|
|
World Psychiatry. 2003 February; 2(1): 3–8. | PMCID: PMC1525061 |
The future of antidepressant pharmacotherapy DAVID BALDWIN1 and CHRIS THOMPSON1 1Community Clinical Sciences Research Division, Faculty of Medicine, Health and Biological Sciences, University of Southampton, UK Although there are many drugs and psychotherapies available for the treatment
of depression, the overall care of depressed patients is usually far from
optimal. This review examines how care might be improved in the future, by
considering a number of alternative approaches: enhanced use of existing treatments,
modifications to existing antidepressant drugs, new targets for antidepressant
pharmacotherapy, and non-pharmacological physical treatments. It examines
how advances in genetics and neuroscience may lead towards individualised
drug treatment, but concludes cautiously, emphasising that theoretical treatment
advances can only improve clinical outcomes if used rationally, in collaboration
with the patient. When considering the future of antidepressant treatment, the properties
of the notional 'ideal antidepressant' need to be examined (Table 1). Clearly, no such drug exists at present. Furthermore,
advances in neuroscience may lead to the development of more efficacious antidepressants,
but if these are not readily acceptable to depressed patients the impact of
new technologies is likely to be limited. ENHANCED USE OF EXISTING TREATMENTS Clinical outcomes in depression might be improved simply by the better
use of existing treatment approaches, for example by prescribing antidepressants
according to evidence-based guidelines, with or without supplementary algorithms;
or through judicious combination of antidepressants with structured psychotherapies. One component of evidence-based practice is the use of clinical guidelines
that are based upon current best research evidence, and designed to help practitioners
and patients make appropriate decisions in specific clinical circumstances.
Many sets of guidelines for the treatment of depression are available, but
their quality is often poor; few demonstrate their origin in research evidence
and most do not present their recommendations in a concise and accessible
format ( 1). Two prominent recent evidence-
based guidelines of high quality are those produced by the British Association
for Psychopharmacology ( 2) and the World
Federation of Societies of Biological Psychiatry ( 3). Despite their widespread availability, guidelines are not used extensively.
A recent review ( 4) of clinical outcomes
in depression stated that "there are no observational studies of routine care
for patients with major depression in the United Kingdom or United States
that have found most patients to be receiving care consistent with evidence-based
guidelines". Outcomes will not necessarily be improved by the arrival of more
effective or better tolerated treatments; the whole process of care for depressed
patients needs to be enhanced, which requires considerable change in the organisation
and function of health care teams. Randomised controlled trials of the treatment of depressed patients in
primary care show that clinical outcomes can be improved, with greater symptom
reduction and improved social function: when examined, the costs of individual
care may be increased, but overall cost-effectiveness is greater ( 5- 11). The interventions
that result in improved outcomes share certain characteristics: namely 'case
management' and some involvement of specialist mental health services. Case
management includes a number of activities, such as assuming responsibility
for patient follow-up, assessing whether depressive symptoms are resolving,
monitoring adherence to treatment, and taking action when patients depart
from guideline-based treatment. This more assertive approach to care usually
requires some sort of active case register of patients with depression who
have not yet recovered. In theory, the impact of treatment guidelines may be enhanced with the
use of supplementary algorithms - i.e., rule-based deductive systems that
operate with inputs, sequences and outputs, that help health professionals
select information that is relevant to clinical decision-making, particularly
when these reflect local circumstances ( 12).
Recent findings from the Texas Medication Algorithm Project ( 13) show that clinical outcomes in depressed patients can
be improved significantly through adherence to computerised treatment algorithms
and decision support systems ( 14). Table 1 The ideal antidepressant Few treatment guidelines have addressed the question of when to combine
antidepressant drugs with psychological treatments in the management of depression,
partly because the effects of this combination have not been examined extensively.
