- Email: [email protected]
Brain spect in drug research and development (DRD): Recent advances
$138
S.18. Recent advances in brain imaging in psychopharmacology
related decline in healthy volunteers studied between age 18 and 84. 3. There appears to be a gender-related difference in brain 5-HT synthesis in healthy volunteers. 4. Brain 5-HT synthesis is reduced during a dietary depletion of the precursor tryptophan (Nishizawa et al. 1997), and increased when 02 tension is raised from below normal (less than 80 mmHg) to supra-physiological levels (over 200 mmHg). 5. Medication-flee patients suffering from major depression exhibit reduced ]lC-ctMTrp trapping in the Anterior Cingnlate cortex, a brain area known to play a role in the regulation and expression of mood and other amotivational syndromes. 6. 11C-ctMTrp trapping is significantly reduced in medial prefrontal, orbital frontal and temporal cortices, as well as anterior cingulate in patients endowed with emotional lability and high impulsivity; i.e., cluster B personality disorders. 7. Reduced 11C_~MTrp trapping in prefrontal and orbital frontal cortex is also seen in subjects selected on the basis of having recently made (within 2 weeks) a high lethality suicide attempt. 8. Symptomatic improvement in OCD, obtained in the course of SSRI or CBT monotherapy, is associated with a significant increase in 11C-c~MTrp trapping. 9. Subjects with a history of MDMA abuse exhibit a marked reduction in 11C_ctMTrp trapping in Raphe Neurons and Basal Ganglia, suggesting neurotoxicity to 5-HT fibers in humans. In summary, though still in its infancy, the H C-~tMTrp/PET method is gradually establishing itself as one of the few available techniques permitting the assessment in oivo of aspects of tryptophan metabolism/5-HT synthesis in the human brain. That many of the validation studies conducted in healthy volunteers, as well as some of the exploratory measurements obtained in clinical samples, appear consistent with predictions derived from animal work and current knowledge of 5-HT physiology and pathophysiology is promising.
References [1] Chugani DC, Muzik 0. J Cereb Blood Flow Metab 2000;20:24. [2] Diksic M, Nagahiro S, Sourkes TL, Yamamoto YL. J Cereb Blood Flow Metab 1990; 10:1-12. [3] Diksic M, Young SN. J Neurochem 2001;78:1185-1200. [4] Leyton M, Okazawa H, Diksic M, Paris J, Mzengeza S, Young SN, Blier P, Rosa P, Benkelfat C. Am JPsychiatry 2001; 158:775-782. [5] Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza, S, de Montigny C, Blier P, Diksic M. PNAS 1997;94:5308 5313. [6] Shoaf SE, Carson R, Hommer D, Williams W, Higley JD, Schmall B, Herscovitch P, Eckelman W, Linnoila M. Neuropsychopharmacology 1998;19:345 353. [7] Tohyama Y, Takahashi S, Merid ME Watanabe A, Diksic M. Neurochem lnt 2002;40:603~510.
•
Brain spect in drug research and development (DRD): Recent advances
A.M. Catafau. GlaxoSmithKline, Barcelona, Spain The development of a drug is a time-consuming, extremely expensive and risky process. This risk is especially high when considering new drugs for neuropsychiatric diseases, since many of these diseases are exclusively human, and therefore animal models are limited or nonexistent. The consequence of inadequate information during the first steps in drug development may be the failure of the candidate compound at later stages, even after launch, when large amounts of time and money have already been invested. Brain emission tomography can help in this process.
