Biological markers of major depression: Are we any closer?

Unresolved issues in the treatment of affective disorders

and mlsdiagnosis has been reported to be common. Accurate diagnosis of AD and MD In the elderly will be reviewed. We have studied 68 AD subjects, 61 MD sUbjects and 40 age-matched normal controls (NC's) with MRI. Atro• phy of temporal lobe structures (hippocampus, amygdala, entorhinal cortex and parahlppocampal cortex) was rated volumetrically and visually on a ()-3 scale from Tl-weighted coronal slices by two experienced neuroradiologlsts. Temporaliobe atrophy was significantly greater In AD subjects than MD's and NC's and provided good discrimination, particularly in subjects under the age of 75 (sensitivity 75%, specificity 95%). Deep white matter lesions .(DWML) and periventr1cular lesions (PVL) were rated visually on a standardised ()-3 scale from T2 weighted scans. Controlling for age and vascular risk factors, depressed subjects had significantly more DWML than other groups and this finding was most pronounced In those presenting Iate-onset depre,sslon. AD subjects had significantly more PVL ~an 0!her groups. ~n concluSIOn, ~­ lural MRI Is a useful adjUnct in the diagnosiS of depresSIon and dementia In the elderly.

127-5 1 Brain change over time In schizophrenia LE. DeUsl, W. Tew, R. Grimson, M. Sakuma, M. Kushner, AL Hoff. Department of Psychiatry. Health Sciences Center. State University of New It>rlc, Stony Brook. New York. USA

Brain structural deviation Is known to be present In chronic patients with Ichizophrenia when compared with normal age-matched Individuals. While the assumptlon Is that these difference are based on a neurodevelopmental disturbance, whether they are static or continue to change throughout the disease process namains unknown. At least 5 Independent nasearch groups, plus our own, have now reported In me~ting pnasentations and the literature that some active brain change Is occumng at an accelerated rate above the normal aging process. However, there Is no agreement as to what these specific changes are or what process underlies them. Although, three naports shoW ventricular enlargement over time, we have found the ventricles to remain at a stable size over the first 4-5 years of Illness, while the whole YOIume of both lett and right hemispheres appears to be decreasing at a rate significantly greater than controls. Methods: Our present data Includes analyses of MRI evaluations per• formed on an approximate annual basis for a minimum of 4 years on 50 first-episode schlzophnanlc patients and 20 controls: Co~puter a~sisted Image analysis measuring the YOIume of several brain regions, usmg the program ANALVZE (Mayo Clinic) was performed on all scans. Patients were compared with controls for the rate of change over tlme in size of structures. Results: No diffenances were found for the volumed of caudate nucleus, temporal lobes, or hippocampus; an no changes in the degree of cerebral laterality were detected. However, there was a significantly gnaater decrease in the overall volumes of left and right hemispheres (p < 0.0009 and 0.007), r1ght cenabellum (p < 0.02) and area of the Isthmus of the corpus callosum (p < 0.05) over lime. In addition, the lett ventricular volume Increased to a significantly greater amount In patients versus controls. These findings are consistent with the occurrence of a subtle a~ve brain process that may be continuing through the first few years of a schlzophnanlc UIne88 causing greater than the normal adult structural brain deteri~tlon. FUlther studies will be needed using other methods of Image analySls ~ over a longer period of time to determine the course and natuna of thiS biologic process.

References II) DeUlII LE., T_, W., )(le, S., Holl, A.L, Sakuma. M., Kushner, M., Lee, G., Shedlack, K., S~1tIl. A./A. and Grirneon, R.1199S). A prospective fol1ow-tJp study 01 breln mor· phology and eognltlon In ftrsl-eplsode ICIll20phrenlc patients: Prellmln8IY ftndlngs.

Biologic81 psychiatry, 38, 349-360.

(2] DeUal L.E. (199S).lelhere progrel8lve morphological braln and cognilive change In

IChlzoPhrenla? In: Schizophrenia. R. Fog, J. Gerlach and R. Hemmingsen (Editors).

Munklgaard, Copenhagen, Alfred Benzon Symposlum 38, pagel 162·176.

