Abstract
The current clinical trials model for antidepressants (AD) was developed in the 1960s. It views major depression as a unitary disorder, and “antidepressants” as having illnessspecific therapeutic actions. The established efficacy measures are the Hamilton symptom rating scale and the CGI, which provide summary measures of improvement. In contrast, the DSM IV defines depression as heterogeneous, with such broad classes as unipolar and bipolar showing different response to treatments. Research further indicates depression to be comprised of major affective and behavioral components which vary in intensity across patients, and the tricyclic ADs to have multiple actions that affect various components sequentially. “New” ADs, products of rapid advancements in the neurosciences, are more precise in their actions on brain monoamine systems, targeted to affect behaviors with greater specificity. A new trials model sensitive to the varied behavioral effects needs to be developed to adapt to these quicker acting, targeted antidepressants. A componential model is recommended that employs an array of behavioral methods, and subtype classification and statistical approaches to estimate onset and sequence of multiple drug actions. The NIMH can intervene to accelerate improvements by initiating funding programs to implement more effective clinical methods and models.
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Notes
Industry-Sponsored Multisite Clinical Trials: Can They Be Improved? Co-chairs: Potter WZ, Demitrack MA, American College of Neuropsychopharmacology 36th Annual Meeting, Hawaii, 1997
In this view, behavioral components are distinguished from “symptoms” the former are seen as structural parts of the disorder rather than as subjective or outward signs of the underlying illness. Anxiety for example, is not viewed as a symptom of the depressive disorder but as a functional component, equal in importance to the structure of the disorder as depressed mood or a specific psychomotor disturbance. This position is presented in more detail in Katz and Maas (1994).
References
American Psychiatric Association. (1987): Diagnostic and Statistical Manual of the Mental Disorders, DSM-III-R. Washington, American Psychiatric Association
Asnis GM, McGinn LK, Sanderson WC . (1995). A typical depression: Clinical aspects and noradrenergic function. Amer J Psychiatry 152: 31–36
Beck AT, Brown G, Steer RA, Eidelson JI, Riskind JH . (1987): Differentiating anxiety and depression: A test of the cognitive specificity hypothesis. J Abnormal Psychology 96: 179–183
Beck AT, Weisman A, Lester D, Trexler L . (1974): The measure of pessimism: The Hopelessness Scale. J Consulting and Clinical Psychology 42: 861–865
Carlsson A . (1976): The contribution of drug research to investigating the nature of endogenous depression. Pharmakopsychiatry 9: 2–10
Clark LA, Watson D . (1991): Tripartite model of anxiety and depression: Psychometric evidence and taxonomic implications. J Abnormal Psychology 100: 316–336
Derogatis LR, Lipman RS, Rickels K, Uhlenhuth EH, Covi L . (1974): The Hopkins Symptom Checklist (HSCL): A measure of primary symptom dimensions. In Pichot P (ed), Psychological Measurements in Psychopharmacology: Modern Problems in Pharmacopsychiatry. Basle, S Karger, 7., pp 79–110
DiMascio A, Meyer RE, Stifler L . (1968): Effects of imipramine on individuals varying in level of depression. Amer J Psychiatry 8(Suppl):55–58
Dunbar GC, Cohn JB, Fabre LF, Feighner JP, Fievre RR, Mendels J, Shrivastava RK . (1991): A comparison of paroxetine, imipramine and placebo in depressed outpatients. Br J Psychiatry 159: 394–398
Endicott J, Spitzer R . (1978): A diagnostic interview: The Schedule of Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35: 837–844
Frazer A . (1997): Pharmacology of antidepressants. J Clin Psychopharmacol 17(Suppl. 1):25–185
Gorman JM . (1997): Comorbid depression and anxiety spectrum disorders. Depression and Anxiety 4: 160–168
Grinker RR Sr, Miller J, Sabshin M, Nunn R, Nunnally JC . (1961): The Phenomena of Depressions. New York, Hoeber
Guy W . (1976): Early Clinical Drug Evaluation Program (ECDEU), Assessment Manual of Psychopharmacology. Rockville, MD, Dept. of Health, Education & Welfare
Hamilton M . (1960): A rating scale for depression. J Neurology, Neurosurgery, and Psychiatry 23: 56–62
Han L, Schmaling KB, Dunner DL . (1995): Descriptive validity and stability of diagnostic criteria for dysthymic disorder. Comprehensive Psychiatry 36: 338–343
Hollister LE, Overall JE . (1965): Reflections on the specificity of action of anti-depressants. Psychosomatics 6: 361–365
Kahn RJ, McNair DM, Lipman RS, Covi L, Riskels K, Downing R, Fisher S, Frankenthaler LM . (1979): Imipramine and chlordiazepoxide in depression and anxiety disorders, II, Efficacy in anxious outpatients. Arch Gen Psychiatry 43: 79–85
