ≥14. Half the participants received 0.25 mg oral haloperidol each day for 7 days, after which they received placebo daily for 4 weeks. The other half received placebo throughout the trial.
Results: One week after stopping the medication, the HAMD ratings of the drug-treated patients fell by 9.96 points, as compared to a reduction of 8.73 points in the placebo-treated patients, when comparing visits 1 and 4. There was no such difference when comparing visits 2 and 4. The differences were not significant, but indicated a trend.
One week after the medication was stopped, the Clinical Global Index fell 1.64 ± 0.18 units for the medication-treated patients, compared to 1.12 ± 0.26 units for the placebo group (P = 0.05). The regimen was well tolerated.
Conclusions: Seven days of an ultra-low dose of 0.25 mg haloperidol, followed by withdrawal of haloperidol, resulted in clinical depression improvement greater than placebo and significantly decreased psychomotor retardation, consistent with haloperidol-induced behavioural supersensitivity to dopamine.
Limitations: The sample was small. More patients are needed in a future study.
Journal of Affective Disorders 09/2014; 166:139–143. · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PET has been used to examine changes in neurotransmitter concentrations in the living brain. Pioneering PET studies on the dopamine system have used D2 and D3 receptor (D2/D3) antagonists such as (11)C-raclopride. However, more recently developed agonist radioligands have shown enhanced sensitivity to endogenous dopamine. A limitation of available agonist radioligands is that they incorporate the short-lived radioisotope (11)C. In the current study, we developed the (18)F-labeled D2/D3 receptor agonist (R)-(-)-2-(18)F-fluoroethoxy-N-n-propylnorapomorphine ((18)F-MCL-524).
In total, 10 PET measurements were conducted on 5 cynomolgus monkeys. Initially, the binding of (18)F-MCL-524 was compared with that of (11)C-MNPA in 3 monkeys. Second, the specificity of (18)F-MCL-524 binding was examined in pretreatment studies using raclopride (1.0 mg/kg) and d-amphetamine (1.0 mg/kg). Third, a preliminary kinetic analysis was performed using the radiometabolite-corrected arterial input function of the baseline studies. Finally, 2 whole-body PET measurements were conducted to evaluate biodistribution and radiation dosimetry after intravenous injection of (18)F-MCL-524.
(18)F-MCL-524 entered the brain and provided striatum-to-cerebellum ratios suitable for reliable quantification of receptor binding using the multilinear reference tissue model. Mean striatal nondisplaceable binding potential (BPND) values were 2.0 after injection of (18)F-MCL-524 and 1.4 after (11)C-MNPA. The ratio of the BPND values of (18)F-MCL-524 and (11)C-MNPA was 1.5 across striatal subregions. After administration of raclopride and d-amphetamine, the (18)F-MCL-524 BPND values were reduced by 89% and 56%, respectively. Preliminary kinetic analysis demonstrated that BPND values obtained with the 1-tissue- and 2-tissue-compartment models were similar to values obtained with the multilinear reference tissue model. Estimated radiation doses were highest for gallbladder (0.27 mSv/MBq), upper large intestine (0.19 mSv/MBq), and small intestine (0.17 mSv/MBq). The estimated effective dose was 0.035 mSv/MBq.
The (18)F-labeled agonist (18)F-MCL-524 appears suitable for quantification of D2/D3 receptor binding in vivo, and the results encourage extension to human studies. The longer half-life of (18)F makes (18)F-MCL-524 attractive for studies on modulation of the dopamine concentration-for example, in combination with simultaneous measurement of changes in blood-oxygen-level-dependent signal using bimodal PET/functional MRI.
