Personalized Medicine & DSM-V: New Developments in diagnostics and treatment of ADHD and Depression

 

For the Brainclinics website on Treatment of Depression with rTMS and Neurofeedback therapy for ADHD  also see www.brainclinics.com The treatment of psychiatric complaints is constantly subject to new insights and scientific developments. Not too long ago lobotomy used to be a common treatment method for serious psychiatric complaints. Nowadays medication and psychotherapy are applied on a large scale. During the past years our neurobiological knowledge of psychiatric disorders has grown rapidly and the implementation of these new insights into practice is a new challenge to everyone working in the mental health care field. Over the past few years there has also been a clear shift from a systemic – or drug treatment – to a more local treatment which is more directed to a specific area or networks in the brain. Examples of local treatment methods are the application of magnetic brain stimulation (TMS or rTMS), deep-brain stimulation and EEG-biofeedback or neurofeedback. Another development which is complementary to the above mentioned one is Personalized Medicine. Its goal is to personalize therapy on the basis of genotypic and phenotypic information in order to reach higher effectiveness for different kinds of treatments. One of the most important questions which will be dealt with is “what is the contribution of local treatment modalities and the application of personalized medicine to the present psychiatric / psychological practice?” Subsequently we will address which difference personalized medicine and these new treatment methods can make specifically for the treatment of ADHD and depression. From a systemic treatment approach to personalized medicine or Theranostics Current conventional treatment methods in the field of mental healthcare are based on psychotherapy and medication (‘systemic’ approach). The effectiveness of medication can be ascribed to a certain neurotransmitter substance such as 5-HT (serotonin) which is increased in the entire brain, although it is oftentimes only required in a specific part of the brain. This explains the side effects of many medications to a great extent. Furthermore, drug treatment in psychiatry only has limited effectiveness (40-60% for depression (Keller et al., 2000) and 60-80% for ADHD (Swanson et al., 1993 & Gordon, 2007)). On the basis of a recent meta-analysis Kirsch et al. (2008) even conclude that there is no clinically relevant effect of antidepressants compared to placebo except for extremely depressed patients where the effect could be attributed to a lower placebo response. Recently a number of new highly promising local treatment methods has been reported such as the treatment of depressive complaints with magnetic brain stimulation (rTMS: Wasserman & Lisanby, 2001); the treatment of tinnitus and chronic pain by means of electric and magnetic stimulation (rTMS) of the auditory and sensomotoric cortex (de Ridder et al. 2007 a; 2007 b); waking up from a “state of coma” (minimally conscious state) through deep brain stimulation (Schiff et al., 2007), the suppression of auditory hallucinations in schizophrenia through magnetic brain stimulation (TMS: Hoffman et al. 2000, 2003, 2005) and neurofeedback / EEG biofeedback treatment of ADHD and epilepsy (Sterman, 2000; Lubar, 1991; Lubar & Lubar, 1984; Lubar, Swartwood, Swartwood & O'Donnell, 1995). These newly developed treatment methods provide us with a completely new view of diagnostics and treatment of brain disorders whereby broad categories such as “depression” and “schizophrenia” are no longer relevant. These new treatment methods rather focus on a specific complaint (such as auditory hallucinations, depressed mood or tinnitus) rather than blindly applying the same treatment to all patients with the same diagnosis. The most critical factor of these new treatment methods is the ‘diagnostics’ – or the personalizing – such as determining whether depressed patients indeed show decreased activity in the left frontal cortex before applying rTMS (Eschweiler et al. 2000) or determining where exactly on the auditory cortex the source of the tinnitus is by using LORETA (source localization) and fMRI (de Ridder et al. 2007a). These local treatment methods have an important advantage: they show less side effects and a potentially higher effectiveness. An important disadvantage, however, is that first a clearly indicated cause has to be found in the diagnosing process before the treatment can be applied, with the consequence that not all patients are eligible for the treatment. The development of these new local treatment methods is also complimentary to the development of personalized medicine. Personalized medicine is a new approach with the goal to create more effective treatments through personalizing treatment. Usually in this context one thinks of a genetic marker which predicts the effect of medication the best such as the classic case of herceptin. Herceptin is a medicine used for breast cancer treatment, but only for patients showing an over-expression for a specific protein better known as Human Epidermal Growth Factor receptor 2 (HER2: Piccart et al., 2005). This medicine only works well with this specific sub-group of patients which is easily