The British Association for Psychopharmacology guidelines recommend that adjunctive
cognitive therapy is considered for residual depressive symptoms in antidepressant-treated
patients, and notes that adjunctive cognitive or interpersonal psychotherapy
may improve outcome in treatment-resistant depressed patients in secondary
care settings ( 2). A recent large randomised
controlled trial of nefazodone, the cognitivebehavioural analysis system of
psychotherapy, and their combination, in patients with chronic depression
found that 48% of patients responded to nefazodone or psychotherapy, as compared
to 73% in the combined-treatment group ( 15). MODIFICATIONS TO EXISTING ANTIDEPRESSANTS Clinical outcomes might also be enhanced by modifications to some of the
antidepressants that are already available. These modifications include the
production of single enantiomeric drugs, when the 'parent' compound is a racemic
mixture; changes to the mode of delivery or pharmacokinetic properties of
an existing drug; and the combination of two psychotropic drugs within a single
tablet, the components being in different formulations to those that are presently
available. Many pharmacological compounds have a chiral centre (usually a carbon atom)
and therefore exist as pairs of enantiomers (non-superimposable mirror images),
differing solely in their three-dimensional characteristics. When a compound
includes a pair of enantiomers it is known as a 'racemic mixture'. Although
enantiomers have identical physicochemical properties, they can show major
differences in their interaction with chiral drug targets in the body, leading
to differences in pharmacodynamic and pharmacokinetic properties. Single enantiomeric drugs can have certain advantages over racemic compounds,
by allowing reduced variability in metabolism and response, simpler dose-response
relationships, reduction in dosage and reduced toxicity ( 16). This is the case with the local anaesthetic levobupivacaine,
where safety has been improved, without compromising efficacy. However, not
all 'enantiomeric switches' have been successful: dexfenfluramine, the active
enantiomer of fenfluramine, was withdrawn from use because of cardiac toxicity.
The antidepressants citalopram and bupropion both exist as racemic mixtures,
and single enantiomers of both compounds have undergone development: the properties
of the more active (+) isomer of bupropion (GW353162) are still being evaluated,
but escitalopram is now available for clinical use. The antidepressant escitalopram is a single enantiomeric drug that is both
more potent and selective than the parent compound, racemic citalopram ( 17). In randomised double-blind placebo-controlled
trials, and pooled analysis of trial data, escitalopram appears to have advantages
over citalopram, in terms of onset of action and greater overall efficacy,
and is similarly tolerated ( 18). An alternative modification to existing antidepressants is to alter their
mode of delivery: this has been attempted with the existing antidepressant
mirtazapine, which appears to be more efficacious than certain selective serotonin
reuptake inhibitors (SSRIs) in the treatment of major depression, having either
greater overall efficacy or an earlier onset of action ( 19). A new formulation of mirtazapine (an orally disintegrating
tablet) has similar bioequivalence ( 20)
to the existing preparation. The preliminary results of an open-label prospective
onset-of-action study suggest that up to 45% of patients are substantially
improved within two weeks ( 21), and
a randomised controlled treatment study showed significant advantages for
mirtazapine over sertraline after four days of treatment ( 22). It seems unlikely that the new formulation itself is
responsible for this rapid onset of action but there has been no direct comparison
between it and the standard tablet. A further approach is to combine two licensed psychotropic drugs into a
new preparation, in which both drugs are present but in different doses to
those available as the single compound. This approach has been adopted in
the development of the olanzapine-fluoxetine combination tablet, currently
being evaluated in the treatment of patients with resistant depression. In
animal models, the combination of olanzapine with fluoxetine produces robust
and sustained increases in extracellular levels of both dopamine and noradrenaline,
greater than those with either drug when given alone. However, combining olanzapine
with sertraline, or fluoxetine with risperidone or clozapine, does not result
in similar changes ( 23). The olanzapine-fluoxetine
combination has now been investigated in a randomised double-blind placebo-controlled
study, and found significantly more efficacious than either drug given alone,
in patients with resistant depression ( 24). NEW TARGETS FOR ANTIDEPRESSANT PHARMACOTHERAPY Potential new antidepressant drugs include antagonists at the substance
P (NK-1) receptor; corticotropin-releasing factor (CRF) receptor antagonists;
glucocorticoid receptor antagonists; vasopressin receptor antagonists; and
melatonin receptor agonists. Selective non-peptide antagonists for tachykinin receptors have been available
for ten years, but drug development has focused on the substance-P-preferring
receptor known as neurokinin-1 (NK1). Originally developed as potential analgesics,
NK1 receptor antagonists have been found to have antidepressant and anxiolytic
properties in animal models ( 25). These
effects are independent of direct actions on monoamine reuptake sites, transporter
proteins or receptors, nor are they due to effects on monoamine oxidase. However,
chronic treatment with the substance P receptor antagonist L-760735 results
in burst firing of the locus coeruleus, without causing functional desensitisation
of somatic alpha-2 adrenoceptors (in contrast to imipramine), suggesting that
L-760735 has a local site of action at the locus coeruleus ( 26). Experiments with 'knock-out' mice lacking NK1 receptors
show that lack of NK1 receptors appears to be associated with down-regulation
or functional desensitisation of 5-HT1A receptors resembling that induced
by chronic treatment with SSRIs ( 27).