Journal of Nuclear Medicine 05/2014; · 5.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adolf Meyer (1866-1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene mutations, brain injury, drug use (cocaine, amphetamine, marijuana, phencyclidine, steroids), prenatal infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors. While the dopamine neural pathway may be a final common route to many of the clinical symptoms, the components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal in schizophrenia patients who are in remission. Post-mortem findings, however, reveal more dimers of D1D2 and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to selectively label D2High receptors in humans. It is suggested that synaptic dopamine supersensitivity in schizophrenia is an attempt at compensation for the original damage by heightening dopamine neurotransmission pathways (preparing the organism for fight or flight). The dopamine overactivity is experienced subjectively as overstimulation, which accounts for some of the clinical symptoms, with attempts at dampening down the stimulation leading to still other symptoms. Reaction and counter-reaction may explain the symptoms of schizophrenia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2014; 48(1):155-160. · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The dopamine D2 receptor continues to be the major target for the treatment of schizophrenia and is one of many genes genetically associated with this disease. Recent data show that fewer short forms of the D2 receptor protein are synthesized if there is a genetic variant in the D2 receptor (with a T in rs 1076560 in intron 6). At the same time, at least six publications report that the binding of radioactive benzamides is reduced in the schizophrenia thalamus. A review of the benzamide pharmacology of the short and long forms of the D2 receptor shows that benzamides have a 2.4-fold higher affinity for the D2Short receptor relative to the D2Long form. Hence, the reduced amount of benzamide binding to the D2 receptors in the schizophrenia thalamus suggests that there is a reduced amount of D2Short receptors in this diseased region, and may possibly also mean fewer presynaptic terminals because that is where D2Short receptors mostly reside. If so, fewer presynaptic dopamine terminals in various brain regions may be the basis of the known behavioural dopamine supersensitivity in schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: It is known that schizophrenia patients are behaviorally supersensitive to dopamine-like drugs (amphetamine, methylphenidate). There is evidence for an increased release of dopamine, a slight increase of dopamine D2 receptors and an increase of dopamine D2High receptors in schizophrenia, all possibly explaining the clinical supersensitivity to dopamine. The elevation in apparent D2High receptors in vivo in schizophrenia matches the elevation in D2High receptors in many animal models of psychosis. The increased amounts of D2High receptors in psychotic-like behaviour in animals may result from a loss of control of D2 by various factors. These factors include the rate of phosphorylation and desensitization of D2 receptors by kinases, the attachment of arrestin to D2 receptors, internalization of D2 receptors, the rate of receptor de-phosphorylation, formation of D2 receptor dimers, and GTP regulation by various GTPases. While at present there are no statistically significant associations of any of these controlling factors and their genes with schizophrenia, investigation of D2High receptors in schizophrenia will require a new radioligand in order to selectively label D2High receptors in vivo in patients. Finally, haloperidol reduces the number of D2High receptors that are elevated by amphetamine, indicating that this therapeutic effect may occur clinically.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2013; · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia patients are behaviorally supersensitive to dopamine-like drugs such as amphetamine or methylphenidate, meaning that patients respond to such drugs with increased psychotic symptoms, as compared to control subjects. A basis of such supersensitivity may be an increased pre-synaptic release of dopamine or a post-synaptic elevation of D2 receptors or of D2High receptors in active stages of schizophrenia. While the pre-synaptic release of dopamine is normal in stable patients with schizophrenia, brain imaging studies find that D2 receptors are increased by an average of 5.8% in antipsychotic-free schizophrenia patients. It is possible that the behavioral supersensitivity may stem from more D2High receptors in schizophrenia. Although the antipsychotic/dopamine D2 receptor can exist in vitro in a state of high affinity for dopamine (as D2High), or in a state of low affinity for dopamine (as D2Low), there is no clear evidence that D2High states can be selectively labeled or stably exist in vivo. Nevertheless, two studies revealed an 80% increase in apparent D2High receptors in schizophrenia patients after reducing endogenous dopamine. The elevation in apparent D2High receptors in vivo in schizophrenia matches the elevation in D2High receptors in vitro in animal models of psychosis, including dopamine-supersensitive animals pretreated with amphetamine, marijuana, or phencyclidine, or animals with gene knockouts in various neurotransmitter pathways, including those for glutamate receptors. The elevation of D2High receptors in vitro and the increased apparent D2High receptors in vivo is consistent with behavioral dopamine supersensitivity in schizophrenia patients.