distinguished by a genetic test. Considering the relatively low effectiveness of for instance antidepressants (40-60%) and stimulants (60-80%) there seems to be a great need for a personalized approach of psychiatric disorders. Besides there is not one psychiatric disorder that is completely genetically determined (Hyman, 2007), which seems to make a genetic approach to personalized medicine for psychiatry less realistic. In this context Gordon (2007) proposed the term ‘neuro-marker’ and Johnstone et al. (2005) the term ‘EEG Phenotype’. The underlying idea of these is that neuro-imaging (e.g. QEEG, fMRI, PET scans) can be considered as a phenotype which includes both the effects of nature and nurture. Therefore it can give a reliable indication of the ‘state of the system’. This potentially makes neuromarkers or EEG phenotypes also reliable predictors for treatment outcome such as antidepressants or stimulants. This principle was already successfully applied in a revolutionary investigation of Suffin & Emory (1995). They prescribed a certain medication to a group of patients with affective problems (depression) or attention problems (ADHD) solely on the basis of quantitative EEG (QEEG). In their study it could happen that a depressed patient received Ritalin and an ADHD patient had to take an antidepressant, as this was determined only on the basis of their QEEG. In their study the effects of the different kinds of medications are as follows: 87% (antidepressants – frontal alpha group), 100% (stimulants frontal theta group), 85% (anticonvulsive medication / lithium – frontal alpha & hyper-coherent) and 80% (anticonvulsive medication – frontal theta & hyper-coherent). The background of this method will be further explained in the section ADHD and depression. The percentages found in this study are clearly higher than the ones generally reported in the literature for antidepressants and Ritalin. From the perspective of treatment effectiveness this seems to be a very promising approach. These new developments already seem to bring about changes in the view of psychological diagnostics as appears to be the case in the following quote of the APA about the development of DSM-V. “It is our goal to translate basic and clinical neuroscience research relating brain structure, brain function, and behaviour into a classification of psychiatric disorders based on etiology and pathophysiology. It is possible, even likely, that such a classification will be radically different from the current DSM-IV approach.” (Charney et al. APA). The long-expected changes with regard to the new version of the most important clinical psychology manual, the DSM-V, are in line with the above mentioned quotation as follows: Axis I: genotype Axis II: neurobiological phenotype Axis III: behavioural phenotype Axis IV: environmental factors Axis V: Therapeutic targets and response (Charney et al. APA) This proposed new outline of the DSM provides us with a completely different approach as compared to the current DSM-IV. We expect especially axis II: the neurobiological phenotype to become very interesting. Biopsychological and neuroscientific research can potentially make an important contribution to this axis and the implications for treatment. In the following part we will deal with two examples of disorders (ADHD and Depression) in order to further demonstrate the importance of personalized assessments and personalized treatment. We will also investigate the implications of these new developments for daily practice. For the ADHD example click here For the Depression example click here

Why Personalized Medicine - Theranostics? For a nice illustration of "Why Personalized Medicine...?",  also see the movie below Limitations to the new local treatment methods Despite the very promising results and possibilities of the above mentioned techniques, it needs to be mentioned that they are still in their infancy and therefore have to be considered experimental. The safety of some of these techniques is still questionable. The deep-brain stimulation for instance can have the necessary complications since it is a surgical operation with many risks. The superficial brain stimulation includes a surgical operation as well. Therefore these methods are only applied in the most severe cases and after all other treatments have been tried. Other techniques such as rTMS for Depression and EEG biofeedback / Neurofeedback for the treatment of ADHD/ADD have been proven safe treatment modalities, but should only be used for specific disorders that have already been well investigated. EEG biofeedback and neurofeedback are currently advertised for all kinds of disorders, but until now there is only evidence for the effectiveness of Neurofeedback in the treatment of epilepsy (Sterman, 2000) and ADHD (Lubar, 1991; Lubar & Lubar, 1984; Lubar, Swartwood, Swartwood & O'Donnell, 1995). Finally, a too one-sided approach of these techniques is never the best choice either. These techniques can effectively and quickly relief symptoms (such as depressed mood), but when used alone they will most often be short-term. Therefore, combining these techniques with adequate clinical-psychological techniques is a requirement in order to achieve good long-term results and to ensure the patient can embed the symptom relief into daily life.