BIOL. PSYCHIATRY 1997:42:1S-mS

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28. Unresolved issues in the treatment of affective disorders

128-31 Future antidepressants: What Is possible?

w:z.. Potter, MA Demilrack. UJly Research Laboratories, A Division of Ell Ully and Company.

Thana are two obvious goals for antidepressant drug development mona rapid onset of clinical action and achieving namlssion In a gnaater proportion of patients. This means that we must establish better means of dlstlngulSh• Ing pattems of vs. extent of response. Confusion of the two has led to pnamatuna claims that certain antidepressants have a mona rapid onset of action. Monaover, uncertainty as to whether thena Is a stable pattem of placebo nasponse makes It difficult to assess the earliest point at which an antidepressant can be distinguished from placebo. It Is certainly the case that marked Improvement can sometimes be demonstrated In some patients by one week while maximum improvement can require over eight weeks In other patients on the same drug. Differential acute but transient namission following sleep deprivation, Improvement following psychostlmulant challenge and naJapse following monoamine depletion indicate that antidepressant response across Indlvid· uals Is very heterogeneous. Such diffenantlal responses suggest that the "set point" of biochemical systems varies widely across patients with similar clinical presentations. Studies showing that varying proportions of depressed patients show abnormalities of noradrenalin, serotonin, HPA, thyroid or sleep EEG function are further evidence In support of such diversity. It also appears that most patients 'refractory" to monotherapy with any available antidepressant go on to naspond to one or another combinations of agents which Involve actions at mUltiple membrane and Intracellular sites (e.g. TCAs and lithium). It therefore Is tempting to speculate that not only greater efficacy but also speed of onset of action may be achieved by agents which act on multiple targets simultaneously. A likely limitation of such approaches Is that acting on all possible targets at once may not achieve the synergy necessary to produce maximal nasponse In any given individual. Since, however, no methods have been validated for measuring the "set poinr of any biochemical system which predicts nasponse to any specific tnaatmenl, we must depend on population studies In the Immediate future to Identify better antidepressants. Data on Individual antidepressant response pattems utilizing drug trial data will be pnasented with suggestions as to possible new approaches to studying onset of therapeutic action. Recent reports claiming more rapid onset from combination treatments speculated to produce some special biochemical effect will be critiqued In light of the limitations of the methods employed. It will be argued that there are many near term possibilities for antidepressants with Improved overall actions but that advances In speed of onset ana more problematic.

128-41 Biological markers of major depression: Are we any closer? C.B. Nemeroff. Department of Psychiatry and Behavioral Sciences. Emory University School of Medicine. In the past several decades a number 01 biological theories of affective disorders have been proposed and considerable evidence supports the view that a myriad of neurotransmitter systems are involved In the pathophysl• ology of depression and bipolar disorder. Prominent among these are the following: (1) the serotonin hypothesis of depression, which posits a nalative deficiency of serotonin at critical synaptic sites In the central nervous sys• tem (CNS); (2) the nonapinephrine hypothesis of depression, which posits a deficiency of nonaplnephrine at critical receptor sites In the CNS; (3) the corti· cotropin-releaslng factor (CAF) hyperactivity hypothesis. which hypothesizes a hypersecretion of CRF within the eNS. In addition, a number of other hy• potheses which repnasent combinations of the three above, and Invoke other neurotransmitter systems, such as somatostatin, opioid peplides and others, have been posited. Biological markers 01 depression have two major uses In psychiatry, namely, diagnostic adjUncts In order to ensuna that the patient has the correct diagnosis and presumably will naspond with a higher probability to treatment, and the development of tnaatment strategies based on bioJogical findings. Thus, If evidence of a serotonergic dysfunction was evident, then patients would be prescribed a drug that acts on serotonergic systems, such as an SSRI. In the past several years, most attention has been given to two