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2013; · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The in vivo labeling and brain imaging of dopamine transporters measures the density of dopamine neuron terminals in the human caudate/putamen. A review of such studies shows that the long-term use of antipsychotics had no major effect on the density of the dopamine terminals in individuals who had no tardive dyskinesia, but had reduced the density in those patients with tardive dyskinesia. In addition, the normal loss of dopamine terminals in healthy individuals was approximately 5% per decade. However, this rate of cell loss was apparently increased by approximately three-fold, to about 15% per decade, in schizophrenia patients using antipsychotics on a long-term basis, as measured by the in vivo imaging of the dopamine transporters in the dopamine neuron terminals. While an apparent reduction in dopamine transporters may result from reduced expression of the transporters secondary to antipsychotic treatment, the seemingly increased loss rate is consistent with the accumulation of antipsychotics in the neuromelanin of the substantia nigra, subsequent injury to the dopamine-containing neurons, and the development of extrapyramidal motor disturbances such as tardive dyskinesia or Parkinson's disease.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/2013; · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 3,4-Dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) is compromised by motor side effects, such as dyskinesia and non-motor problems, including psychosis. Because of the marked reduction in brain dopamine in PD and the resultant dopamine D2 receptor supersensitivity, it is impossible to use standard potent dopamine D2 receptor antagonists such as haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of L-DOPA. Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism. CLR151 (100mg/kg p.o.) reduced L-DOPA-induced dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action. CLR151 (100mg/kg) also reduced psychosis-like behaviour (i.e. reduced apparent visual hallucinations by 78%). Nevertheless, this dose of CLR151 significantly reduced the duration of anti-parkinsonian action of L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2 dopamine receptor antagonists, with D2-off-rate values close to those for CLR151, are unlikely to be useful in the treatment of dyskinesia and psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2013; · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug-receptor interactions are traditionally quantified in terms of affinity and efficacy, but there is increasing awareness that the drug-on-receptor residence time also affects clinical performance. While most interest has hitherto been focused on slow-dissociating drugs, D(2) dopamine receptor antagonists show less extrapyramidal side effects but still have excellent antipsychotic activity when they dissociate swiftly. Fast dissociation of clozapine, the prototype of the "atypical antipsychotics", has been evidenced by distinct radioligand binding approaches both on cell membranes and intact cells. The surmountable nature of clozapine in functional assays with fast-emerging responses like calcium transients is confirmatory. Potential advantages and pitfalls of the hitherto used techniques are discussed, and recommendations are given to obtain more precise dissociation rates for such drugs. Surmountable antagonism is necessary to allow sufficient D(2) receptor stimulation by endogenous dopamine in the striatum. Simulations are presented to find out whether this can be achieved during sub-second bursts in dopamine concentration or rather during much slower, activity-related increases thereof. While the antagonist's dissociation rate is important to distinguish between both mechanisms, this becomes much less so when contemplating time intervals between successive drug intakes, i.e., when pharmacokinetic considerations prevail. Attention is also drawn to the divergent residence times of hydrophobic antagonists like haloperidol when comparing radioligand binding data on cell membranes with those on intact cells and clinical data.
Archiv für Experimentelle Pathologie und Pharmakologie 02/2012; 385(4):337-72. · 2.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The features of schizophrenia are consistent with increased sensitivity to endogenous dopamine. Animal models of schizophrenia reveal an increase in the in vitro proportion of striatal dopamine D2 receptors in the high-affinity state for dopamine (i.e., D2High), as measured by dopamine/[(3) H]domperidone competition. However, in vivo studies did not reveal the dopamine agonist [(11) C](+)PHNO to be elevated in amphetamine-sensitized rats. Also, no increase was found in the in vivo binding of [(11) C](+)PHNO in schizophrenia patients. This work was done to resolve the contradictory findings. It was found that the in vitro density of rat striatal D2 receptors was 18 pmol/g for [(3) H]raclopride and 12 pmol/g for [(3) H](+)PHNO; most of the latter sites disappeared in the presence of guanine nucleotide. Using 2 nM [(3) H](+)PHNO (K(d) of 0.72 nM at D2) to label D2 receptors in the striata and the human D2 clone, 10 nM to 100 nM dopamine inhibited 10-20% of the [(3) H](+)PHNO bound, representing high-affinity binding of [(3) H](+)PHNO, with the remainder inhibited above 100 nM dopamine, representing low-affinity binding of [(3) H](+)PHNO. It was found that (+)PHNO and (-)NPA dissociated from the D2 clone with half-times of 96 and 600 s, respectively. These rates are slower than the reported sub-second dissociation of the G protein from a receptor, suggesting that these two ligands still occupy the D2Low receptor after the G protein has separated. Thus, the radio-agonist label for (+)PHNO is not selective for dopamine D2High receptors, but also binds to the D2Low state of the dopamine receptor.