PET is the king technique in this field due to the high accuracy of measurements, image resolution, and feasibility of labeling drugs with positron emitters such as llC. However, SPECT is more and more being considered a valuable tool for DRD due to its wider availability and lower cost, which allow the study of larger samples of subjects. Both perfusion (functional) and neurotransmission (biochemical) SPECT modalities can actually contribute to DRD. Cerebral perfusion SPECT has been demonstrated to provide insight into the pathophysiology of psychiatric diseases, and contributes to the study of pharmacological effects on the human brain. Biochemical SPECT imaging has a great potential in psychopharmacology RD, as long as new radioligands for different neurotransmission systems are being developed. SPECT is useful in identifying new targets (i.e. new mechanisms involved in the disease) and therefore in suggesting new opportunities for treatment. It also helps to the proof of concept of neuropsychiatric drugs by demonstrating central effect of the drug either directly using neurotransmission SPECT to identify occupancy of receptors/transporters and drug-radioligand displacement studies, or indirectly, by imaging changes in cerebral perfusion induced by the drug. This approach may help to establish whether new drugs are likely to be therapeutically effective. Using labeled ligands, biochemical neuroimaging can provide insight into the mechanism of action of the drug. This can be achieved by determining the interaction of the drug with a desired binding site at the synapse level, which can be a receptor, a transporter or a enzyme, or by indirectly measuring neurotransmitter concentration. Examples are the growing number of 123I-IBZM SPECT studies on dopaminergic D2 receptor occupancy mapping induced by different antipsychotics, which can be done either at a single time point or over time. These receptor occupancy studies are important, since antipsychotic dosage tailoring is very difficult, and rational drug dosing is one of the critical and risky decisions in the pharmaceutical industry. Measurement of endogenous neurotransmitter concentration changes can be performed by measuring the radioligand displacement after a drug challenge. The most known example is the decreased D2 receptor availability measured by 123I-IBZM SPECT after injection of amphetamine. The percentage of decrease of 123I-IBZM uptake is proportional to the amount of endogenous dopamine released, and correlates with the intensity of the behavioral responses to the amphetamine administration. These studies are helpful in checking the effects of new drugs on endogenous dopamine release, which seem to have a promising future in the control of drug addictive behavior. Finally, SPECT has also a role in the study of drug pharmacodynamics. Pharmaceutical interactions in the synapse imply brain metabolic changes, and therefore cerebral blood flow changes, which determine the final effect for CNS drugs, being a modified behavior. To measure drug induced cerebral blood flow changes, a baseline study (in naive conditions) is necessary prior to the SPECT study on medication. Test-retest values should be used to validate results. Feasibility of SPECT studies during cognitive activation makes possible the assessment of drug effects on cognition. The drug induced cerebral perfusion changes can be related to clinical parameters, such as the score in psychopathological scales. In conclusion, brain SPECT is a low cost and available technique that contributes to DRD from the early stages such as target identification to the proof of concept - first time in human, giving information on drug mechanism of action and pharmacodynamics. Both cerebral perfusion and neurotransmission images are useful. Although several neurotransmission systems can already be imaged by SPECT,
S. 19. Better antidepressant drugs synthesis of new radioligands for neurotransmission will certainly contribute to further contribution of this technique to DRD.
S.19. Better antidepressant drugs ~
Augmentation strategies: 5-HT and beyond
P. Cowen. University of Oxford, Department of Psychiatry,
Oxford, United Kingdom Selective serotonin re-uptake inhibitors (SSRIs) are widely used in the management of major depression. While undoubtedly useful agents SSRIs have a number of deficiencies that limit their clinical utility. For example, about a third of patients fail to show a satisfactory clinical response to an adequate course of therapy. Further, many of those who do respond (defined conventionally as a 50% decrease in the Hamilton Rating Scale for Depression) are left symptomatic and at heightened risk of subsequent relapse. Finally the lag time of onset of therapeutic effect remains a troublesome issue. These problems have led to a number of attempts to improve the efficacy of SSRI treatment. Particularly in patients who have failed to respond to SSRIs, pharmacological augmentation strategies are employed in the hope of enhancing the therapeutic effect of SSRI therapy. Although such augmentations often employ innovative pharmacological approaches, assessment of the efficacy of many augmentation treatments is limited by lack of randomised controlled trials. Results from open case series have to be taken with a certain amount of caution. For example, the clinical utility of tricyclic antidepressant