Katz MM, Maas JW . (1994): Psychopharmacology and the etiology of psychopathological states: Are we looking in the right way? Neuropsychopharmacology 10: 139–144
Katz MM, Koslow SH, Berman N, Secunda S, Maas JW, Casper R, Kocsis J, Stokes P . (1984): Multivantaged approach to the measurement of behavioral and affect states for clinical and psychobiological research. Psychol Rep. 55: 619–791
Katz MM, Koslow SH, Maas JW, Frazer A, Bowden CL, Casper R, Croughan J, Kocsis J, Redmond E . (1987): The timing, specificity and clinical prediction of tricyclic drug effects in depression. Psychol Med 17: 297–309
Katz MM, Wetzler S, Koslow SH, Secunda S . (1989): Video methodology in the study of the psychopathology and treatment of depression. Psychiatric Annals 19: 372–381
Katz MM, Koslow SH, Maas JW, Frazer A, Kocsis J, Secunda S, Bowden CL, Casper R . (1991): Identifying the specific clinical actions of amitriptyline: Interrelationships of behavior, affect, and plasma levels in depression. Psychol Med 21: 599–611
Katz MM, Koslow SH, Frazer A . (1997): Onset of antidepressant action: Reexamining the structure of depression and multiple drug actions. Depression and Anxiety 4: 257–267
Kielholz P, Poldinger W . (1968): Die behandlung endogener depressionen mit psychopharmaka. Dt med Wschr 93: 701–704
Klein DF, Zitrin CM, Woerner M . (1978): Antidepressants, anxiety, panic and phobia. In Lipton MA, DiMasco A, Killam KF (eds), Psychopharmacology: A Generation of Progress. New York, Raven Press, pp 1401–1410
Klerman GL, Weissman MM, Frank E, Kocsis JH, Markowitz JC, Montgomery S . (1994): Evaluating drug treatment of depressive disorders. In Prien RF, Robinson DS (eds), Clinical Evaluation of Psychotropic Drugs: Principles and Guidelines. New York, Raven Press, pp 281–326
McGinn LK, Asnis GM, Rubinson E . (1996): Biological and clinical validation of atypical depression. Psychiatry Research 60: 191–198
McNair DM, Lorr M, Droppleman LF . (1971): Manual: Profile of Mood States. San Diego, CA, Educational and Industrial Testing Service
Mitchell P, Hadzi-Pavlovic D, Parker G, Hickie I, Wilhelm K, Brodaty H, Boyce P . (1996): Depressive psychomotor disturbance, cortisol, and dexamethasone. Biol Psychiatry 40: 941–950
Montgomery SA . (1995): Rapid onset of action of venlafaxine. Int Clin Psychopharmacol 10(Suppl. 2):21–27
Prien RF, Robinson DS . (eds) (1994): Clinical Evaluation of Psychotropic Drugs: Principles and Guidelines. New York, Raven Press
Quitkin FM, McGrath PJ, Stewart JW, Harrison W, Tricamo E, Wagner SG, Ocepek-Welikson K, Nunes E, Rabkin JG, Klein DF . (1990): Atypical depression, panic attacks, and response to imipramine and phenelzine. Arch Gen Psychiatry 47: 935–941
Raskin A, Schulterbrandt J, Reatig N, Rice CE . (1967): Factors of psychopathology in interview, ward behavior, and self-report ratings of hospitalized depressives. J Consult Psychol 31: 270–278
Rickels K, Derivan A, Entusah R, Miska S, Rudolph R . (1995): Rapid onset of antidepressant activity with venlafaxine treatment. Depression 3: 146–153
Small JG, Milstein V, Kellams JJ, Small IF . (1981): Comparative onset of improvement in depressive symptomatology with drug treatment, electroconvulsive therapy, and placebo. J Clin Psychopharmacol 1(Suppl. 6):62–69
Smith WT, Glaudin V, Panagides J, Gilvary E . (1990): Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depressive disorder. Psychopharmacol Bull 26: 191–196
Spitzer RL, Endicott JD, Robins E . (1978): Research diagnostic criteria: Rationale and reliability. Arch Gen Psychiatry 35: 773–782
Spitzer RL, Williams JW . (1983): Instructions Manual for the Structured Clinical Interview for DSM-III (SCID), Revision. New York, Biometrics Research Dept., New York State Psychiatric Institute
Tollefson GD, Holman SL . (1994): How long to onset of antidepressant action: A meta-analysis of patients treated with fluoxetine or placebo. Int Clin Psychopharmacol 9: 245–250
Watson D, Clark LA, Weber K, Assenheimer JS, Strauss ME, McCormick RA . (1995): Testing a tripartite model: II. Exploring the symptom structure of anxiety and depression in student, adult, and patient samples. J Abnormal Psychology 104: 15–25
Wetzler S, Katz MM . (1989): Problems with the differentiation of anxiety and depression. J Psychiatr Res 23: 1–12
Wittenborn JR . (1966): The assessment of clinical change. In Cole JO, Wittenborn JR (eds), Pharmacotherapy of Depression. Springfield, IL, Charles C Thomas Publisher, pp 67–90
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Katz, M. Need for a New Paradigm for the Clinical Trials of Antidepressants. Neuropsychopharmacol 19, 517–522 (1998). https://doi.org/10.1016/S0893-133X(98)00065-7
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DOI: https://doi.org/10.1016/S0893-133X(98)00065-7
