User:Nuklear/sandbox

From Wikipedia, the free encyclopedia

SNDRI compounds rapidly elevate 5-HT and catecholamines in the synaptic cleft for a sustained period of time. These 3 biogenic monoamines are associated with depression, so increasing their endogenous availability will have uses in the treatment of this illness.

Contents

[edit] SNDRI Compounds: MDD Applications

Significant studies recently published are advocating the need for innovative new drugs, that either confer multiple layers of activity (B. Roth, et al. 2004),[1] or that confer radically different mechanisms of activity to the older medications (Berton and Nestler, 2006).[2]

  • The DAT system is evolving into an important recognition site for MDD (D'Aquala, et al. 2000),[3] (Papakostas, et al. 2005).[4]
  • Consequently, serotonin/dopamine interaction is a focus in the design of new AD drugs (E. Esposito, 2006).[5]
  • DOV pharmaceuticals have conducted lengthy clinical trials on one such compound (Skolnick and Basile, 2007).[6]
  • P. Carlier and co-workers have also been developing SNDRI agents over the last decade (A. Shaw, et al. 2007).[7]
    • Infact, it was this group that first coined the phrase "SNDRI" when referring to these compounds (1998).[8]

[edit] Evidence for DA Deficits linked to Depression

A role for DA deficiency in the pathophysiology of depression is supported by studies demonstrating reduced levels of DA and its metabolite HVA in depressed and/or suicidal patients compared to normal individuals (G. Engström, et al. 1999),[9] (Hamner and Diamond, 1996),[10] (H. Mitani, et al. 2006),[11] and reduced DAT activity (J. Meyer, et al. 2001).[12]

D2/D3 receptor binding affinity (V. Klimek, et al. 2002),[13] D2 (P. Willner, et al. 2005).[14]

Brain Imaging Studies (D. Nutt, et al. 2006).[15]

There is a strong link between the mesolimbic dopamine reward circuit and the 'pathological' symptoms of depression (E. Nestler, 2006).[16]

[edit] Public Health Burden of Depression

Depression is a leading cause of disabilty, second only to heart disease.

  • Depressed patients have an increased risk of premature death (Harris and Barraclough, 1998).[17]
  • Depression is considered a significant risk factor for the development of coronary heart disease and stroke (D. Musselman, et al. 1998).[18]
  • Depression can increase the mortality rate of cancer (Edna Maria, et al. 2004),[19] (W. Somerset, et al. 2004).[20]

Endocrine disease (N. Sonino, et al. 2004).[21]

[edit] Cost of Depression on the Economy

  • Depression costs the US economy >$80 billion / year, mostly due to lost workplace productivity (P. Greenberg, et al. 2003).[22]
  • The economic cost of depression in Europe was estimated at €118 billion in 2004, or €253 per inhabitant (P. Soboki, et al. 2006).[23]


[edit] SSRI Side-Effect

(D. Nutt, et al. 2006).[24]

  • Sleepiness/fatigue: Bupropion augmentation to alleviate based side-effects of SSRI based treatments (G. Papakostas, et al. 2006).[25]
  • Fatigue/lethargy in depression, treatment-resistant depression, and sexual side effects (D. Nutt, et al. 2006).[26]
  • Sexual dysfunction: one of the principle drivers for the use of bupropion as augmentation therapy is a dampening or reversal of the produced by SSRIs and SNRIs (S. Zisook, et al. 2006).[27]

Perhaps the most frequent side effect associated with SSRIs and SNRIs is nausea.

  • Addiction & Physical Dependency

[edit] Anhedonia in Depression

Anhedonia, or lack of interest in normally pleasurable activities, is a core symptom of depression and has been linked to deficits in DA mesolimbic system, an area important for mediating reward and incentive motivation. Chronic treatment with different classes of AD's consistently leads to a potentiation of DA neurotransmission suggesting that a compound with immediate effects on DA signaling may be more effective and faster acting than a drug w/o DA activity, esp. for alleviation of symptoms related to reward and motivation. A recent study examined the effects of treatment with duloxetine combined with bupropion, in a small sample of patients who had not yet achieved symptom remission with either treatment alone.

Anhedonia is necessary for diagnosis of depression (P. Keedwell, et al. 2005),[28]

[edit] Social Anxiety Disorder (SAD)

Application in the treatment of social anxiety disorder (H. Robinson, et al. 2006).[29]

[edit] Treatment Resistent Depression

About 65% of patients ultimately respond to antidepressant therapy (D. Steffens, et al. 1997),[30] while about 15% of depressed patients are resistant to all known forms of therapy (M. Keller, et al. 1992).[31] Thus, there is a need for new meds with better efficacy, fewer side effects, and a more rapid onset of action.