augmentation of SSRIs has yet to be confirmed in a controlled trial. From the point of view of controlled trials the best established augmentation strategy is lithium addition. The total number of patients studied in randomised trials is still relatively small, just over 200 subjects but the number to treat (NNT) is 3.7 (Bauer and Dopfmer, 1999). This means that between 3 4 patients need to be treated with lithium augmentation to gain one additional responder relative to placebo. In general NNT values of less than 10 are thought to indicate a treatment of clinical value, depending of course on the risks both of the condition and the proposed treatment. The mechanism by which lithium enhances the therapeutic effect of SSRIs is not known. There is much evidence from animal studies that lithium enhances brain serotonin (5-HT) function and neuroendocrine measures suggest that lithium increases brain 5-HT function in patients receiving antidepressant treatment. Whether this plays a role in the therapeutic effect of lithitun/SSRI combination is not known. An interesting approach derived from animal experimental research is the proposed facilitation of the therapeutic effects of SSRI by blockade of 5-HT1A autoreceptors. 5-HT1A autoreceptors are located on 5-HT cell bodies and respond to increased levels of 5-HT by decreasing the firing rate of 5-HT neurones. It has been suggested that 5-HT1A autoreceptors need to be desensitised before SSRIs produce a substantial increase in brain 5-HT levels in terminal regions. The time needed for this adaptive change could explain the delay in the onset of the antidepressant action of SSRIs. Furthermore, in animals, even after repeated SSRI treatment 5-HT 1A autoreceptors retain the ability to restrain 5-HT cell firing. These findings have led to the notion that concomitant blockade of 5-HT 1A autoreceptors will speed the onset of action of SSRIs and enhance their overall therapeutic efficacy. At present there are no selective 5-HT1A receptor antagonists available for clinical use and most attention has focused on
S139
the use of pindolol, a b-adrenoceptor antagonist with 5-HT1A receptor antagonist properties. The clinical studies with pindolol have been somewhat equivocal and a recta-analysis of randomised trials in our Department in almost 600 subjects gave an NNT of 12.0. A major problem in interpreting these data is that it is difficult to estimate from the doses of pindolol used to treat clinical hypertension (a b-adrenoceptor antagonist action) what the effective 5-HT1A receptor blocking dose in humans might be. We have explored this issue using the selective 5-HT1A receptor antagonist [C11]-WAY 100635 in conjunction with positron emission tomography (PET) to measure the ability of pindolol to occupy 5-HT1A receptors in the human brain. Acute doses of pindolol (10mg) appeared to occupy about 30-40 % of 5-HT1A receptors, with a dose of 10mg appearing to have some preference for 5-HT1A autoreceptors relative to post-synaptic 5-HT1A receptors. However, in depressed patients receiving treatment with SSRIs the usual dose of pindolol employed in augmentation studies (7.5mg daily) produced no significant occupancy of 5-HT1A receptors (Rabiner et al, 2001). These findings indicate that if pindolol 7.5mg daily, does enhance the efficacy of SSRIs, the mechanism is unlikely to involve 5-HT1A receptor blockade. Both lithium and pindolol augmentation were conceived as treatments that would produce an enhancement of brain 5-HT function greatre than that seen with the SSRI itself. Another approach to gaining increased efficacy is to supplement the enhancement of brain 5-HT function with effects on noradrenaline or dopamine. There is, in fact some evidence that drugs that potentiate both 5-HT and noradrenaline such as amitriptyline and venlafaxine are modestly more effective than SSRIs and such drugs are often recommended in patients who have not responded to SSRI treatment. Clinically it is common practice in SSRI non-responders to add a noradrenergic potentiating agent such as a tricyclic antidepressant. Despite this, current randomised trials do not support the utility of this approach. Interestingly recent studies in animals suggest that may be possible to increase cortical noradrenaline and dopamine release via 5-HT2C receptor blockade. Theoretically, therefore, a combination of SSRI and a 5-HT2C receptor antagonist could be an effective treatment in SSRI non-responders. An action of this nature may underlie the reported efficacy of olanzapine augmentation of fluoxetine in treatment resistant patients. However, a recent large randomised study of the combination of mianserin (also a 5-HT2C receptor antagonist) and sertraline showed no potentiating effect of these two treatments relative to sertraline alone (Licht and Qvitzau, 2002).
References [1] Bauer M, Dopfmer S (1999) Lithium augmentation in treatment resistant depression: Meta-analysis of placebo-controlled trials. J Clin Psychopharmacol 19, 427-434. [2] Licht RW, Qvitzau S (2002) Treatment Strategies in patients with major depression not responding to first-line sertraline treatment. Psychopharmacology (published on-line 23.3.02). [3] Rabiner EA, Bhagwagar ZB, Gunn RN et al (2001) Pindolol augmentation of selective serotonin reuptake inhibition: PET evidence that the dose used in clinical trials is too low. Am J Psychiat 158, 2080-2082.