A randomised controlled trial with the substance P antagonist MK 869 found
that it had similar efficacy to paroxetine in patients with major depression
( 28). However, the antidepressant effect
of MK 869 was not confirmed in a subsequent treatment study. Many further
compounds are currently under development ( 29). An alternative approach to antidepressant drug development targets the
CRF receptor. Two CRF subtypes are known to exist, differing in their localisation
and receptor pharmacology. The CRF1 receptor is abundant within cerebral cortex,
cerebellum and pituitary, whereas CRF2 receptors are found mainly in the septum,
ventromedial hypothalamus and dorsal raphe nucleus ( 30). Administration of CRF in animal models results in decreased
appetite, disrupted sleep, decreased sexual activity and reduced exploratory
behaviour; as depressed patients are often hypercortisolaemic, it has been
suggested that CRF may be hypersecreted in depressed patients. A number of
selective CRF1 receptor antagonists are being developed, preliminary evidence
indicating that they are likely to be efficacious in the treatment of depression
and anxiety disorders ( 31, 32). A similar approach may be possible in developing psychotropic drugs that
are effective in the treatment of psychotic depression, a condition that is
associated with a higher rate of dexamethasone non-suppression than is seen
in non-psychotic major depression ( 33).
High cortisol levels can be reduced by blocking the synthesis of cortisol
- for example by treatment with metyrapone, aminoglutethamide or ketoconazole
- but these compounds are all troublesome to use, with major adverse effects
and untoward drug interactions ( 34).
An alternative approach is to antagonise central glucocorticoid receptors:
as cortisol has a similar structure to progesterone, the progesterone antagonist
mifepristone (RU486) has been evaluated as a potential treatment for psychotic
depression. A recent preliminary double-blind placebo-controlled crossover
study with mifepristone ( 35) suggests
that it is efficacious, and more extensive trials are being conducted. Another potential approach to the development of new antidepressant and
anxiolytic compounds might arise from research into the role of vasopressin
receptors in stress responses. Arginine vasopressin (AVP) is produced in the
hypothalamus and is involved in the regulation of secretion of corticotropin
by the pituitary gland; AVP-containing neurones project to the limbic system,
and vasopressin receptors (V1A and V2A) are located in the septum and hippocampus.
Recent results show that an antagonist at vasopressin V1B receptors (SSR149415)
is effective in rodent models of both anxiety and depression, these effects
probably occurring through receptors in limbic structures ( 36). An alternative approach to antidepressant drug development is to focus
on the effects of melatonin receptor agonists. Normal circadian rhythms can
be disturbed in certain groups of depressed patients: for example, seasonal
depression may be associated with phase-advance of the circadian rhythm of
melatonin relative to the sleep temperature rhythm ( 37). Melatonin agonists may possess both chronobiotic and
antidepressant activity. For example, one such compound (agomelatine, which
also has 5- HT2C antagonist properties), previously demonstrated to exert
chronobiotic effects ( 38, 39), has shown antidepressant- like activity in five behavioural
models of depression in the rat, and is currently being investigated as a
treatment for major depression. NOVEL NON-PHARMACOLOGICAL PHYSICAL TREATMENTS The last decade has seen advances in the management of resistant depression
by non-pharmacological physical treatments, including vagus nerve stimulation
(VNS) and transcranial magnetic stimulation (TMS). Treatments such as these
are likely to be adopted only infrequently, in patients who have not responded
to more conventional approaches, but they may offer some additional insight
into the pathophysiology of depression and the mechanism of the antidepressant
response. Following the observation that intermittent electrical stimulation of the
vagus nerve can alter electrical activity and reduce seizures in dogs, over
6000 people have received this procedure for treatment-resistant epilepsy:
it is now being investigated as a potential treatment for refractory depression
( 40). In an open pilot study of VNS
in resistant depression, a ten-week course was found efficacious in 30.5%
of patients, the most common adverse event being hoarseness ( 41). A further nine-months openlabel treatment increased
response and remission rates ( 42).