[edit] Therapeutic Lag

The ability to increase synaptic concs of DA may more immediately address the hypodopaminergia than 2nd order processes induced by long-term elevations in synaptic SER/NE levels. Thus, the therapeutic lag associated with convential AD therapy, is the time taken for adaptive neurochemical changes that must occur before a therapeutic response is met (D'Aqualia, et al. 2000),[32] (Skolnick 2000).[33] Many of these adaptive processes are now known to extend beyond the BMA synapses. Nonetheless, in preclinical studies, senstization of DA mesolimbic receptors is consistently the most reliable change following chronic AD treatment. This sensitization, which occurs on the behavioral, cellular and molecular levels, is produced by structurally diverse antidepressants, electroconvulsive shock and REM sleep deprivation. [34] it is hypothesized that the several weeks of AD treatment required to produce this increased sensitivity to DA stimulation may reflect the therapeutic lag common to BMA based antidepressants. Thus, an agent that immediately increases DA tone, by increasing either synaptic DA levels or DA receptor sensitivity, may be expected to reduce the time required to achieve a clinically meaningful response.

[edit] Do TRI drugs differ in their efficacy vs. conventional antidepressants?

The evidence that addition of DA component will result in a more effective AD than a single/dual uptake inhibitor is derived from clinical studies where DA agent is combined with a single/dual uptake inhibitor. AD therapy can be viewed in several dimensions, reflecting outcome measures such as increase in the percentage patients with a significant reduction in depressive symptomatology, a response following failure of one or more conventional agents, or a reduction in relapse rates. The strategy used in the majority of these studies was administration of bupropion in combination with an SSRI, although there are several reports describing combinations of an AD with a DA agonist. Until the recent publciation of the Sequenced Treatment Alternatives to Relieve Depression trial (STAR*D),[35] these studies were generally small, not blinded and lacked appropriate controls. Zisook, et al.<> recently reviewed this literature, which indicates four prospective studies, three retrospective reviews, and several case reports describing the effects of combining bupropion with an SSRI or SNRI as an attempt to augment monotherapy in patients unresponsive to, or exhibiting a partial response to an SSRI, SNRI, or bupropion alone. Augmentation therapy resulted in improvement in several dimensions, inc. larger reductions in HAM-D scores, higher prop. patients with 50% red. in HAM-D score, significantly higher remission rates, and clinically meaningful responses in patients previously unresponsive to monotherapy.


[edit] Clinical Experience

There is an emerging clinical lit. creating functional TRI–drugs by adding bupropion to an SSRI, SNRI or TCA. Sept '06, only publish clin. study in dpressed patients using a TRI in the trial design used DOV 216,303.<> This compound was reported safe and well tolerated in normal volunteers at single doses up to 150mg and multiple doses 100mg x 10 days.

[edit] Conclusions

SSRIs and SNRIs represent a structurally diverse group of molecules and the NE/5HT/DA transporters belong to the same gene superfamily of twelve transmembrane proteins. In this context, the design of TRI drugs would appear straightforward given the ready availability of "reagents", high throughput screening, and sophisticated molecular modeling programs. However, as in other areas of drug development, adding the element of "drugability" is a formidable challenge. The inherent difficulties in producing such a molecule are reflected in both the numb publications in this arena and numb trials TRI drugs pub disclosed. Perhaps a greater challenge lies in developing a molecule with the optimal potencies in blocking uptake at each transporter, allowing an unequivocal test of the hypothesis that a TRI will be superior to a single or dual mode inhibitor. It is clear that the relative potencies of antidepressants to inhibit SER versus NE uptake vary over several orders of magnitude. DOV 216,03, which inhibits NE/5HT uptake with ~equal potency, would be predicted to possess AD properties. However, the relative increases in synaptic concs of SER/NE/DA may affect not only speed of onset and efficacy, but also side-effect profile.

[edit] Alternative Recent Developments in MDD Therapy

Despite rapid advances in molecular neuroscience, neither candidate gene association studies nor genome-wide linkage scans have consistently identified genes for unipolar depression (D. Levinson, 2006).[36] This is not surprising, because depression is a heterogenous disorder based on clusters of symptoms that change over time. In others words, it is a dynamic and not a static disorder. Further, the high comorbidy of depression with anxiety can lead to changes in diagnosis during the course of the illness, further hampering identification of candidate genes.