[Show abstract][Hide abstract] ABSTRACT: In the treatment of schizophrenia, all currently available oral antipsychotics are administered at least once daily, with strict adherence strongly encouraged to minimize risk of relapse. Based on a better understanding of the brain kinetics of antipsychotics, we have proposed a variation of this approach, "extended" dosing, which allows for intermittent but regular dosing.
We carried out a randomized, double-blind, placebo-controlled trial evaluating 35 individuals with DSM-IV-defined schizophrenia who had been stabilized on antipsychotic therapy. Over a 6-month interval, 18 subjects received their medication as usual (daily), while 17 received their antipsychotic therapy every second day (extended). Outcome measures included clinical scales to assess symptoms (Brief Psychiatric Rating Scale [the primary outcome measure], Calgary Depression Scale), illness severity (Clinical Global Impressions-Severity of Illness scale), and relapse (ie, rehospitalization) rates. Side effects were also assessed, including movement disorders (Barnes Akathisia Scale, Simpson-Angus Scale, Abnormal Involuntary Movement Scale) and weight. The study was conducted from February 2003 to July 2007.
Individuals in the extended dosing group were not at greater risk of symptom exacerbation, relapse, or rehospitalization; indeed, more rehospitalizations occurred in those receiving regular dosing. At the same time, though, there was no indication that side effects were significantly reduced in the extended dosing group.
These results challenge the long-standing dogma that oral antipsychotics must be administered daily in stabilized patients with schizophrenia. Further studies with larger samples are needed to replicate these findings, as well as to elucidate whether postulated clinical advantages can be established and determined to outweigh potential risks.
clinicaltrials.gov Identifier: NCT00431574.
The Journal of Clinical Psychiatry 08/2011; 72(8):1042-8. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although the precise cause of Alzheimer's disease is not known, the β-amyloid peptide chains of 40-42 amino acids are suspected to contribute to the disease. The β-amyloid precursor protein is found on many types of cell membranes, and the action of secretases (β and γ) on this precursor protein normally releases the β-amyloids at a high rate into the plasma and the cerebrospinal fluid. However, the concentrations of the β-amyloids in the plasma and the spinal fluid vary considerably between laboratories. The β-amyloids adsorb in the nanomolar concentration range to receptors on neuronal and glial cells. The β-amyloids are internalized, become folded in the β-folded or β-pleated shape, and then stack on each other to form long fibrils and aggregates known as plaques. The β-amyloids likely act as monomers, dimers, or multimers on cell membranes to interfere with neurotransmission and memory before the plaques build up. Treatment strategies include inhibitors of β- and γ-secretase, as well as drugs and physiological compounds to prevent aggregation of the amyloids. Several immune approaches and a cholesterol-lowering strategy are also being tested to remove the β-amyloids.
[Show abstract][Hide abstract] ABSTRACT: The dopamine D2 receptor is the common target for antipsychotics, and the antipsychotic clinical doses correlate with their affinities for this receptor. Antipsychotics quickly enter the brain to occupy 60-80% of brain D2 receptors in patients (the agonist aripiprazole occupies up to 90%), with most clinical improvement occurring within a few days. The D2 receptor can exist in a state of high-affinity (D2(High) ) or in a state of low-affinity for dopamine (D2Low).
The present aim is to review why individuals with schizophrenia are generally supersensitive to dopamine-like drugs such as amphetamine or methyphenidate, and whether the D2(High) state is a common basis for dopamine supersensitivity in the animal models of schizophrenia.
All animal models of schizophrenia reveal elevations in D2(High) receptors. These models include brain lesions, sensitization by drugs (amphetamine, phencyclidine, cocaine, corticosterone), birth injury, social isolation, and gene deletions in pathways for NMDA, dopamine, GABA, acetylcholine, and norepinephrine.
These multiple abnormal pathways converge to a final common pathway of dopamine supersensitivity and elevated D2(High) receptors, presumably responsible for psychotic symptoms. Although antipsychotics alleviate psychosis and reverse the elevation of D2(High) receptors, long-term antipsychotics can further enhance dopamine supersensitivity in patients. Therefore, switching from a traditional antipsychotic to an agonist antipsychotic (aripiprazole) can result in psychotic signs and symptoms. Clozapine and quetiapine do not elicit parkinsonism or tardive dyskinesia because they are released from D2 within 12 to 24 h. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to tardive dyskinesia. Future goals include imaging D2(High) receptors and desensitizing them in early-stage psychosis.
[Show abstract][Hide abstract] ABSTRACT: The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.