~The
place of peptide systems in major depression and anxiety
E Holsboer. Max Planck Institute of Psychiatry, Munich, Germany Peptides and proteins exhibit the largest structural and functional variation of all classes of biologically active molecules. In the
S.18. Recent advances in brain imaging in psychopharmacology
related decline in healthy volunteers studied between age 18 and 84. 3. There appears to be a gender-related difference in brain 5-HT synthesis in healthy volunteers. 4. Brain 5-HT synthesis is reduced during a dietary depletion of the precursor tryptophan (Nishizawa et al. 1997), and increased when 02 tension is raised from below normal (less than 80 mmHg) to supra-physiological levels (over 200 mmHg). 5. Medication-flee patients suffering from major depression exhibit reduced ]lC-ctMTrp trapping in the Anterior Cingnlate cortex, a brain area known to play a role in the regulation and expression of mood and other amotivational syndromes. 6. 11C-ctMTrp trapping is significantly reduced in medial prefrontal, orbital frontal and temporal cortices, as well as anterior cingulate in patients endowed with emotional lability and high impulsivity; i.e., cluster B personality disorders. 7. Reduced 11C_~MTrp trapping in prefrontal and orbital frontal cortex is also seen in subjects selected on the basis of having recently made (within 2 weeks) a high lethality suicide attempt. 8. Symptomatic improvement in OCD, obtained in the course of SSRI or CBT monotherapy, is associated with a significant increase in 11C-c~MTrp trapping. 9. Subjects with a history of MDMA abuse exhibit a marked reduction in 11C_ctMTrp trapping in Raphe Neurons and Basal Ganglia, suggesting neurotoxicity to 5-HT fibers in humans. In summary, though still in its infancy, the H C-~tMTrp/PET method is gradually establishing itself as one of the few available techniques permitting the assessment in oivo of aspects of tryptophan metabolism/5-HT synthesis in the human brain. That many of the validation studies conducted in healthy volunteers, as well as some of the exploratory measurements obtained in clinical samples, appear consistent with predictions derived from animal work and current knowledge of 5-HT physiology and pathophysiology is promising.
References [1] Chugani DC, Muzik 0. J Cereb Blood Flow Metab 2000;20:24. [2] Diksic M, Nagahiro S, Sourkes TL, Yamamoto YL. J Cereb Blood Flow Metab 1990; 10:1-12. [3] Diksic M, Young SN. J Neurochem 2001;78:1185-1200. [4] Leyton M, Okazawa H, Diksic M, Paris J, Mzengeza S, Young SN, Blier P, Rosa P, Benkelfat C. Am JPsychiatry 2001; 158:775-782. [5] Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza, S, de Montigny C, Blier P, Diksic M. PNAS 1997;94:5308 5313. [6] Shoaf SE, Carson R, Hommer D, Williams W, Higley JD, Schmall B, Herscovitch P, Eckelman W, Linnoila M. Neuropsychopharmacology 1998;19:345 353. [7] Tohyama Y, Takahashi S, Merid ME Watanabe A, Diksic M. Neurochem lnt 2002;40:603~510.
•
Brain spect in drug research and development (DRD): Recent advances
A.M. Catafau. GlaxoSmithKline, Barcelona, Spain The development of a drug is a time-consuming, extremely expensive and risky process. This risk is especially high when considering new drugs for neuropsychiatric diseases, since many of these diseases are exclusively human, and therefore animal models are limited or nonexistent. The consequence of inadequate information during the first steps in drug development may be the failure of the candidate compound at later stages, even after launch, when large amounts of time and money have already been invested. Brain emission tomography can help in this process.