[edit] PRC Compounds

The PRC compounds possess a (gamma) γ-amino alcohol and are believed to possess the desired triple mode of action. These are chemically related to, yet far more advanced and stronger in effects than the older drug venlafaxine [1990].[37] The fossilized synthetic chemistry of these compounds is remarkable, it involves what is called a "nitrile aldol" rxn, there is a racemic pair of diastereoisomers. The dia/stereochemistry can be tweaked in order to get a level of selectivity.[38][39]

PRC Antidepressants Triple QSAR utilizing Human/Rat Neurotransporters and Tritiated Monoamine Radiotracers (concentrations in nM)
Compound [3H]5-HT Uptake [3H]NE Uptake [3H]DA Uptake Ki ÷ Kd Uptake Ratio
Compound hSERT Kd (Ki) hNET Kd (Ki) hDAT Kd (Ki) 5-HT NE DA NE ÷ 5-HT DA ÷ 5-HT DA ÷ NE
PRC025 6.0 ± .8 (6.0 ± .8) 19 ± 2 (10 ± .5) 100 ± 10 (53 ± 1) 1.000 .5263 .5300 3.167 (1.667) 16.67 (8.833) 5.263 (5.3)
PRC050 6.0 ± .3 (12 ± 2) .40 ± .05 (1.2 ± .1) 120 ± 10 (43 ± 7) 2.000 3.000 .358 .0667 (.1) 20 (3.583) 300 (38.83)
Venlafaxine 9.0 ± 0.3 (39 ± 3) 1060 ± 40 (210 ± 20) 9.3K ± 50 (5.3K ± 6h) 4.333 .1981 .5700 5.385 (117.8) 1033 (135.9) 8.774 (25.24)
Values Represent the geometric mean of at least 3 different experiments for PRC025 and PRC50.

Desvenlafaxine Succinate: A New Serotonin and Norepinephrine Reuptake Inhibitor. 2006

Interactions of antidepressants with neurotransmitter transporters and receptors and their clinical relevance. Elliott Richelson (2003)

The clinical relevance of antidepressant interaction with neurotransmitter transporters and receptors. Richelson E. (2002)


[edit] Dopamine and Addiction

Given its prominent role in reward and emotion (R. Wise, 2005),[40] the DA system is a focal point of research to uncover the mechanisms underlying addiction and a key target for the development of drugs in the treatment of substance abuse. Behavioral, neurochemical, and molecular studies have demonstrated that the mesocorticoaccumbens DA pathway, which originates in DA somata of the VTA and terminates in the NAc and PFC, serves as a common substrate for the acute effects of all drugs of abuse, regardless of their individual mechanisms of action (E. Nestler, 2005).[41]

(Ritz, et al. 1987),[42] (Madras, et al. 1989),[43] (Kuhar, et al. 1991).[44] Although studies on DAT knock-out mice suggested the involvement of other neuronal circuitry in delivering the rewarding effects associated with cocaine (G. Uhl, et al. 2002),[45] this point has little more than artistic merit. Recent studies conducted on DAT knock-in mice have now definatively proven that the DA elevating actions of cocaine account for 100% of its self-administration propensity (R. Chen, et al. 2006).[46] High occupancy and blockage of the DAT is not the only mechanism through which synpatic DA concentrations can be elevated. Presynaptic DA autoreceptors, for example, also govern this phenomena (Qun Wu, et al. 2002),[47] although nodoubt there are several biochemical mechanisms besides this. Cocaine affects neurotransmission in various DA systems, leading to a variety of behavioral effects. Facilitation of DA transmission in the nigrostriatal system likely contributes to the prominent behavioral-stimulant effects of coca. The mesolimbic/mesocortical DA system consists of dopaminergic cell bodies in the ventral tegmental area (VTA), which project to subcortical areas inc. the medial prefrontal cortex. This system is understood to be an important mediator of reinforcing effects of coca.

There is a possible link between stuttering and basal ganglia (Per Alm, 2004).[48]

[edit] Cocaine Therapy

There has been good progress in developing drugs with the intent of treating cocaine addiction (F. Vocci, et al. 2005).[49] For example, RTI-336 has recently been reported (F. Carroll, et al. 2006),[50] and RTI-51 also appears to possess favorable characteristics (S. Wee, et al. 2006).[51] This document was recently published by the same author also.[52] This is okay in the field of psychostimulant abuse, but there is evidence that drugs with more general uses need to have molecular structures dissimilar from cocaine. Phencyclidine, for example, is much more cost effective, and less likely to result in bankruptcy. In the pharmaceutical industry, synthesis affordability is an important factor in drug design and manufacture. This, however, is much less relevent in a purely academic coverage of the subject.

(E. Dailly, et al. 2004).[53]

The mesolimbic DA pathway, composed of dopaminergic neurons in the midbrain ventral tegmental area and their projections to the nucleus accumbens, allows an organism to identify emotionally salient stimuli in the environment, to learn about outcomes associated with those stimuli, and to express appropriate approach or avoidance responses (W. Schultz, 2006).[54]

[edit] Serotonin

Serotonin Receptors as Targets in Drug Discovery and Medicinal Chemistry

Serotonin neurons originate in the raphe nuclei in the midbrain and project to numerous regions throughout the brain, interacting with many of the known neurotransmitter systems.