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1997;42: lS--297S

major biological markers; those thal measure serotonergic alterations In de• pression and lhose lhat measure CRF hyperactivity. Du~ng lhis presentat!on the evidence lhat serotonin Is Involved In lhe pathophysiology of depression and lhe markers that have been scrutinized will be presented. These In· elude plasma tryptophan concentrations, brain and .platelet serotonin up~ke and serotonin transporter binding. platelet and brain 5HT2 receptor binding and, most recently. PET studies. The latter include PET studies in which serotonin transporter binding can now be measured in vivo, as well as PET studies using nuorodeoxyglucose. In which serotonerglc provocative stimuli are studied In depressed patients and compared to controls. Concemlng lhe CRF studies In particular, and lhe HPA axis In general, current status of lhe dexamelhasone suppression test, lhe CRF stimulation test. lhe DEXlCRF test and cerebrospinal fluid measurements of CRF will be described. There is lillie doubt lhat 1he advances In functional brain imaging represent lhe most promising new biological markers in patients wilh mood disorders. References [I] Nalhan KI, Musselman DL, Schatzberg AF and NemerollCB (1995); Biology of Mood Disorders. In AF SChatzberg and ca Nemerofl (ads), Textbook of Psychopharmaccl• ogy, Washington, APA PrSS8, pp 43~78. (2) Nemeroll ca, Knight DL, Franks J, Craighead WE and Krlahnan KRR (1994): Further studies on platelet serotonin transporter binding In depression. Am J Psych~t 151: 1623-1625. [3J Nemeroll CB (1996); The cortJcotropln-rsleeslng faclor (CRF) hypothesis 01 deprQ• alan: new findings and new directions. Molecular Psych~try 1: 336-342.

128-51

Frontal functions from memory to supervisory processes

BIOL. PSYCHIATRY

Maintenance treatment of high relapse-prone patients

J.F. Rosenbaum. Massachusetts General Hospital, Departmenl of Psychiatry. Boston, Massachusetts. USA In contrast to lhe view of Major Depressive Disorder (MOD) as a self·limited condition wilh full restitution, chronicity, residual symptoms. and recurrence are lhe rule ralher than lhe exception with respect to course and outcome. A majority of patients who do recover from an Initial episode will experience a recurrence and most will experience multiple episodes. Patients wllh MOD at highest risk for relapse and recurrence Include those with multiple prior episodes. residual symptoms despite treatment, very long (2 years or more) Index episodes, "double" depreSSion, comortlid psychiatric disorders (including Axis 2) and late (or early) age of onsel The Increasing risk of recurrence with each subsequent episode argues strongly for early and Intensive efforts at prevention. Clinical trials 01 conllnuation and maintenance phannaC01herapy wilh TCAs. MAOls and SSRls MICale superiority 01 antidepressant treatment over placebo In lhe prevention 01 relaps~ and recu.rrence but also d~ strate lhat sustained monotherapy at irtillally effective doses Is suboptimal for many. Clinical variables lhat may be associated with loss of benefit despite ongo• Ing antidepressant treatment include: initial "pl~cebo" ~espo~se, compliance failure treatment emergent side-effects lhat either limit doslrtg adequacy or mimic'affective symptoms, partial prophylaxis. brief Inadvertent interruption 01 shorter acting agents. untreated comorbld conditions, true tachyphylaxis, or abrupt discontinuation (particularly of shorter acting agents). Each of 1hese factors calls for different lherapeutic strategies which Will be discussed. The potential role of a psychotherapeutic intervention Is often under· appreciated wilh partial, but additive, protection against relapse offered by interpersonal, cognitive, and olher psychotherapies. Even for antidepressant responders, Increased levels of depressive cognitions are present compared to untreated non-depressed oontrol subjects. Indicating ongoing vulnerability to environmental rlsk factors. These "negative attributions' are a potential target of cognitive lherapy. Pilot data from our center for fluox~tine ~spon­ dars suggests a role for cognitive therapy for enhancing contlrtuallon and maintenance treatment efficacy. With respect to pharmacolherapy. data from lhe Massachusetts General Hospital Depression Research Program support lhe efficacy of Increased dose bolh as offering enhanced protection agalnst relapse and recurrence following Initial treatment response to fluoxetine and as lhe initial lherapeutic response to breaklhrough symptoms or recurrence Additional clinical strategies requiring further study but In common practice for patients at high risk for loss of benefit include augmentation an~ c0m• bination lheraples as well as switching antidepressant agents, particularly to drugs 01 a different class or mechanism 01 action. when initial efforts at maintenance lherapy have failed.

