in their analysis on the clinical significance of randomised controlled trials , kraemer and kupfer ( 2006 ) advocated the  number needed to treat ( nnt ) and some other parameters to convey the clinical and practical significance of the outcome of a trial . they indicate that such parameters may deviate largely , so nnts ranging from 2 to 100 might be relevant depending on the context . it means that one may treat 2 up to 100 subjects to establish the desired effect in a single person . high nnt may point either to weak diagnostic criteria for a particular therapy or to an ineffective intervention . in their paper on the usefulness of the medical model in psychiatry , shah and mountain ( 2007 ) define  the  medical model  as a process whereby informed by the best available evidence , doctors advise on , coordinate or deliver interventions for health improvement . it can be summarily stated as  does it work? this definition of a diagnosis refers to utility ( usefulness in a particular context ) , rather than to validity ( a true aspect of the real world ; kendell and jablensky 2003 ) . the medical model assumes causality , and that is the basis of rational and evidence - based medicine . the concept of ( strict ) causality in medicine may originate in classical physics , where force and its consequences are understood as deterministic processes . in medical sciences , the idea of causality is most often expressed in terms of restoration of a steady - state condition . pathological processes lead to a deviation from the steady state , and the intervention is applied by the medical doctor to eliminate the pathological state . so the biological basis of recovery from a medical disorder is the capacity of an organism to restore and maintain its internal milieu or homeostasis . a reversible disorder ( or disease ) points to the capacity of an organism to eliminate or compensate the pathology , whereas a chronic course is indicative of a failing capacity . we consider psychiatry primarily as a medical discipline and a psychiatric disorder as an undesired condition that a medical doctor should help to eliminate . a diagnosis should then recognise a disorder and the therapy proposed should cure the patient , i.e. let disappear the disorder ( or at least helps to have a decent life ) . psychiatric disorders are primarily concerned with the brain and their manifestation may therefore be more variable than that of somatic disorders , because of the higher complexity of the brain . such complexity may be greater than in neurological disorders . the clinical consequences , including the time course , of the latter disorders are primarily determined by underlying cellular processes . in contrast , organic pathology is absent or relatively insignificant so far in most psychiatric conditions , in particular , in the so - called functional disorders , including depression . we will consider the issue whether functional psychiatric disorders and , in particular , major depressive disorder can be conceptualised in the conventional framework of strict causality and steady - state dynamics . the term evidence - based medicine alludes to a firm scientific basis of the medical practice . often , the evidence is based on clinical trials comparing two or more interventions , including placebo treatment , showing statistically significant different outcomes . the issue is whether a thus defined efficacy allows predicting the outcome of a therapy in the individual patient . the psychiatrist has to propose ( or perhaps to decide ) which treatment is most adequate for the patient sitting in his office or lying in the hospital bed . this is not meant as a rhetoric question ; we acknowledge that many treatments are effective in the individual patient . in psychiatry ( perhaps also in other disciplines of medicine , but that is not our concern ) , however , there are also treatments that are  at least in large cohorts  a little more effective than placebo . one may , for instance , refer to the recent discussion on antidepressant drugs ( kirsch et al . 2008 ; turner et al . 2008 ; moncrieff and kirsch 2005 ) . if an active treatment is hardly better than placebo , it is impossible to make a rational decision about the treatment of the individual patient : this is in fact challenging the assumption of causality . we chose major depressive disorder as a representative functional disorder , because of the availability of illustrative data . another obstacle is the nature of cerebral functioning : we argue that brain processes are not as deterministic as often thought . in line with this contention , we describe nondeterministic time courses of recovery from depression that differ fundamentally from that of reversible somatic disorders . finally , we emphasise that current disease markers or psychological inquiry does not necessarily provide the information required for rational therapeutic strategies . the scope of the present mini - review differs from that of recent related papers , where the philosophical framework and utility or validity of psychiatric diagnosis ( shah and mountain , 2007 ; kendell and jablensky 2003 ; kendell 