The 5-HT2AR and 5-HT2CR, encoded by two different genes, are highly homologous receptors. The ability of these receptors to modulate output of VTA DA neurons is a relevent characteristic, worth considering.

Systematic administration of 5-HT2CR agonists decreased basal firing rates of VTA DA neurons, and decreased DA release in the NAc. Likewise, 5-HT2CR antagonists yield the reverse scenario, although these also enhance DA release in the PFC. These results suggest that the 5-HT2CR tonically inhibits DA mesocorticoaccumbens output.

Although the 5-HT2AR does not exert tonic influence upon DA neuronal firing or DA release, stimulation of this receptor with an exogenous agonist reveals an enhancement of DA neuronal output (cf. LSD-25).

Acute systematic injections of selective 5-HT2AR ant/agonists block/enhance hypermotive and discriminative stimulus effects of cocaine.
Acute systematic injections of selective 5-HT2CR ant/agonists enhance/block hypermotive and discriminative stimulus effects of cocaine.

Thus, the 5-HT2AR and the 5-HT2CR appear to have opposing influences on stimulant-induced behaviors.

A selective 5-HT2CR ant/agonist increased/reduced rates of cocaine self-administration, and also increased/reduced cocaine-hyperactivity.

[edit] Discussion

In other words, magic car bombs may be superior to magic bullets in treating severe mental health issues, like schizoaffective disorder. For example, clozapine is frequently prescribed to patients with treatment resistant psychosis, although it is not one of the first line treatments due to its potentially life-threatening side-effects. Thus development of a drug that can deliver the same clinical efficacy as many of these older medicines, but with a significantly improved side-effect profile, could be useful.

A number of studies have suggested that modulation of the serotonergic system can reduce the biochemical and behavioral stimulant actions of cocaine and related DARI molecules. Chemical lesions of brain 5-HT systems were shown to enhance the reinforcing efficacy of cocaine (Roberts, et al. '94),[55] whereas dietary supplement with 5-HT precursors can attenuate cocaine self-administration in rodents (Carroll, et al. '90). Furthermore, self-administration of cocaine is decreased by SSRI meds in rats (Richardson and Roberts, 1991) and monkeys (Kleven and Woolverton, 1993),[56] although similar effects are observed on food maintained behavior. 5-HT can also dement the behavioral-stimulant effect of cocaine in squirrel monkeys (Howell and Byrd, '95).[57] Brain 5-HT systems are ideally situated to modulate the activity of DA neurons and the behavioral effects of DARI compounds such as cocaine. 5-HT neurons from the dorsal and median raphe nuclei innervate the dopaminergic cell bodies and terminal regions of the nigrostriatal and mesolimbic DA systems, and the convergence of 5-HT terminals and DA neurons has been visualized in the VTA and NAcc under the microscope (Phelix and Broderick, '95).[58] It is possible that 5-HT acts on cell bodies to decrease the firing rate of DA neurons or at terminals to decrease DA release. Alternatively, the ability of 5-HT to dement the behavioral actions of coca may be caused by an attenuation in cocaine-induced extracellular DA elevations. Also, 5-HT may act on post-synaptic DA neurons, interfering with the DA target sites and therefore dumbing the response normally expected from an increased synpatic DA availability. E.g, RTI-112 is a nonselective PT analog with aprox equal in vitro SERT/DAT binding affinities, but this agent was only weakly self administered by monkeys though (K. Lindsey, et al. 2004),[59] (B. Ginsberg, et al. 2005).[60] Also, a number of studies where an SSRI or a serotonin agonist are administered in conjunction with cocaine or other DAT inhibitors were studied. Here, it was demonstrated that serotonin decreases the propensity for drug administration (P. Czoty, et al. 2001),[61] (L. Howell, et al. 2006/7).[62]

Some aromatic-isopropylamine based monamine releasers were recently prepared and their pharmacology tested (S. Wee, et al. 2005),[63] (R. Rothman, et al. 2005,[64] 2006),[65] (S. Negus, et al. 2006).[66] All of this cutting-edge research is also partisan to the notion that serotonergic action limits the abuse liability of DA elevators.

[edit] Conclusion

Thus, both the DAT and the SERT might need to be highly occupied, by the medication, inorder to elicit the full-spectrum of rewarding stimuli, without all of the problems associated with physical dependancy. The analogy for this is that if an artist is planning a painting, then it is likely that they are going to want to use all of the 1° colors, and not just the one that is corresponding to dopamine.

[edit] SNDRI Pat Retrieval

[67][68][69][70] [71][72][73][74][75][76][77][78][79]
The Dupont compound looks similar to Nomifensine.