Neuropsychological testing indicates that VNS does not affect cognitive functions
adversely: rather, improvement from depression is accompanied by improvements
in motor speed, psychomotor function and executive functions ( 43). Repetitive TMS may be efficacious as an alternative to electroconvulsive
therapy in the treatment of selected patients with depression, bipolar affective
disorder or schizophrenia. An early parallel-design double-masked sham-controlled
treatment study in 30 patients found that daily left prefrontal cortex TMS
was significantly more efficacious than sham treatment ( 44). A subsequent study, in patients who had not responded
to a median of four previous antidepressant treatments, found statistically
significant but clinically modest reductions in depressive symptoms ( 45). However, the early findings of a recent
comparative treatment study show that TMS and electroconvulsive therapy have
similar overall efficacy ( 46). Two
recent systematic reviews of the efficacy of TMS have produced conflicting
results ( 47, 48). The mechanism underlying the antidepressant effects
of TMS is unclear, but the behavioural and neuroendocrine effects in animal
models are similar to those seen with antidepressant drugs ( 49). TREATMENT ADVANCES BASED ON PHARMACOGENOMIC RESEARCH Variations in the human genome account for the genetic component of individuality,
susceptibility to disease and response to drug treatment. Much of the variation
in the genome is due to single nucleotide polymorphisms (SNPs) where two alternate
bases occur at one position ( 50). Many
thousands of polymorphisms have been identified and ordered in high-density
SNP maps (51), that are useful in identifying genes associated with polygenic
diseases, where each gene variant contributes only a small increase in relative
risk. Such is the case with depression, where no single major candidate gene
has been identified; furthermore the phenotype of 'major depression' is rather
illdefined - two depressed patients can fulfil the same set of diagnostic
criteria, without sharing a single symptom. Pharmacogenomics uses high-density SNP maps to correlate a patient's genetic
profile with his response to a certain drug. The goal of pharmacogenomic research
is to match an individual patient phenotype with an individual drug treatment,
targeted against proteins containing functionally relevant SNPs ( 52). For this approach to be successful, patients have to
be characterised in great detail: for example, the Munich Antidepressant Response
Signature (MARS) project collects data on current psychopathology, early experience,
life events, previous treatment response, drug levels, and functional measures,
including neuropsychological performance, sleep electroencephalography and
neuroendocrine parameters ( 53). If successful, depressed patients could then be separated into clinical
sub-groups, within what used to be considered a single disorder. A patient
genotype would determine the likelihood of response to a particular antidepressant;
conceivably, this should result in treatment that has an earlier onset of
action and greater overall efficacy, and which is better tolerated with fewer
side effects. However, great effort would be required, in terms of detailed
patient characterisation and expensive genetic analyses, before such an approach
become a clinical reality. A somewhat different genetic approach has recently been successful in another
complex phenotype - asthma. Here, a standard linkage approach in a large,
well-characterised cohort demonstrated a gene that accounted for a moderate
(40%) proportion of the variance in asthma. The protein (ADAM 33) that it
coded for was identified and its mechanism of action elucidated. This new
knowledge may well facilitate the discovery of new pathophysiologies and treatments
for asthma in the future and there is no theoretical or technological reason
why the same process cannot succeed in depression. The existing antidepressant drugs are far from ideal. Typically, patients
derive little benefit during the first four weeks of treatment, and many patients
do not achieve the goal of remission of symptoms. There is a need for both
faster-acting and more effective antidepressants, but the methodology for
assessing onset of antidepressant effects is complex ( 19) and symptom-based definitions of remission may not take
into account other aspects of recovery from depression, such as social functioning
( 54). More efforts are required to
better define the efficacy of treatment. Furthermore, the assessment of the
tolerability of treatment needs to move from simple counts of treatmentemergent
adverse effects towards a more detailed assessment of any unacceptable effects
on everyday life. There are many approaches towards the development of potential new antidepressant
treatments, but the likely impact of new health technologies is hard to predict.