2001 ; kendler 2005 ; angst 2007 ; jablensky 2005 ) were discussed . parts of this paper were recently presented elsewhere ( korf 2008 ; stoyanov et al . he construed a closed diagnostic system leading to a personally dedicated treatment . despite its apparent rationality , emil kraepelin is the founder of the present diagnostic approaches and his ideas are the basis of current classification proposals ( shorter 1997 ) . subsequently a variety of diagnostic systems , including the diagnostic and statistical manual of mental disorders ( dsm ) and the international classification of diseases ( icd ) , were introduced . these systems were developed as a reaction to the psychoanalytic framework and were aimed not only to serve the clinician with a standardised terminology but also to provide a scientific basis of psychiatry ( shorter 1997 ) . it was well realised from the onset onwards that any classification needs a firm scientific basis . many investigators consider such number as exuberant , but there is as yet no scientific argumentation whether such number is too much , too little or just perfect . the arguments are rhetoric instead : do we need also 300 diagnoses of liver diseases ? a way to avoid such fruitless discussions would be to assume that the dsm classification does not define disease entities , but defines ( psychological ) disorders . but then the question arises : what should be considered as a disorder and what not , and do nonpsychological parameters ever become relevant ? the dsm ( for instance ) allows some diagnostic variations , as some symptoms are more important for the diagnosis of major depressive disorder ( code 296xx ) than others : duration of a depressed mood for at least 2  weeks is mandatory , but the presence of only four of the following symptoms is required : disturbed appetite ; weight ; sleep ; psychomotor activity ; energy ; feelings of worthlessness or guilt ; ability to think , concentrate or make decisions ; recurrent thought of death or suicidal ideation , plans or attempts . we now propose a thought  an experiment challenging a classification system and so illustrating its scientific status . assume that current classification systems are no ex cathedra formulated diagnostic standards ( which they are to a large extent ) but rather as a ( possibly pre - scientific ) hypothesis that may be falsified in the popperian sense . then the question arises when is a parameter sufficiently strong to falsify the dsm ? consider a parameter investigated by the best available methodology found in 80% of the subjects of a cohort and in 20% of a perfectly matched control group [ think of , e.g. the dexamethason suppression test ( dst ) or with a corticotrophin - releasing hormone infusion ( dex - crh ) ] of melancholic/ major depression ( carroll et al . the carroll ( and several later ) studies have proposed that the dst might well indicate or reflect pathological mechanisms or processes underlying depression . such reasoning does  albeit indirectly  most often support the concept of depression as defined by the dsm . the issue here is : could the dst challenge the dsm concept of depression ? not likely . a formal argument is that the dsm does not mention cortisol excretion or dexamethason suppression as a feature of major depression . besides such formal argument , it is more likely that a parameter that is present in a limited number of patients defined with the dsm criteria will be considered as diagnostically useless . another example : consider a symptom or parameter that is responsible for only certain aspects of depression ( say , irritability ; russo et al . , an intervention may prove to be therapeutically effective in a cohort , but only in 60% of the subjects . this is , for instance , the case with antidepressants ( kirsch et al . 2008 ; turner et al . 2008 ; moncrieff and kirsch 2005 ) . apparently also , the therapeutic response is not an argument to redefining a diagnostic classification . another obstacle for a more fundamental discussion on the utility ( or better validity , kendell and jablensky 2003 ) of the dsm is the publication bias . it is generally discouraged to publish psychiatric investigations without adherence to the dsm classification ( or another classification system ) . these considerations together argue that studies on ( objective ) parameters ( e.g. genes , hormones , course of the disorder or response to therapy ) are unable to challenge the dsm classification system . is this really bad for psychiatry ? scientifically speaking , there is no argument : adherence to a nontestable classification system hinders progress . it may be even worse ( e.g. kendell and jablensky 2003 and references therein ) : the dsm classification may obstruct scientific progress , because it forces to compare heterogeneous cohorts (  apples and pears ) for common characteristics (  genes , colour , etc . ) . but common sense also tells that not every single parameter is sufficiently strong to challenge a psychiatric classification system . and as mentioned , one can not attack the dsm with criteria that were never included . to compare with the medical practice , a first medical diagnosis is a provisional hypothesis about an illness , and further investigations are required to support or to reject the initial diagnosis . we thought that an experiment suggests that the rational medical practice does not apply to a psychiatric diagnostic systems . our reasoning implies that a scientific foundation of psychiatry by using the dsm classification is practically unreachable . to avoid the yes / no argumentation , we suggest a way of challenging current classification systems by searching for diagnostic prototypes ( jablensky 2005 ; kendell and jablensky 2003 ) . our suggestion is related to the notion of  zones of rarity to indicate natural boundaries between diagnostic entities . this implies a deterministic relationship between an external or internal event and the emerging state of the organism . in that case a rational diagnosis and predictable outcome of a therapy is  at least in theory this idea does not necessarily apply to psychiatry , as will be illustrated with recent work on depression . the major pathogenic hypotheses of depression assumes the involvement of life events ( kendler et al . 1999 ; kendler 2008 ; keller et al . 2007 ) , biogenic amines ( in particular , serotonin ; russo et al . 2007 ) and stress hormones ( cortisol ; holsboer 2000 ) . objective response to a stressful life event should be distinguished from subjective response , because life events are stressful only when perceived as such . the subjective perception depends primarily on the memory of previous experiences , whereas the objective response may be modified by genetic and other biochemical dispositions . it is generally believed that the combination of objective and subjective features of stress coping contribute to the development of depression ( e.g. kendler 2008 ) . various aspects of monoamines have been investigated including failing synthesis of brain serotonin or genetically programmed variations of proteins ( transporters or catabolic enzymes ) . close inspection shows that 10% or less of the variance can be explained by the environmental and biochemical factors ( russo et al . for instance , spengler and associates ( murgatroyd et al . 2009 ) highlighted the crucial role of early life stress events for the emergence of epigenetic marking ( hypomethylation ) of key regulatory region for the expression of arginine vasopressin in the para ventricular hypothalamic nucleus . this reflects on the function of hypothalamo - pituitary - adrenal axis in the proper adaptation and represents potential model for the vulnerability of the nervous system to environmental and behavioural stimuli . however , such data might point also to the contribution of several more but as yet unknown factors . the question arises whether a more complete knowledge of these factors is possible and , if so , whether their number is sufficient small to construct a useful diagnosis . by far , most of the depressive episodes are reversible : meaning that in the general population with or without professional therapeutic interventions , about 80% recovers ( spijker et al . 2002 ) we measured and modeled the incidence of recovery of a depressive cohort extracted from the general population with or without comorbid psychiatric or somatic pathology ( van der werf et al . 2006 ; kaptein et al . it appeared that the rate of recovery follows an exponential time course , indicating that the probability to recover from depression is independent of the length of the depressive episode . in other words , the chance to recover in the first month after the onset of depression is the same than to recover in , for instance , the third month . the exponential function could explain more than 98% of the variance and was applicable irrespective of comorbidities . the model showed that the 2-week criterion of the dsm is rather arbitrary and not a characteristic ( i.e. an  incubation period ) for major depression ( van der werf et al . 1992 ) suggest that the time - to - recovery curves can be modelled with exponential functions as well . a prospective study on recurrent depression showed that the durations of preceding or subsequent depressive episodes and depression - free intervals were all unrelated ( kaptein 2008 ) . the exponential function of recovery from depression can best be explained and modelled by assuming random - mood swings : this means that the brain might transit randomly from one ( examples of fast brain - state transitions are sleep stages , fear and happiness . within seconds , we fall asleep or transit from the slow - wave sleep into the paradoxical ( rapid eye movement ) sleep and vice versa . transitions to or from a depressive state are also fast : a positive response after one night of sleep deprivation may disappear during ( or after ) a nap of a few minutes ( riemann et al . 1993 ) . the occurrence of fast and random mood transitions questions how deterministic and thus predictable brain transitions are . korf and gramsbergen ( 2007 ) argued that the brain operates as an iso - energetic system , meaning that there are minimal energy barriers to initiate or execute neural activities ( fig .  