[Tesofensine Replicate] Tropane-derivatives, their preparation and use[80]

2-METHOXYMETHYL-3-(3,4-DICHLOROPHENYL)-8-AZABICYCLO[3.2.1]OCTANE TARTRATE SALTS[81][82]

This invention relates to novel (1R,2R,3S,5S)-2-methoxymethyl-3-(3,4dichlorophenyl)-8-azabicyclo[3.2.1]octane tartrate salts, such as L-tartrate monohydrates and anhydrates. The salts are useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these salts in a method for therapy and to pharmaceutical compositions comprising the salts of the invention.

Paxil[83]

[edit] References

  1. ^ [1]Nature Reviews Drug Discovery 3, 353-359 (2004); doi:10.1038/nrd1346 MAGIC SHOTGUNS VERSUS MAGIC BULLETS: SELECTIVELY NON-SELECTIVE DRUGS FOR MOOD DISORDERS AND SCHIZOPHRENIA Bryan L. Roth, Douglas J. Sheffler & Wesley K. Kroeze
  2. ^ [2]Nature Reviews Neuroscience 7, 137-151 (February 2006) New approaches to antidepressant drug discovery: beyond monoamines Olivier Berton and Eric J. Nestler
  3. ^ [3]European Journal of Pharmacology, Volume 405, Issues 1-3, 29 September 2000, Pages 365-373 Paolo Stefano D'Aquila, Maria Collu, Gian Luigi Gessa and Gino Serra
  4. ^ [4]Dopaminergic-based pharmacotherapies for depression George I. Papakostas European Neuropsychopharmacology Volume 16, Issue 6, August 2006, Pages 391-402
  5. ^ [5]Serotonin-Dopamine Interaction as a Focus of Novel Antidepressant Drugs. Esposito, Ennio Current Drug Targets, Volume 7, Number 2, February 2006, pp. 177-185(9)
  6. ^ [6]Triple Reuptake Inhibitors (“Broad Spectrum” Antidepressants) Skolnick, Phil; Basile, Anthony S. CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders), Volume 6, Number 2, April 2007, pp. 141-149(9)
  7. ^ [7]Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050 Amanda M. Shaw European Journal of Pharmacology Volume 555, Issue 1, 19 January 2007, Pages 30-36
  8. ^ [8]Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group. Bioorganic & Medicinal Chemistry Letters, V8, Issue 5, 1998, pp 487-492
  9. ^ [9]European Neuropsychopharmacology, Volume 9, Issue 5, September 1999, Pages 399-405 Gunnar Engström, Christer Alling, Kaj Blennow, Göran Regnéll and Lil Träskman-Bendz
  10. ^ [10]Psychiatry Research, Volume 64, Issue 3, 16 October 1996, Pages 209-211 Mark B. Hamner and Bruce I. Diamond
  11. ^ [11]Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 30, Issue 3, May 2006, Pages 531-534 Hideaki Mitani, Yukihiko Shirayama, Takeshi Yamada and Ryuzou Kawahara
  12. ^ [12]Lower dopamine transporter binding potential in striatum during depression. BRAIN IMAGING Neuroreport. 12(18):4121-4125, December 21, 2001. Meyer, Jeffrey H. CA; Kruger, Stephanie; Wilson, Alan A.; Christensen, Bruce K.; Goulding, Verdell S.; Schaffer, Ayal; Minifie, Candace; Houle, Sylvain; Hussey, Doug; Kennedy, Sidney H.
  13. ^ [13]Biological Psychiatry, Volume 52, Issue 7, 1 October 2002, Pages 740-748 Violetta Klimek, Jane E. Schenck, Hui Han, Craig A. Stockmeier and Gregory A. Ordway
  14. ^ [14]Dopaminergic mechanism of antidepressant action in depressed patients Journal of Affective Disorders, Volume 86, Issue 1, May 2005, Pages 37-45 Paul Willner, Anthony S. Hale and Spilios Argyropoulos
  15. ^ [15]J Clin Psychiatry. 2006;67 Suppl 6:3-8. The role of dopamine and norepinephrine in depression and antidepressant treatment. Nutt DJ.
  16. ^ [16]The Mesolimbic Dopamine Reward Circuit in Depression Biological Psychiatry Volume 59, Issue 12, 15 June 2006, Pages 1151-1159
  17. ^ [17]Excess mortality of mental disorder EC Harris and B Barraclough Br J Psychiatry 173: 11-53.
  18. ^ [18]The Relationship of Depression to Cardiovascular Disease: Epidemiology, Biology, and Treatment Dominique L. Musselman; Dwight L. Evans; Charles B. Nemeroff Arch Gen Psychiatry. 1998;55:580-592.