But there is much room for optimism, with current advances in genetic research
and neuroscience. The development of treatments that are more efficacious
or earlier to act remains a goal of drug discovery, but if new treatments
are complex for doctors to conduct, hard for patients to tolerate, or too
expensive for healthcare providers to offer, they will have a rather limited
impact. Ground-breaking treatments can only alter the burden of illness when
they are adopted widely by clinicians, and accepted readily by patients. 1. Peveler R. Kendrick T. Treatment delivery and guidelines in primary care. Br Med Bull. 2001;57:193–206. [PubMed] 2. Anderson I. Nutt DJ. Deakin JFW. Evidence-based guidelines for treating depressive disorders
with antidepressants. A revision of the 1993 British Association for Psychopharmacology
guidelines. J Psychopharmacol. 2000;14:3–20. [PubMed] 3. Bauer M. Whybrow P. Angst J, et al. World Federation of Societies of Biological Psychiatry guidelines
for biological treatment of unipolar depressive disorders. Part 1: Acute and
continuation treatment of major depressive disorder. World J Biol Psychiatry. 2002;3:5–43. [PubMed] 4. von Korff M. Goldberg D. Improving outcomes in depression. Br Med J. 2001;323:948–949. [PubMed] 5. Katon W. von Korff M, et al. Lin E, et al. Collaborative management to achieve treatment guidelines: impact
on depression in primary care. JAMA. 1995;273:1026–1031. [PubMed] 6. Katon W. Robinson P. von Korff M, et al. A multifaceted intervention to improve treatment of depression
in primary care. Arch Gen Psychiatry. 1996;53:924–932. [PubMed] 7. Katon W. von Korff M. Lin E, et al. Stepped collaborative care for primary care patients with persistent
symptoms of depression. Arch Gen Psychiatry. 1999;56:1109–1115. [PubMed] 8. Rost K. Nutting P. Smith J, et al. Improving depression outcomes in community primary care practice.
A randomized trial of the QuEST intervention. J Gen Intern Med. 2001;16:143–149. [PubMed] 9. Wells K. Sherbourne C. Schoenbaum M, et al. Impact of disseminating quality improvement programs for depression
in managed primary care. A randomized controlled trial. JAMA. 2000;283:212–220. [PubMed] 10. Simon G. von Korff K. Rutter C, et al. Randomised trial of monitoring, feedback, and management of
care by telephone to improve treatment of depression in primary care. Br Med J. 2000;320:550–554. [PubMed] 11. Peveler R. George C. Kinmonth A-L, et al. Effect of antidepressant drug counselling and information leaflets
on adherence to drug treatment in primary care: randomised controlled trial. Br Med J. 1999;319:612–615. [PubMed] 12. Stein D. Xin Y. Osser D, et al. Clinical psychopharmacology guidelines: different strokes for
different folks. World J Biol Psychiatry. 2002;3:64–67. [PubMed] 13. Rush AJ. Crimson M. Toprac M, et al. Implementing guidelines and systems of care: experiences with
the Texas Medication Algorithm Project (TMAP). J Pract Psychiatr Behav Health. 1999;5:75–86. 14. Trivedi M. Lessons from the Texas Medication Algorithm Project. Int J Neuropsychopharmacol. 2002;5(Suppl.1):S11. 15. Keller M. McCullough J. Klein D, et al. A comparison of nefazodone, the cognitive-behavioural analysis
system of psychotherapy, and their combination for the treatment of chronic
depression. N Engl J Med. 2000;342:1462–1470. [PubMed] 16. Wainer IW. The therapeutic promise of single enantiomers: introduction. Hum Psychopharmacol Clin Exp. 2001;16(Suppl.2):S73–S77. 17. Owens MJ. Knight DL. Nemeroff CB. Second-generation SSRIs: human transporter binding profile