1 ) . so neural activities in milliseconds do not depend on energy recruitment but are a manifestation of already present energy resources , designated as potential energy . potential energy is equivalent with trans - membrane ion gradients ( i.e. k , nacl ) and neurotransmitter pools ( i.e. gaba , glutamate ) and is ( nearly ) same all over the brain . the potential energy becomes available with minimal effort : as with a battery by changing a switch . brain - state transitions may appear randomly not only to the external observer but also to the subject himself . 1schematic representation of the concept of iso - energetic brain in relation to complexity of neurobiological processes . to reach iso - energicity , energy metabolism ( via glucose and oxygen ) once the brain near iso - energetic nondeterministic processes , such as random , stochastic and chaotic processes , become possible , more complex functions are confined to the iso - energetic brain and are thus less deterministic schematic representation of the concept of iso - energetic brain in relation to complexity of neurobiological processes . to reach iso - energicity , energy metabolism ( via glucose and oxygen ) once the brain near iso - energetic nondeterministic processes , such as random , stochastic and chaotic processes , become possible , more complex functions are confined to the iso - energetic brain and are thus less deterministic conventionally biological systems are considered deterministic , i.e. that a brain state can be predicted from a previous state ( goldberger 1996 ; williams 1997 ; gottschalk et al . the iso - energetic concept allows indeterminacy , so nonpredictable ( i.e. random ) or near - random ( i.e. stochastic ) fluctuations are possible . the iso - energetic and some other concepts corroborate the idea that the brain is amenable to chaos theory . in a chaotic ( in the mathematical sense ) system , this idea has previously been emphasised in studies on bipolar depression and related affective states ( gottschalk et al . 1995 ; mandell and selz 1995 ; pezard et al . the brain may exert transitions on external or internal signals that are not well predictable in time and in intensity . the concept of an iso - energetic brain implies a rather loose and often untraceable connection between input  output and therefore challenges strict causality underlying classical medical models . an iso - energetic brain makes emotional and behavioural reactions to minor external triggers or life events plausible . the type 1 intervention aims to remove the disease - causing agent either by direct challenging its existence in the patient s body or to assist the disease - eliminating activity of the organism . compensation is the type 2 intervention : a component with a similar or identical activity is prescribed or measures are taken to enhance the production of a missing compound . many anti - diabetic treatments or the l - dopa therapy and dopamine agonists in parkinson s disease are examples . the type 3 intervention aims to remove a pathological agent with nonspecific toxins , mechanical devices or irradiation . finally , type 4 treatment is primarily aimed to reduce suffering by , for instance , palliative treatment . each of these treatments is rational and likely to be evidence - based to a certain extent at least . to what category do psychiatric treatments belong ? in depression , the routine treatments include cognitive behavioural therapies and medication ( with antidepressant drugs ) . other regimens include physical exercise , sleep deprivation , light exposure therapy and  in severe cases  electroconvulsive treatment , alone or combined with the routine treatments . medication has often been thought as type 1 or type 3 interventions , but there is as yet little evidence that deficiencies of brain monoamines actually cause depression . it appeared that low brain serotonin ( due to low plasma tryptophan ) is associated with failing impulse control and aggression rather than with depression ( e.g. russo et al . cognitive therapies have been developed to correct misconceptions associated with the depression ( i.e. to reduce the impact of life events ; beck et al . whether their reported positive effects are due to a type 4 rather than a type 1 ( or perhaps type 3 ) effect remains to be proven . interventions , such as physical exercise , sleep deprivation , light exposure therapy and electroconvulsive treatment , are certainly not type 1 , 2 or 3 treatments . the latter are perhaps type 4 treatments ( alleviating suffering ) , but that indexation may feel as artificial . in view of the transition hypothesis ( see previous section ) , the anti - depressive interventions may facilitate switching from the depressive to the nondepressed state . their effects could be seen as type 1 therapies , as hypo - activity is often a prominent symptom of depression , whereas exposure to light activates or compensates failing mechanisms in seasonal affective disorders , respectively . therefore , we suggest to adding another type of treatment . our type 5 treatment is to facilitate brain transitions this idea might be seen