  19. ^ [19]Stress, depression, the immune system, and cancer Pages 617-625 Edna Maria Vissoci Reiche, Sandra Odebrecht Vargas Nunes and Helena Kaminami Morimoto
  20. ^ [20]1: Oncology (Williston Park). 2004 Jul;18(8):1021-34; discussion 1035-6, 1047-8.
  21. ^ [21]Persistent Psychological Distress in Patients Treated for Endocrine Disease. Psychother Psychosom 2004;73:78-83
  22. ^ [22]Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe SW, Berglund PA, Corey-Lisle PK. Related Articles, Links The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003 Dec;64(12):1465-75.
  23. ^ [23] J Ment Health Policy Econ. 2006 Jun;9(2):87-98. Cost of depression in Europe.Sobocki P, Jonsson B, Angst J, Rehnberg C.
  24. ^ [24]The other face of depression, reduced positive affect: the role of catecholamines in causation and cure J Psychopharmacol. 2006 Oct 18; Nutt DJ, Demyttenaere K, Janka Z, Aarre T, Bourin M, Canonico PL, Carrasco JL, Stahl S.
  25. ^ [25]Resolution of Sleepiness and Fatigue in Major Depressive Disorder: A Comparison of Bupropion and the Selective Serotonin Reuptake Inhibitors Biol Psychiatry. 2006 Dec 15;60(12):1350-5. Papakostas GI, Nutt DJ, Hallett LA, Tucker VL, Krishen A, Fava M.
  26. ^ [26]J Clin Psychiatry. 2006;67 Suppl 6:46-9. Nutt DJ, Baldwin DS, Clayton AH, Elgie R, Lecrubier Y, Montejo AL, Papakostas GI, Souery D, Trivedi MH, Tylee A.
  27. ^ [27]Use of Bupropion in Combination with Serotonin Reuptake Inhibitors Biological Psychiatry, Volume 59, Issue 3, 1 February 2006, Pages 203-210 Sidney Zisook, A. John Rush, Barbara R. Haight, Dawn C. Clines and Carol B. Rockett
  28. ^ [28]The Neural Correlates of Anhedonia in Major Depressive Disorder Biological Psychiatry, Volume 58, Issue 11, 1 December 2005, Pages 843-853 Paul A. Keedwell, Chris Andrew, Steven C.R. Williams, Mick J. Brammer and Mary L. Phillips
  29. ^ [29]Rev Bras Psiquiatr. 2006 Dec;28(4):263-4. Dopamine and social anxiety disorder. Robinson HM, Hood SD, Bell CJ, Nutt DJ.
  30. ^ [30]Depression and Anxiety Volume 6, Issue 1, Date: 1997, Pages: 10-18 David C. Steffens, K. Ranga R. Krishnan, Michael J. Helms
  31. ^ [31]M. B. Keller; P. W. Lavori; T. I. Mueller; J. Endicott; W. Coryell; R. M. Hirschfeld; T. Shea Arch Gen Psychiatry. 1992;49:809-816.
  32. ^ [32]The role of dopamine in the mechanism of action of antidepressant drugs European Journal of Pharmacology, Volume 405, Issues 1-3, 29 September 2000, Pages 365-373 Paolo Stefano D'Aquila, Maria Collu, Gian Luigi Gessa and Gino Serra
  33. ^ [33]Antidepressants for the new millennium European Journal of Pharmacology, Volume 375, Issues 1-3, 30 June 1999, Pages 31-40 Phil Skolnick
  34. ^ [34]The role of the brain reward system in depression Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 25, Issue 4, May 2001, Pages 781-823 Claudio A. Naranjo, Lescia K. Tremblay and Usoa E. Busto
  35. ^ [35]Medication Augmentation after the Failure of SSRIs for Depression
  36. ^ [36]The Genetics of Depression: A Review Biological Psychiatry, Volume 60, Issue 2, 15 July 2006, Pages 84-92 Douglas F. Levinson
  37. ^ [37]J. Med. Chem.; 1990; 33(10); 2899-2905.
  38. ^ [38]Paul R. Carlier, Kam Moon Lo, Michael M-C. Lo, Ian D. Williams J. Org. Chem.; 1995; 60(23); 7511-7517.
  39. ^ [39]Paul R. Carlier, Kam Moon Lo, Michael M.-C. Lo, Priscilla C.-K. Lo, and Cedric W.-S. Lo. J. Org. Chem.; (Article); 1997; 62(18); 6316-6321.
  40. ^ [40]Forebrain substrates of reward and motivation The Journal of Comparative Neurology Volume 493, Issue 1, Date: 5 December 2005, Pages: 115-121 Roy A. Wise
  41. ^ [41]Nature Neuroscience 8, 1445 - 1449 (2005) Published online: 26 October 2005; Is there a common molecular pathway for addiction? Eric J Nestler