Literature Arns, M., Gunkelman, J., Breteler, M., Spronk, D. & Gordon, E. (2008) EEG Phenotypes predict treatment outcome to stimulants in children with ADHD. Journal of Integrative Neuroscience. Baehr, E., Rosenfeld, J.P., Baehr, R., & Earnest, C. (1998) Comparison of two EEG asymmetry indices in depressed patients vs. normal controls. International Journal of Psychophysiology, 31, 89-92. Baehr, E., Rosenfeld, J.P., & Baehr, R. (2001) Clinical use of an alpha asymmetry neurofeedback protocol in the treatment of mood disorders: Follow-up study one to five years post therapy. Journal of Neurotherapy, 4 (4), 11-18. Bruder, G.E., Tenke, C.E., Stewart, J.W., Towey, J.P., Leite, P., Voglmaier, M. & Quitkin, F.M. (1995) Brain event-related potentials to complex tones in depressed patients: Relations to perceptual asymmetry and clinical features. Psychophysiology, 32, 373-381. Bruder, G.E., Tenke, C.E., Stewart, J.W., McGrath, P.J. & Quitkin, F.M. (1999) Predictors of Therapeutic Response to Treatments for Depression: A Review of Electrophysiologic and Dichotic Listening Studies. CNS Spectrums, 9, 30-36. Bruder, G., Tenke, C., Jayser, J., Leite, P., McGrath, P. & Quitkin, F. (2001) Pretreatment Differences in ERPs between SSRI Antidepressant Responders and Non-Responders. Presented at the 41stAnnual Meeting of the Society for Psychophysiological Research (SPR), Montreal, Canada, October 13. Chabot, R. & Serfontein, G. (1996) Quantitative electroencephalographic profiles of children with attention deficit disorder. Biological Psychiatry 40, 951-963. Charney, D., Barlow, D., Botteron, K., Cohen, J., Goldman, D., Gur, R., Lin, K.M., Lopez, J.F., Meador-Woodruff, J.H., Moldin, S.O., Nestler, E.J., Watson,  S.J. & Zalcman, S.F. (2002) Neuroscience research agenda to guide development of a pathophysiologically based classification system, in A Research Agenda for DSM-V. Edited by Kupfer D, First M, Regier D. Washington, DC, American Psychiatric Association, 31-84 Clarke, A.R., Barry, R.J., McCarthy, R. & Selikowitz, M. (1998) EEG analysis in attention-deficit/hyperactivity disorder: a comparative study of two subtypes. Psychiatry Research 81, 19–29. Clarke, A.R., Barry, R.J., McCarthy, R. & Selikowitz, M. (2001) Age and sex effects in the EEG: differences in two subtypes of attention-deficit/hyperactivity disorder. Clinical Neurophysiology, 112, 815–826. Clarke, A.R., Barry, R.J., McCarthy, R. & Selikowitz, M. (2002) EEG differences between good and poor responders to methylphenidate and dexamphetamine in children with attentiuon-deficit/hyperactivity disorder. Clinical Neurophysiology, 113, 194-205. Davidson, R.J. (2004) What does the prefrontal cortex "do" in affect: Perspectives on frontal EEG asymmetry research. Biological Psychology, 67, 219-234. De Ridder, D., De Mulder, G., Verstraeten, E., Seidman, M., Elisevich, K., Sunaert, S., Kovacs, S., Van der Kelen, K., Van de Heyning, P. & Moller, A. (2007) Auditory cortex stimulation for tinnitus. Acta Neurochirurgica Supplement, 97(2), 451-462. De Ridder, D., De Mulder, G., Verstraeten, E., Sunaert, S. & Moller, A. (2007) Somatosensory cortex stimulation for deafferentation pain. Acta Neurochirurgica Supplement, 97(2), 67-74. Dunkin, J.J., Leuchter, A.F., Cook, I.A., Kasl-Godley, J.E., Abrams, M. & Rosenberg-Thompson, S. (2000) Executive dysfunction predicts nonresponse to fluoxetine in major depression. Journal of Affective Disorders, 60, 13-23. Eschweiler, G.W., Wegerer, C., Schlotter, W., Spandl, C., Stevens, A., Bartels, M. & Buchkremer, G. (2000) Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression.  