as an extension of type 1 because they assist the organism to battle the ailment , but that is a rather artificial formulation for randomly occurring brain states . there is an ongoing debate on the therapeutic efficacy of antidepressants ( see previous sections ) . in several meta - analyses , their effects appear to be modest as compared to placebo , explaining about 2% of the variance of depressive symptoms on top of placebo . first , the response of depressed subjects to medication varies widely : both fast and clear - cut responses and no response at all have been reported and second , the placebo response is relatively high and variable . apparently no meaningful distinction can be made between subjects who need medication and those who recover without medication ( or placebo ) . is this a matter of lack of knowledge or is this inherent of the current conception of depression ? the placebo - drug controversy may serve as another argument supporting the random mood concept , and , if so , the drug treatment is a type 5 intervention . . 2010 ) which suggest the application of inhibitors of dna methyl transferase and histone deacetylase ( hdac ) as potential therapeutic agents in the causal treatments of psychiatric disorders . this is entailed from the assumption that altered patterns of mrna and protein expression are downregulated in the pathogenesis of such disorders like unipolar depression or schizophrenia . therefore , hdac are supposed to activate the mrna expression in these conditions . in short , we argued that  perhaps except cognitive psychotherapy so an antidepressive treatment is often not aimed to influence the depressive feelings directly , but to influence the course and severity of a depression . considering the stochastic mood concept , thus assuming near - random brain transitions , a strict causality between diagnosis and therapeutic response must be considered as unlikely . medical disorders , including psychiatric disorders , are diagnosed by the content ( e.g. mood ) , severity , time course and coexistent factors . in the case of depression , for instance , mood characteristics , severity of the depression , duration of the depressive episode and comorbid anxiety , dysthymia or somatic disorders are , among others , important criteria for diagnosis , treatment and prognosis . the diagnosis is mainly based on phenomenology and self - reports (  what the psychiatrist sees and hears ) , together referring to the content of a disorder . such assessments might be biased by the theoretical framework of the therapist and by the feelings of the patient . for instance , the negative attributions of patients about the origin of their depression ( feelings of guilt and worthlessness ) are well known ( beck et al . for instance , infusing cortisol gave more negative associations in volunteers and patients , suggesting that hypercortisolaemia might bias the patient s report ( tops et al . the most explored biological markers for depression include hormones and associated receptors ( e.g. dst or dex - crh ) , a wide variety of genes , blood or urine levels reflecting metabolic processes , physiological responsiveness and brain imaging ( for an extensive review , see mssner et al . these markers do not inform on the thought contents but may be related to severity , course and comorbidity . most often , markers are explored in cross - sectional study designs by comparing a cohort of depressed patients and a matched nondepressed cohort . one longitudinal study claims that normalisation of the dst or the dex - crh test precedes recovery from depression ( carroll et al . 1981 ; holsboer 2000 ) . despite 30  years of research and strong initial claims , the dst and the dex - crh tests have not contributed significantly to a better diagnosis of depression . it is also not clear to what aspect of depression ( severity , course , comorbidity ) an abnormal cortisol function is associated . extensive studies have appeared on serotonin - related genes ( particularly serotonin transporter regulating genes and their polymorphisms ) in relation to depression and life events . claims that severe and repeated life events provoke depression in the s / s genotype subjects ( caspi et al . 2003 ) have subsequently not been replicated ( uhe and mcguffin 2008 ) . there is certain progress in the research focused on the exploration of peripheral markers to define the epigenetic risk for depression . special interest is paid in a pilot study of the promoter methylation of the serotonin transporter gene ( olsson et al . , we and others ( mssner et al . 2007 ) conclude that none of the current candidate markers supports the diagnosis of depression . morphological and functional neuroimaging have the potential to show anatomical brain abnormalities or aberrant physiological responses during a mental task , respectively . morphological changes are usually considered as irreversible , but in depression , reversible changes of regional brain volumes were reported ( drevets 2003 ; kronmller et al . how fast these volumes change is as yet unknown , but most likely not within days or weeks . therefore , we consider morphological changes conditional rather than causing depression ( kronmller et al . 