  42. ^ [42]Science 4 September 1987: Vol. 237. no. 4819, pp. 1219 - 1223 DOI: 10.1126/science.2820058
  43. ^ [43]Madras, B. K., Spealman, R. D., Fahey, M. A., Neumeyer, J. L., Saha, J. K. and Milius, R. A.: Cocaine receptors labeled by [3H]2-carbomethoxy-3-(4-fluorophenyl)tropane. Mol. Pharmacol. 36: 518-524, 1989
  44. ^ [44]The dopamine hypothesis of the reinforcing properties of cocaine Trends in Neurosciences, Volume 14, Issue 7, July 1991, Pages 299-302 M. J. Kuhar, M. C. Ritz and J. W. Boja
  45. ^ [45]Cocaine, reward, movement and monoamine transporters. G R Uhl, F S Hall and I Sora. Molecular Psychiatry (2002) 7, 21-26.
  46. ^ [46]Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. R. Chen, M. R. Tilley, H. Wei, F. Zhou, F.-M. Zhou, S. Ching, N. Quan, R. L. Stephens, E. R. Hill, T. Nottoli, D. D. Han, and H. H. Gu (2006) PNAS 103, 9333-9338
  47. ^ [47]The Journal of Neuroscience, July 15, 2002, 22(14):6272-6281 Concurrent Autoreceptor-Mediated Control of Dopamine Release and Uptake during Neurotransmission: An In Vivo Voltammetric Study Qun Wu, Maarten E. A. Reith, Q. David Walker, Cynthia M. Kuhn, F. Ivy Carroll, and Paul A. Garris.
  48. ^ [48]
  49. ^ [49]Frank J. Vocci, Jane Acri, and Ahmed Elkashef Medication Development for Addictive Disorders: The State of the Science Am J Psychiatry 2005 162: 1432-1440
  50. ^ [50]Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ. Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse. AAPS Journal. 2006; 8(1): E196-E203. DOI: 10.1208/aapsj080124
  51. ^ [51]Neuropsychopharmacology (2006) 31, 351–362. doi:10.1038/sj.npp.1300795; published online 15 June 2005 Preclinical Research A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants Sunmee Wee, F Ivy Carroll and William L Woolverton.
  52. ^ [52]Sunmee Wee, Sheila E. Specio, and George F. Koob Effects of Dose and Session Duration on Cocaine Self-Administration in Rats J. Pharmacol. Exp. Ther. 2007 320: 1134-1143.
  53. ^ [53]Eric Dailly, Franck Chenu, Caroline E. Renard, Michel Bourin (2004) Dopamine, depression and antidepressants Fundamental & Clinical Pharmacology 18 (6), 601–607
  54. ^ [54]Annual Review of Psychology. Volume 57, Page 87-115, Jan 2006
  55. ^ [55]Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food Pharmacology Biochemistry and Behavior, Volume 49, Issue 1, September 1994, Pages 177-182 D. C. S. Roberts, E. A. Loh, G. B. Baker and G. Vickers
  56. ^ [56]Effects of three monoamine uptake inhibitors on behavior maintained by cocaine or food presentation in rhesus monkeys Drug and Alcohol Dependence, Volume 31, Issue 2, January 1993, Pages 149-158 Mark S. Kleven and William L. Woolverton
  57. ^ [57]LL Howell and LD Byrd Serotonergic modulation of the behavioral effects of cocaine in the squirrel monkey J. Pharmacol. Exp. Ther. 1995 275: 1551-1559.
  58. ^ [58]Light microscopic immunocytochemical evidence of converging serotonin and dopamine terminals in ventrolateral nucleus accumbens Brain Research Bulletin, Volume 37, Issue 1, 1995, Pages 37-40 Clyde F. Phelix and Patricia A. Broderick
  59. ^ [59]Journal of Pharmacology And Experimental Therapeutics Fast Forward First published on February 24, 2004; DOI: 10.1124/jpet.103.060293
  60. ^ [60]Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys Pharmacology Biochemistry and Behavior, Volume 80, Issue 3, March 2005, Pages 481-491 Brett C. Ginsburg, Heather L. Kimmel, F. Ivy Carroll, Mark M. Goodman and Leonard L. Howell
  61. ^ [61]Paul W. Czoty, Brett C. Ginsburg, and Leonard L. Howell Serotonergic Attenuation of the Reinforcing and Neurochemical Effects of Cocaine in Squirrel Monkeys J. Pharmacol. Exp. Ther. 2002 300: 831-837.