Psychiatry Research: Neuroimaging Section, 99, 161-172. Farmacotherapeutisch Kompas (2007) Medisch farmaceutische voorlichting/uitgave van de Commissie Farmaceutische Hulp van het College voor zorgverzekeringen, Amstelveen. Gordon, E. (2007) Integrating genomics and neuromarkers for the era of brain-related personalized medicine. Personalized Medicine, 4(2), 201-215. Hermens, D.F., Williams, L.M., Lazzaro, I., Whitmont, S., Melkonian, D. & Gordon, E. (2004) Sex differences in adult ADHD: a double dissociation in brain activity and autonomic arousal. Biological Psychology, 66, 221-233. Hoffman, R.E., Boutros, N.N., Hu, S., Berman, R,M., Krystal, J.H., Charney, D.S. (2000) Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet, 355: 1073-1075. Hoffman, R.E., Hawkins, K.A., Gueorguieva, R. Boutros, N.N., Rachid, F., Carroll, K., Krystal, J.H. (2003) Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Archives of General Psychiatry, 60: 49-56. Hoffman, R.E., Gueorguieva, R., Hawkins, K.A., Varanko, M., Boutros, N.N., Wu, Y.T., Carroll, K., Krystal, J.H. (2005). Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and predictors in a fifty patient sample. Biological Psychiatry; 58:97-104. Hyman, S.E. (2007) Can Neuroscience be integrated into the DSM-V? Nature Reviews, 8, 725-732 Johnstone, J., Gunkelman, & J.  Lunt, J. (2005) Clinical database development: Characterization of EEG Phenotypes. Clinical EEG and Neuroscience, 36(2); 99-107 Joyce, P.R. & Paykel, E.S. (1989) Predictors of Drug Response in Depression. Archives of General Psychiatry, 46, 89-99. Keller, M.B., McCullough, J.P., Klein, D.N., Arnow, B., Dunner, D.L., Gelenberg, A.J., Markowitz, J.C., Nemeroff, C.B., Russell, J.M., Thase, M.E., Trivedi, M.H., & Zajecka, J. (2000). A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N.Engl.J.Med., 342, 1462-1470. Kirsch, I., Deacon, B.J., Huedo-Medina, T.B., Scoboria, A., Moore, T.J. & Johnson, B.T. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration PLoS Medicine, 5(2), 260-268. Lazzaro, I., Gordon, E., Whitmont, S., Plahn, M., Li, W., Clarke, S., Dosen, A. & Meares, R.A. (1998). Quantified EEG activity in adolescent attention deficit hyperactivity disorder. Clinical Electroencephalography 29, 37–42. Lazzaro, I., Gordon, E., Li, W., Lim, C.L., Plahn, M., Whitmont, S., Clarke, S., Barry, R.J., Dosen, A. & Meares, R.A. (1999). Simultaneous EEG and EDA measures in adolescent attention deficit hyperactivity disorder. International Journal of Psychophysiology 34,123-134. Lubar, J.F. (1991). Discourse on the development of EEG diagnostics and biofeedback  for attention-deficit/hyperactivity disorders. Biofeedback and Self-Regulation,16, 3, 201-225. Lubar, J.O., & Lubar, J.F. (1984). Electroencephalographic biofeedback of SMR and beta for treatment of attention deficit disorders in a clinical setting. Biofeedback and Self-Regulation, 9, 1, 1-23. Lubar, J.F., Swartwood, M.O., Swartwood, J.N., & O'Donnell, P.H. (1995). Evaluation  of  the effectiveness of EEG neurofeedback training for ADHD in a clinical setting as measured by changes in TOVA scores, behavioral ratings, and WISC-R performance. Biofeedback and Self-Regulation, 20, 1, 83-99. Mann, C.A., Lubar, J.F., Zimmerman, A.W., Miller, C.A. & Muenchen, R.A. (1992). Quantitative analysis of