PET is the king technique in this field due to the high accuracy of measurements, image resolution, and feasibility of labeling drugs with positron emitters such as llC. However, SPECT is more and more being considered a valuable tool for DRD due to its wider availability and lower cost, which allow the study of larger samples of subjects. Both perfusion (functional) and neurotransmission (biochemical) SPECT modalities can actually contribute to DRD. Cerebral perfusion SPECT has been demonstrated to provide insight into the pathophysiology of psychiatric diseases, and contributes to the study of pharmacological effects on the human brain. Biochemical SPECT imaging has a great potential in psychopharmacology RD, as long as new radioligands for different neurotransmission systems are being developed. SPECT is useful in identifying new targets (i.e. new mechanisms involved in the disease) and therefore in suggesting new opportunities for treatment. It also helps to the proof of concept of neuropsychiatric drugs by demonstrating central effect of the drug either directly using neurotransmission SPECT to identify occupancy of receptors/transporters and drug-radioligand displacement studies, or indirectly, by imaging changes in cerebral perfusion induced by the drug. This approach may help to establish whether new drugs are likely to be therapeutically effective. Using labeled ligands, biochemical neuroimaging can provide insight into the mechanism of action of the drug. This can be achieved by determining the interaction of the drug with a desired binding site at the synapse level, which can be a receptor, a transporter or a enzyme, or by indirectly measuring neurotransmitter concentration. Examples are the growing number of 123I-IBZM SPECT studies on dopaminergic D2 receptor occupancy mapping induced by different antipsychotics, which can be done either at a single time point or over time. These receptor occupancy studies are important, since antipsychotic dosage tailoring is very difficult, and rational drug dosing is one of the critical and risky decisions in the pharmaceutical industry. Measurement of endogenous neurotransmitter concentration changes can be performed by measuring the radioligand displacement after a drug challenge. The most known example is the decreased D2 receptor availability measured by 123I-IBZM SPECT after injection of amphetamine. The percentage of decrease of 123I-IBZM uptake is proportional to the amount of endogenous dopamine released, and correlates with the intensity of the behavioral responses to the amphetamine administration. These studies are helpful in checking the effects of new drugs on endogenous dopamine release, which seem to have a promising future in the control of drug addictive behavior. Finally, SPECT has also a role in the study of drug pharmacodynamics. Pharmaceutical interactions in the synapse imply brain metabolic changes, and therefore cerebral blood flow changes, which determine the final effect for CNS drugs, being a modified behavior. To measure drug induced cerebral blood flow changes, a baseline study (in naive conditions) is necessary prior to the SPECT study on medication. Test-retest values should be used to validate results. Feasibility of SPECT studies during cognitive activation makes possible the assessment of drug effects on cognition. The drug induced cerebral perfusion changes can be related to clinical parameters, such as the score in psychopathological scales. In conclusion, brain SPECT is a low cost and available technique that contributes to DRD from the early stages such as target identification to the proof of concept - first time in human, giving information on drug mechanism of action and pharmacodynamics. Both cerebral perfusion and neurotransmission images are useful. Although several neurotransmission systems can already be imaged by SPECT,
S. 19. Better antidepressant drugs synthesis of new radioligands for neurotransmission will certainly contribute to further contribution of this technique to DRD.
S.19. Better antidepressant drugs ~
Augmentation strategies: 5-HT and beyond
P. Cowen. University of Oxford, Department of Psychiatry,
Oxford, United Kingdom Selective serotonin re-uptake inhibitors (SSRIs) are widely used in the management of major depression. While undoubtedly useful agents SSRIs have a number of deficiencies that limit their clinical utility. For example, about a third of patients fail to show a satisfactory clinical response to an adequate course of therapy. Further, many of those who do respond (defined conventionally as a 50% decrease in the Hamilton Rating Scale for Depression) are left symptomatic and at heightened risk of subsequent relapse. Finally the lag time of onset of therapeutic effect remains a troublesome issue. These problems have led to a number of attempts to improve the efficacy of SSRI treatment. Particularly in patients who have failed to respond to SSRIs, pharmacological augmentation strategies are employed in the hope of enhancing the therapeutic effect of SSRI therapy. Although such augmentations often employ innovative pharmacological approaches, assessment of the efficacy of many augmentation treatments is limited by lack of randomised controlled trials. Results from open case series have to be taken with a certain amount of caution. For example, the clinical utility of tricyclic antidepressant augmentation of SSRIs has yet to be confirmed in a controlled trial. From the point of view of controlled trials the best established