Reference. (1) Fava M., BIeaa E., Otto M.W., Pava J.A. and Rosenbaum J.F. (1994): Dysfunctional attitudes in major depression: Changes wtth pharmacotherapy. J Nervous Menr Dis 182(1); 46-60. 12] Fava M., Rappe S.M., Pava J.. Nierenberg A.A., Alpert J.E. and Rosenbaum J.F. (1995): Relapse In patients on long-term fiuexetine treatment; Response to Incree8ed ftuoxetine dose. J Clln Psych/etry 56(2): I I 7-123. (3) Rosenbeum J.F., Fava M. and Nierenberg AA (1994): The pharmacologic treatment of mood disorders. In Psyc/lllJlrtc Clinics of North Ametfca. Philadelphia: W.B. SaUl!• deB Company, pp 17-60.

29. Frontal functions from memory to supervisory processes 129-1

I frontal Disturbed self-awareness In patients with focal lesions: A parallel to psychiatric disorders?

D.T. Stuss. M.P. Alexander, T.W. Picton, G. Gallup, P. Shamml. Rotman Research inslirute, Baycrest Centre for Geriatric Cere. Unillersity of Toronto. Canada The understanding of the frontal lobes of lhe brain has been difficult for many reasons. These Include lhe inadequacy of1he experimental designs. lhe difficulty In isolating processes, the lack of a lheory to direct research. and Inadequate documentation of lhe population studied. We summarize several melhods we used to address lhese issues. particularly In relation to disturbed self·awareness. The potential of using lhese approaches to Study psychiatric disorders completes lhe presentation. To address frontal lobe functions. more precise anatomical documentation of lhe brain regions being studied Is necessary for dissociation of processes. We present a model for understanding lhe anatomy of the frontal lobes, and briefly present a study on v8!bal fluency indicating lhe specificity of brain-behaviour relations within lhe frontal lobes. In our model, 01 self-awareness lhere are two major components. First, our past experience results in an accumulated body of knowledge which we use to interpret current experience. This modeling and evaluation Is biologically based. Second. our awareness of self is hierarchical In lhe brain and In the related content, the highest level necessitating the role of lhe fronta/lobes. Clinical examples Illustrate 1he effects of neurological damage on different levels of lhe model self·awareness. Disturbances of awareness can be knowledge (domain) specific (e.g•• heml-attention); can relate to specific. memories (reduplicative paramnesia, Cspgras Syndrome); or can impair the reflection ot one's entire self. _ Two more experimental approaches addressing lhese clinical observations are presented as possible techniques to address these disorders. The first Is a study of an individual's ability to appreciate humour, which requires the . reflective appraisal of lhe situation or Information. The second addresses the ability to use past experience to model and understand the experiences of olhers, a necessary basis for self·awareness. It is proposed lhat both these abilities require intact frontal lobes. Both of these approaches underline lhe heterogeneity of frontal lobe funclionlng. Depending on task demancJs, patients with pathology In different localized regions may be more signifICantly impaired. New experimental approaches, lhe oonstruction of lhe appropriate models, and improved localization of brain functioning have provided new Insight Into lhe disturbance of self-awareness In patients wllh focal frontal lesions. SUCh a biological approach provides a template to address similar disturbances In patients with supposedly pure psychiatric diagnoses. Biological PSYchiatry requires the Integration of anatomy, psychology, neurology, and PSychiatry.

Reference. [II Alexandef M.P., Stu.. D.T. and Benson D.F. (1979) Capgru ayndrome: A redupllca• live phenomenon. Neurology, 29. 334-339.

(2) Picton T.W. and Stuas D.T. (1994) Neurobiology of conscious axperlence. Cun.nr OpInion In Neurobiology. ... 256-265. [3] Stu.. D.T. (1991) sen, awareness, and the lrontallobes: A neuropsychological per• apectlve. In Strauss J. and Goethals G.R. (Eda.), The $BIt JntenJ~.yo proaches. Springer·Verlag, New YOlk, 255-278.