EEG in boys with attention-deficit-hyperactivity disorder: controlled study with clinical implications. PediatricNeurology 8, 30–36. Mayberg, H.S., Lozano, A.M., Voon, V., McNeely, H., Seminowicz, D., Hamani, C., Schwalb, J.M. & Kennedy, S.H. (2005) Deep brain stimulation for Treatment-Resistant Depression. Neuron, 45, 651-660. Newman, J.R., Ewing, S.E., McColl, R.D., Borus, J.S., Nierenberg, A.A., Pava, J. & Fava, M. (2000) Tridimensional personality questionnaire and treatment response in major depressive disorder: a negative study. Journal of Affective Disorders, 57, 241-247. Petersen, T., Papakostas, G.I., Bottonari, K., Iacoviello, B., Alpert, J.E., Fava, M. & Nierenberg. (2002) NEO-FFI factor scores as predictors of clinical response to fluoxetine in depressed outpatients. Psychiatry Research, 109, 9-16. Piccart, M.J., Procter, M., Lelyland-Jones, B., Goldhirsch, A., Untch, M., Smith, I., Gianni, L., Baselga, J., Bell, R., Lackisch, C., Cameron, D., Dowsett, M., Barrios, C.H., Steger, G., Huang, C.S., Andresson, M., Inbar, M., Lichinitser, M., Lang, I., Nitz, U., Iwata, H., Thomssen, C., Lohrisch, C., Suter, T.M., Ruschoff, J., Suto, T., Greatorex, V., Ward, C., Straehle, C., McFadden, E., Dolci, M.S. & Gelber, R.D. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. New England Journal of Medicine, 353(16), 1659-1672. Prichep, L.S., Mas, F., Hollander, E., Liebowitz, M., John, E.R., Almas, M., De Caria, C.M. & Levine, R.H. (1993)  Quantitative electroencephalographic subtyping of obsessive-compulsive disorder. Psychiatry Research, 50(1), 25-32. Satterfield, J.H., Cantwell, D.P., Lesser, L.I. & Podosin, R.L. (1972) Physiological studies of the hyperkinetic child. American Journal of Psychiatry 128, 1418–1424. Schiff, N.D., Giacino, J.T., Kalmar, K., Victor, J.D., Baker, K., Gerber, M., Fritz, B., Eisenberg, B., O'Connor, J., Kobylarz, E.J., Farris, S., Machado, A., McCagg, C., Plum, F., Fins, J.J., and Rezai, A. R. (2007) Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 448, 600-603. Spronk, D., Arns, M., Bootsma, A., van Ruth, R. & Fitzgerald, P.B. Long term effects of left frontal rTMS on EEG and ERP’s in patients with Depression. (submitted) EEG and Clinical Neuroscience. Sterman, M.B. (2000) Basic Concepts and Clinical Findings in the Treatment of Seizure Disorders with EEG Operant Conditioning. Clinical Electroencephalography, 31(1), 45-55 Suffin, S.C. & Emory, W.H. (1995) Neurometric subgroups in attentional and affective disorders and their association with pharmacotherapeutic outcome. Clinical Electroencephalography, 26, 76-83. Swanson, J., McBurnett, K., Wigal T., Pfiffner, L.J., Lerner, M.A., Williams, L., Christian, D., Tamm, L., Willcutt, E., Crowley, K., Clevenger, W., Khouzam, N., Woo, C., Crinella, F.M. & Fisher, T.D. (1993). Effect of stimulant medication on children with attention deficit disorder: A “Review of Reviews”. Exceptional Children, 60,154–162. Trivedi, M.H., Rush, A.J., Wisniewski, S.R., Nierenberg, A.A., Warden, D., Ritz, L, Norquist, G., Howland, R.H., McGrath, P.J., Shores-Wilson, K., Biggs, M.M., Balasubramani, G.K. & Fava, M. (2006) Evaluation of Outcomes With Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. The American Journal of Psychiatry, 163(1):28-40, 2006. Wasserman, E.M. & Lisanby, S.H. (2001) Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clinical Neurophysiology, 112, 1367-1377.

 

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