augmentation strategy is lithium addition. The total number of patients studied in randomised trials is still relatively small, just over 200 subjects but the number to treat (NNT) is 3.7 (Bauer and Dopfmer, 1999). This means that between 3 4 patients need to be treated with lithium augmentation to gain one additional responder relative to placebo. In general NNT values of less than 10 are thought to indicate a treatment of clinical value, depending of course on the risks both of the condition and the proposed treatment. The mechanism by which lithium enhances the therapeutic effect of SSRIs is not known. There is much evidence from animal studies that lithium enhances brain serotonin (5-HT) function and neuroendocrine measures suggest that lithium increases brain 5-HT function in patients receiving antidepressant treatment. Whether this plays a role in the therapeutic effect of lithitun/SSRI combination is not known. An interesting approach derived from animal experimental research is the proposed facilitation of the therapeutic effects of SSRI by blockade of 5-HT1A autoreceptors. 5-HT1A autoreceptors are located on 5-HT cell bodies and respond to increased levels of 5-HT by decreasing the firing rate of 5-HT neurones. It has been suggested that 5-HT1A autoreceptors need to be desensitised before SSRIs produce a substantial increase in brain 5-HT levels in terminal regions. The time needed for this adaptive change could explain the delay in the onset of the antidepressant action of SSRIs. Furthermore, in animals, even after repeated SSRI treatment 5-HT 1A autoreceptors retain the ability to restrain 5-HT cell firing. These findings have led to the notion that concomitant blockade of 5-HT 1A autoreceptors will speed the onset of action of SSRIs and enhance their overall therapeutic efficacy. At present there are no selective 5-HT1A receptor antagonists available for clinical use and most attention has focused on
S139
the use of pindolol, a b-adrenoceptor antagonist with 5-HT1A receptor antagonist properties. The clinical studies with pindolol have been somewhat equivocal and a recta-analysis of randomised trials in our Department in almost 600 subjects gave an NNT of 12.0. A major problem in interpreting these data is that it is difficult to estimate from the doses of pindolol used to treat clinical hypertension (a b-adrenoceptor antagonist action) what the effective 5-HT1A receptor blocking dose in humans might be. We have explored this issue using the selective 5-HT1A receptor antagonist [C11]-WAY 100635 in conjunction with positron emission tomography (PET) to measure the ability of pindolol to occupy 5-HT1A receptors in the human brain. Acute doses of pindolol (10mg) appeared to occupy about 30-40 % of 5-HT1A receptors, with a dose of 10mg appearing to have some preference for 5-HT1A autoreceptors relative to post-synaptic 5-HT1A receptors. However, in depressed patients receiving treatment with SSRIs the usual dose of pindolol employed in augmentation studies (7.5mg daily) produced no significant occupancy of 5-HT1A receptors (Rabiner et al, 2001). These findings indicate that if pindolol 7.5mg daily, does enhance the efficacy of SSRIs, the mechanism is unlikely to involve 5-HT1A receptor blockade. Both lithium and pindolol augmentation were conceived as treatments that would produce an enhancement of brain 5-HT function greatre than that seen with the SSRI itself. Another approach to gaining increased efficacy is to supplement the enhancement of brain 5-HT function with effects on noradrenaline or dopamine. There is, in fact some evidence that drugs that potentiate both 5-HT and noradrenaline such as amitriptyline and venlafaxine are modestly more effective than SSRIs and such drugs are often recommended in patients who have not responded to SSRI treatment. Clinically it is common practice in SSRI non-responders to add a noradrenergic potentiating agent such as a tricyclic antidepressant. Despite this, current randomised trials do not support the utility of this approach. Interestingly recent studies in animals suggest that may be possible to increase cortical noradrenaline and dopamine release via 5-HT2C receptor blockade. Theoretically, therefore, a combination of SSRI and a 5-HT2C receptor antagonist could be an effective treatment in SSRI non-responders. An action of this nature may underlie the reported efficacy of olanzapine augmentation of fluoxetine in treatment resistant patients. However, a recent large randomised study of the combination of mianserin (also a 5-HT2C receptor antagonist) and sertraline showed no potentiating effect of these two treatments relative to sertraline alone (Licht and Qvitzau, 2002).
References [1] Bauer M, Dopfmer S (1999) Lithium augmentation in treatment resistant depression: Meta-analysis of placebo-controlled trials. J Clin Psychopharmacol 19, 427-434. [2] Licht RW, Qvitzau S (2002) Treatment Strategies in patients with major depression not responding to first-line sertraline treatment. Psychopharmacology (published on-line 23.3.02). [3] Rabiner EA, Bhagwagar ZB, Gunn RN et al (2001) Pindolol augmentation of selective serotonin reuptake inhibition: PET evidence that the dose used in clinical trials is too low. Am J Psychiat 158, 2080-2082.
~The
place of peptide systems in major depression and anxiety
E Holsboer. Max Planck Institute of Psychiatry, Munich, Germany Peptides and proteins exhibit the largest structural and functional variation of all classes of biologically active molecules. In the