2008 ) , possibly by impairing mood transitions . in this respect , morphological changes are similar to somatic disorders such as cardiovascular heart- and brain - pathology , often associated with depression ( de jonge et al . 2006 , 2007 ) . following exposure to emotional stimuli , abnormal responses of brain amygdala , frontal cortex and some meso - limbic areas as detected with functional mri , oxygen pet and water pet were observed ( drevets 2003 ) . it is difficult to decide whether imaging results have to be attributed to abnormal processing of the stimuli or that the depressive state overrules brain processing . neuroimaging and endocrine studies have been used to define endo - phenotypes , i.e. subjects who are more susceptible for stress because of certain genes or gene polymorphisms . vulnerable endo - phenotypes have indeed been reported , suggesting that the subjective perception of stress , and by inference of life events , may render individuals more prone to develop depression ( e.g. jabbi et al . psychiatric disorders are characterised by the content ( e.g. mood ) , severity , time course , and coexistent factors . few if any attempts have been made to differentiate between associations with the pathopsychological content or with the course , severity or other characteristics of depression . we have emphasised four major challenges for a rational and causal conceptualisation of functional disorders in psychiatry ( table  1 ) . each of these challenges could well lead to the conclusion that a rational and evidence - based psychiatry is theoretically and practically impossible . the present conclusions are mainly based on data of major depression . besides making a critical analysis we start the discussion on strong and weak points of our analysis . 
 table  1some obstacles to reach ( strict ) causality in psychiatry1 . classification systems are not falsifiable , because of  ( a ) heterogeneity of categories  ( b ) inclusion of novel factors and  ( c ) publication bias2 . brain functions are at least , in part , not - deterministic , because of  ( a ) iso - energeticity and consequently  ( b ) chaotic / random and stochastic processes3 . therapies are not directed to core symptoms / characteristics , because they  ( a ) do not influence subjective feelings  ( b ) influence course and not pathogenesis and  ( c ) are relatively ineffective4 . markers and inquiry  ( a ) do not inform on the core symptoms  ( b ) but possibly on course and severity , and  ( c ) inquiry is biased because of subjectivity some obstacles to reach ( strict ) causality in psychiatry first , we consider some philosophical aspects . more than in somatic medicine the question is whether a psychiatric disorder is a real thing or a construct that does not necessarily refer to a real world . such criticism is not justified , because any scientific theory , diagnosis or hypothesis is not more than a construct that describes phenomena as long as there is no better idea . this philosophical issue touches the problem of irreducibility of real - world processes and objects . an alternative view is that scientific theories and clinical protocols have no or little common basis . real progress is possible only when both the scientific and clinical views converge to unambiguous conceptualisations . as long as that is not the case in psychiatry , one has to live with certain and unavoidable inconsistencies between a medical and scientific framework of psychiatry . we considered classification systems primarily as useful constructs and not so much as describing real world objects . as an alternative to evidence , we considered the term  proof and  proven to emphasise causality . more exactly , these terms indicate causality of two types : ( i ) strict linear causality in relatively simple systems useful for lower levels of complexity ; ( ii ) nonlinear , dynamic causality , applicable to single cells up to the endo - phenotype . there remains the possibility to establish bridge laws ( nagel et al . 1971 ; nagel 1979 ) between multitude complexities at micro ( neuronal ) and macro ( behavioural ) levels ( also indicated in fig .  1 ) . in this case , we do not exemplify empirical reduction but we may introduce  patchy reduction ( kendler 2005 ) or inter - theoretic reduction between paradigms . the concept of the iso - energetic brain 24 may be seen as a provisional bridge law ( nagel 1979 ) and as  a patchy reductive explanation ( kendler 2005 ) . in the following , we suggest a strategy to explore some of the discussed issues . the core of our proposal is to re - analyse epidemiological , psychological and laboratory data but not only according to currently accepted diagnostic systems . for instance , genes or biochemical parameters may well be related to severity , course or other features of a disorder ( kendell and jablensky 2003 ) . if so , then the same gene variants may be associated not only with depression but also with , e.g. anxiety or schizophrenia or even with nonpsychopathological symptoms as well . . this could give information