  62. ^ [62]Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys. L. L. Howell, F. I. Carroll, J. R. Votaw, M. M. Goodman, and H. L. Kimmel (2007) J. Pharmacol. Exp. Ther. 320, 757-765
  63. ^ [63]S. Wee, K. G. Anderson, M. H. Baumann, R. B. Rothman, B. E. Blough, and W. L. Woolverton Relationship between the Serotonergic Activity and Reinforcing Effects of a Series of Amphetamine Analogs J. Pharmacol. Exp. Ther. 2005 313: 848-854.
  64. ^ [64]Richard B. Rothman, Bruce E. Blough, William L. Woolverton, Karen G. Anderson, S. Stevens Negus, Nancy K. Mello, Bryan L. Roth, and Michael H. Baumann Development of a Rationally Designed, Low Abuse Potential, Biogenic Amine Releaser That Suppresses Cocaine Self-Administration J. Pharmacol. Exp. Ther. 2005 313: 1361-1369.
  65. ^ [65]R. B ROTHMAN and M. H BAUMANN Balance between Dopamine and Serotonin Release Modulates Behavioral Effects of Amphetamine-Type Drugs. Ann. N.Y. Acad. Sci., August 1, 2006; 1074: 245 - 260.
  66. ^ [66]. S. S. Negus, N. K. Mello, B. E. Blough, M. H. Baumann, and R. B. Rothman Monoamine Releasers with Varying Selectivity for Dopamine/Norepinephrine versus Serotonin Release as Candidate "Agonist" Medications for Cocaine Dependence: Studies in Assays of Cocaine Discrimination and Cocaine Self-Administration in Rhesus Monkeys J. Pharmacol. Exp. Ther. 2007 320: 627-636.
  67. ^ United States Patent, 6268535 Moussa, et al. July 31, 2001
  68. ^ United States Patent 6,700,018 Richelson, et al. March 2, 2004
  69. ^ United States Patent 6,069,177 Carlier, et al. May 30, 2000
  70. ^ United States Patent 6,914,080 Richelson, et al. July 5, 2005
  71. ^ United States Patent 7,098,230 Lippa, et al. August 29, 2006
  72. ^ United States Patent 7,081,471 Lippa, et al. July 25, 2006
  73. ^ United States Patent 7,041,835 Lippa, et al. May 9, 2006 (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor
  74. ^ United States Patent 6,716,868 Lippa, et al. April 6, 2004
  75. ^ United States Patent 6,569,887 Lippa, et al. May 27, 2003
  76. ^ WO2004052858 Publication date: 2004-06-24 Inventor: CLARK BARRY PETER (GB); CASES-THOMAS MANUEL JAVIER (GB); GALLAGHER PETER THADDEUS (GB); GILMORE JEREMY (GB); MASTERS JOHN JOSEPH (US); TIMMS GRAHAM HENRY (GB); WHATTON MARIA ANN (GB); WOOD VIRGINIA ANN (GB) Applicant: LILLY CO ELI (US); CLARK BARRY PETER (GB); CASES-THOMAS MANUEL JAVIER (GB); GALLAGHER PETER THADDEUS (GB); GILMORE JEREMY (GB); MASTERS JOHN JOSEPH (US); TIMMS GRAHAM HENRY (GB); WHATTON MARIA ANN (GB); WOOD VIRGINIA ANN (GB
  77. ^ WO2005092885 Publication date: 2005-10-06 Inventor: BOULET SERGE LOUIS (US); CLARK BARRY PETER (GB); FAIRHURST JOHN (GB); GALLAGHER PETER THADDEUS (GB); JOHANSSON ANETTE MARGARETA (US); WHATTON MARIA ANN (GB); WOOD VIRGINIA ANN (GB) Applicant: LILLY CO ELI (US); BOULET SERGE LOUIS (US); CLARK BARRY PETER (GB); FAIRHURST JOHN (GB); GALLAGHER PETER THADDEUS (GB); JOHANSSON ANETTE MARGARETA (US); WHATTON MARIA ANN (GB); WOOD VIRGINIA ANN (GB)
  78. ^ WO2006020049 Publication date: 2006-02-23 Inventor: MOLINO BRUCE F (US); LIU SHUANG (US); BERKOWITZ BARRY A (US); GUZZO PETER R (US); BECK JAMES P (US); COHEN MARLENE (US) Applicant: AMR TECHNOLOGY INC (US); SQUIBB BRISTOL MYERS CO (US)
  79. ^ WO2006058016 Publication date: 2006-06-01 Inventor: MOLINO BRUCE F (US); BERKOWITZ BARRY (US); COHEN MARLENE (US) Applicant: AMR TECHNOLOGY INC (US)
  80. ^ US2002128284, 2002-09-12, SCHEEL-KRUGER JORGEN (DK); MOLDT PETER (DK); WAETJEN FRANK (DK)
  81. ^ WO2005011694 FROSTRUP BRIAN (DK); WAETJEN FRANK (DK); JENSEN KLAUS SNEJ (DK) 2006-03-15.
  82. ^ DE602004005048D, 2007-04-12, FROSTRUP B (DK); WAETJEN F(DK); JENSEN (DK)
  83. ^ United States Patent 3,912,743 Christensen, et al. October 14, 1975 4-Phenylpiperidine compounds