of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50:345–350. [PubMed] 18. Gorman JM. Korotzer A. Su G. Efficacy comparison of escitalopram and citalopram in the treatment
of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums. 2002;7(Suppl.1):40–44. [PubMed] 19. Thompson C. Onset of action of antidepressants: results of different analyses. Hum Psychopharmacol Clin Exp. 2002;17(Suppl.1):S27–S32. 20. van den Houvel MW. Kleijn HJ. Peeters PAM. Bioequivalence trial of orally disintegrating mirtazapine tablets
and conventional oral mirtazapine tablets in healthy volunteers. Clin Pharmacokinet. 2001;21:437–442. 21. Roose SP. Holland PJ. Hassman HA, et al. Multi-site, open-label, observational study of the effectiveness
and safety of Remeron SolTab (mirtazapine orally disintegrating tablets) in
depressed patients who are at least 50 years of age. Data on file, N.V. Organon. 22. Kennedy S. Vester-Blokland ED., and the RAPID study group. Mirtazapine (Remeron SolTab) vs. sertraline: a prospective onsetof-action
trial. Data on file, N.V. Organon. 23. Zhang W. Perry KW. Wong DT, et al. Synergistic effects of olanzapine and other antipsychotic agents
in combination with fluoxetine on norepinephrine and dopamine release in rat
prefrontal cortex. Neuropsychopharmacology. 2000;23:250–262. [PubMed] 24. Shelton RC. Tollefson GD. Tohen M, et al. A novel augmentation strategy for treating resistant major
depression. Am J Psychiatry. 2001;158:131–134. [PubMed] 25. Stout S. Owens M. Nemeroff C. Neurokinin (1) receptor antagonists as potential antidepressants. Annu Rev Pharmacol Toxicol. 2001;41:877–906. [PubMed] 26. Maubach K. Martin K. Chicchi G, et al. Chronic substance P (NK1) receptor antagonist and conventional
antidepressant treatment increases burst firing of monoamine neurones in the
locus coeruleus. Neuroscience. 2002;109:609–617. [PubMed] 27. Froger N. Gardier A. Moratalla R, et al. 5-hydroxytryptamine (5- HT) 1a autoreceptor adaptive changes
in substance P (neurokinin 1) receptor knock-out mice mimic antidepressantinduced
desensitization. J Neurosci. 2001;21:8188–8197. [PubMed] 28. Kramer M. Cutler N. Feighner J, et al. Distinct mechanism for antidepressant activity by blockade
of central substance P receptors. Science. 1998;281:1640–1645. [PubMed] 29. Argyropoulos S. Nutt D. Substance P antagonists: novel agents in the treatment of depression. Exp Opin Invest Drugs. 2000;9:1871–1875. 30. Chalmers D. Lovenberg T. Grigoriadis D, et al. Corticotropinreleasing factor receptors: from molecular biology
to drug design. Trends Pharmacol Sci. 1996;17:166–172. [PubMed] 31. Zobel A. Nickel T. Kunzel H, et al. Effects of the high-affinity corticotropin- releasing hormone
receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res. 2000;34:171–181. [PubMed] 32. Nemeroff C. New directions in the development of antidepressants: the interface
of neurobiology and psychiatry. Hum Psychopharmacol Clin Exp. 2002;17:S13–S16. 33. Nelson J. Davis J. DST studies in psychotic depression: a metaanalysis. Am J Psychiatry. 1997;154:1497–1503. [PubMed] 34. McQuade R. Young AH. Future therapeutic targets in mood disorders: the glucocorticoid
receptor. Br J Psychiatry. 2000;177:390–395. [PubMed] 35. Belanoff JK. Flores BH. Kalezhan M, et al. Rapid reversal of psychotic depression using mifepristone. J Clin Psychopharmacol. 2001;21:516–521. [PubMed] 36. Griebel G. Anxiolytic- and antidepressant-like effects of the nonpeptide
vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach
for the treatment of stress-related disorders. Proc Natl Acad Sci USA. 2002;99:6370–6375. [PubMed] 37. Dahl K. Avery DH. Lewy AJ, et al. Dim light melatonin onset and circadian temperature during
a constant routine in hypersomnic winter depression. Acta Psychiatr Scand. 1993;88:60–66. [PubMed] 38. Redman JR. Guardiola-Lemaitre B. Brown M, et al. Dose-dependent effects of S-20098, a melatonin agonist on direction
of reentrainment of rat circadian rhythms. Psychopharmacology. 1995;118:385–390. [PubMed] 39. Ying SW. Rusak B. Delagrange P, et al. Melatonin analogues as agonists and antagonists in the circadian
system and other brain areas. Eur J Pharmacol. 1996;296:33–42. [PubMed] 40. George MS. Sackheim HA. Rush AJ, et al. Vagus nerve stimulation: a new tool for brain research and
therapy. Biol Psychiatry. 2000;47:273–275. [PubMed] 41. Sackheim HA. Rush AJ. George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression:
efficacy, side effects and predictors of outcome. Neuropsychopharmacology. 2001;25:713–728. [PubMed] 42. Marangell LB. Rush AJ. George MS, et al. Vagus nerve stimulation for major depressive episodes: one
year outcomes. Biol Psychiatry. 2002;51:280–287. [PubMed] 43. Sackheim HA. Keilp JG. Rush AJ, et al. The effects of vagus nerve stimulation on cognitive performance
in patients with treatmentresistant depression. Neuropsychiatr Neuropsychol Behav Neurol. 2001;14:53–62. 44. George MS. Nahas Z. Molloy M, et al. A controlled trial of daily prefrontal cortex TMS for treating
depression. Biol Psychiatry. 2000;48:959–961. [PubMed] 45. Berman RM. Narasimhan M. Sanacora G, et al. A randomized clinical trial of repetitive transcranial magnetic
stimulation in the treatment of major depression. Biol Psychiatry. 2000;47:332–337. [PubMed] 46. Janicak PG. Dowd SM. Martis B, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive
therapy for major depression: preliminary results of a randomized trial. Biol Psychiatry. 2002;51:659–667. [PubMed] 47. Martin J. Barbanoj MJ. Sclaepfer TE, et al. Transcranial magnetic stimulation for treating depression. Cochrane Database Syst Rev. 2002;2 CD003493. 48. McNamara B. Ray JL. Arthurs OJ, et al. Transcranial magnetic stimulation for depression and other
psychiatric disorders. Psychol Med. 2001;31:1141–1146. [PubMed] 49. Keck ME. Welt T. Post A, et al. Neuroendocrine and behavioural effects of repetitive transcranial
magnetic stimulation in a psychopathological animal model are suggestive of
antidepressantlike effects. Neuropsychopharmacology. 2001;24:337–349. [PubMed] 50. Taillon-Miller P. Gu Z. Li Q, et al. Overlapping genomic sequences: a treasure-trove of single-nucleotide
polymorphisms. Genome Res. 1998;8:748–754. [PubMed] 51. Roses A. Pharmacogenetics and the practice of medicine. Nature. 2000;405:857–865. [PubMed] 52. Roses A. Genome-based pharmacogenetics and the pharmaceutical industry. Nature Drug Discov. 2002;1:541–549. 53. Holsboer F. Antidepressant drug discovery in the postgenomic era. World J Biol Psychiatry. 2001;2:165–177. [PubMed] 54. Hirschfeld R. Montgomery S. Keller M, et al. Social functioning in depression: a review. J Clin Psychiatry. 2000;61:268–275. [PubMed] 55. Van Eerdewegh P. Little RD. Dupuis J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002;418:426–430. [PubMed]
|
PHARMACOLOGICAL PHYSICAL TREATMENTS