on the significance of some pathophysiological parameters to evoke particular symptoms or group of symptoms present in different disorders and , ideally , how they can be affected by therapy . many of current ideas on psychopathology are developed from relatively large cross - sectional or longitudinal epidemiological investigations . indeed , such studies may disclose general trends , but the results are not necessarily applicable to a single patient . a firm causal basis for psychiatry ( and any medical discipline ) requires a reasonable guess about the diagnosis in the single individual . in practice , several relatively nondisorder - specific factors converge to a diagnosis that has implications for further therapeutic regimens . furthermore , we emphasise that a diagnosis has to define a typical condition ( disease ) of a prototypical individual ( patient ) . one aim of a medical psychiatry could be to define and redefine diagnostic prototypes ( kendell and jablensky 2003 ; jablensky 2005 ; nagel 1979 ; schaffner 2004 ; kendler 2008 ; kendler and campbell 2008 ) . following this line ; we suggest that data analysis in epidemiological and other population - based studies might focus to delineate relatively small subcohorts that are defined by a limited number of parameters . these parameters may include not only psychopathological symptoms but also physiological , biochemical or genetic characteristics . and they may be related to severity , time course and other characteristics of the disorder . a similar approach has been elaborated on the distinction of validity and utility of psychiatric diagnosis ( kendell and jablensky 2003 ; jablensky 2005 ; schaffner 2004 ) . one criterion is that in a multidimensional space of symptoms a syndrome is defined by detectable discontinuities . so there should be boundaries of rarity , distinguishing syndrome ( disease ) from sanity or from other syndromes ( diseases or disorders ; jablensky 2005 ; schaffner 2004 ; kendler 2008 ) . . the outcome of such exercise could be the following : first , one or several of the diagnostic prototypes are identical or very close to categories of existing diagnostic systems ( e.g. the dsm ) , second , these prototypes are completely different and not easy to reconcile with current diagnostic systems , or third such hypothesised diagnostic prototypes do not exist or can not be recognised as yet . the first outcome provides a strong support for a scientific basis and clinical relevance of  or at least a part of  the tested diagnostic system . the second outcome forces to reconsider the diagnostic system under investigation and might eventually lead to new diagnostic systems . the third outcome might lead to a temporary anarchy of diagnostic systems as no cues for developing a new system are revealed . future scientific developments may enable more pertinent conclusions in line with the first or second outcome . in the latter case , there is as yet no urgent need to reconsider the diagnostic system under study . the present assay is not aimed to provide a conceptual or philosophical framework of psychiatry , as done recently . these papers ( kendler 2005 , 2008 ; kendler and campbell 2008 ) emphasise the multilevel character of explanatory models in psychiatry and warn against too simple monolevel explanations , e.g. at the molecular or psychological level . we agree with this viewpoint as is also illustrated in fig .  1 and acknowledge the implications for research paradigms . our intention is to bring the discussion to a more operational level : what should be done to rationalise psychiatry . the medical model was chosen as starting point in our analysis , because it is in our opinion the best tool to discern shortcomings and weak points . our concern about utility of validity of current diagnostic constructs is shared by others ( e.g. angst 2007 ) . our emphasis is on utility , not on validity of diagnostic constructs ( kraemer and kupfer 2006 ) . from a scientific point of view , the distinction between validity and utility is rather artificial , because validity of a concept can only be proven by practical testing , in the medicine preferentially by showing utility . the medical model is the basis of evidence - based medicine : to establish causality between diagnosis , interventions and therapeutic effects . we have discussed four major obstacles : first the nonfalsifiable nature of current classification systems , second the nondeterministic character of many cerebral processes , third divergence between therapeutic approaches and pathogenesis and fourth inadequacy of diagnostic tools . one has to appreciate that knowledge about the world is far more than what can be communicated between human beings . one unavoidable shortcoming might be due to the impossibility to describe professional knowledge ( or perhaps better professional intuition ) of the psychiatrist verbally that said without the previously mentioned theoretical biases . so we might eventually have to consider the possibility that professional experience is an essential element not only in everyday health care but also in evidence - based psychiatry .