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The target symptoms for treatment of depressive illness revisited
Comprehensive Psychiatry Official J o u r n a l o f l h c A m e r i c a n l ' s y c h o p a t h o l o g i c a l A s s o c l a l i o n
VOL.
20, NO.
6
NOVEMBER
/ DECEMBER
1979
The Target S y m p t o m s for Treatment of Depressive Illness Revisited Fritz A. Freyhan
p
~RIOR T O T H E A D V E N T O F m o d e r n p s y c h o p h a r m a c o l o g y , p s y c h i a t r y in t h e U n i t e d States w a s d e p l o r a b l y d i v i d e d into t w o c a m p s , t h e o n e psyc h o a n a l y t i c a l , t h e o t h e r s o m a t i c . B o t h differ f u n d a m e n t a l l y in regard to t h e r a p y and t r e a t m e n t o f m e n t a l d i s o r d e r s . T h e n e u r o s e s w e r e c o n c e d e d to be the territory o f the p s y c h o a n a l y s t , while t h e p s y c h o s e s w e r e the d o m a i n o f the so-called biologically o r i e n t e d psychiatrist. W h e n I e n t e r e d the stage o f clinical psychiatric r e s e a r c h , t h e m a j o r s o m a t i c t r e a t m e n t s w e r e insulin c o m a , electroconvulsive treatment (ECT), and leukotomies. T h e average patient suffering from s c h i z o p h r e n i c a n d affective illness was t r e a t e d with insulin c o m a a n d / o r ECT, d e p e n d i n g on t h e p r i m a r y diagnosis. Patients w h o b e c a m e c h r o n i c and a p p e a r e d resistant to t h e s e t r e a t m e n t s w e r e c a n d i d a t e s f o r prefrontal or subs e q u e n t l y o t h e r l e u k o t o m y p r o c e d u r e s . Clinical results i n d i c a t e d the effectiven e s s o f t h e s e s o m a t i c t r e a t m e n t s , e s p e c i a l l y E C T , for p a t i e n t s with serfous depressions. While t h e r e w a s a clinical c o n s e n s u s r e g a r d i n g the use o f t h e s e t r e a t m e n t s . clinical r e s e a r c h p r o d u c e d w i d e l y conflicting data o n the e v a l u a t i o n o f therapeutic results. In t h e c a s e o f insulin c o m a , f e w p u b l i s h e d s t u d i e s a g r e e d on the statistically a s c e r t a i n e d f r e q u e n c i e s o f i m p r o , , ; e m e n t , let a l o n e r e c o v e r i e s . Similarly, statistics o n E C T - i n d u c e d r e m i s s i o n o f d e p r e s s i o n s varied b e t w e e n 51)% a n d 90%. t T h e s e a m a z i n g d i s c r e p a n c i e s on claims for t h e r a p e u t i c results w e r e in large m e a s u r e attributable to t h e simplistic a p p l i c a t i o n o f diagnostic entities. Alt h o u g h a n y k n o w l e d g e r e g a r d i n g the etiology o f the m a j o r m e n t a l d i s o r d e r s w a s c o n j e c t u r a l at b e s t , the n o t i o n p r e v a i l e d that t h e t r e a t m e n t s w e r e d i r e c t e d at unitary diseases. Therapeutic evaluations were therefore based on such entities as s c h i z o p h r e n i c or a f f e c t i v e d i s o r d e r s , b r o k e n d o w n into c o n v e n t i o n a l subg r o u p s s u c h as c a t a t o n i c o r p a r a n o i d s c h i z o p h r e n i a ; a n d r e a c t i v e , m a n i c d e p r e s s i v e , o r involutional t y p e o f affective illness. O t h e r qualifying factors i n c l u d e d age, d u r a t i o n o f illness, and sex. W h e n in "1954 c h l o r p r o m a z i n e and, later, m a n y o t h e r p s y c h o a c t i v e drugs w e r e i n t r o d u c e d , patient s e l e c t i o n for P r e s e n t e d at the Depression S y m p o s i u m , Utrecht, The Netherlatzds, Alarch 30, 1979. A d d r e s s reprint requests t o Fritz A . Freyhan. M . D . , 2015 R Street. ~I. ~V., IJ,'ashington. D.C. 20009. © 1979 b v G r u n e & Stratton, Inc. 0010-440)(179.r2006-0001501.0010
Comprehensive Psychiatry. Vol. 20. No. 6 (November~December). 1979
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drug t r e a t m e n t f o l l o w e d this n o s o l o g i c a l l y i n a d e q u a t e p r o c e d u r e . I f clinical p s y c h o p h a r m a c o l o g y h a d a c h i e v e d n o t h i n g else, w e w o u l d h a v e to p a y t r i b u t e to the role that it had p l a y e d in the r e d i s c o v e r y o f clinical p s y c h o p a t h o l o g y . T h e n e u r o l e p t i c as well as the a n t i d e p r e s s a n t drugs c l e a r l y s h o w e d s e l e c t i v e effects o n the clinical s y m p t o m a t o l o g y o f p s y c h i a t r i c d i s o r d e r s . It t h e r e f o r e n o longer s e e m e d r e a s o n a b l e to e x p e c t t h a t the m o s a i c a n d p o l a r i t y o f s y m p t o m s c o n v e n t i o n a l l y s u b s u m e d w i t h i n b : o a d d i a g n o s t i c c a t e g o r i e s could r e s p o n d in an identical m a n n e r to the s a m e d r u g ' s m o d e o f a c t i o n . M e t h o d o l o g i c a l l y , t h e idea o f t h e r a p e u t i c t a r g e t s r e p r e s e n t i n g s y m p t o m a t o l o g i e s w i t h i n the f r a m e w o r k o f nosological entities s e e m e d to me a logical c o n c e p t u a l requirem e n t . Clinical observatio~ls s t r o n g l y s u g g e s t e d that p s y c h o a c t i v e drugs act s e l e c t i v e l y o n definable f u n c t i o n a l a r e a s . Different c e r e b r a l s y s t e m s a p p e a r to be i n v o l v e d in p r o d u c i n g c a t a t o n i c s t u p o r o r e x c i t e m e n t , d e p r e s s i v e a n e r g i a o r a n x i o u s agitation, nihilistic d e l u s i o n s o r p a r a n o i d h a l l u c i n a t i o n s . B a s e d o n earlier s t u d i e s o f the effect o f c h l o r p r o m a z i n e a n d p r o c h l o r p e r a z i n e , I dev e l o p e d in 1955 a n i n v e s t i g a t i o n a t m e t h o d b a s e d o n "'target s y m p t o m s " in o r d e r to i d e n t i f y the a r e a s o f d r u g - t r e a t a b l e p s y c h o p a t h o l o g y . T M T h e s e target s y m p t o m s w e r e not c o n c e i v e d as isolated islands in a n o s o l o g i c v a c u u m , but on the c o n t r a r y w e r e i n t e n d e d to lend s u b s t a n c e to individual p s y c h o p a t h o l o g i c d i f f e r e n t i a t i o n within d i a g n o s t i c entities. N e i t h e r on clinical n o r on pharm a c o l o g i c g r o u n d s did it s e e m likely t h a t d r u g s w o u l d act like b u l l d o z e r s digging up a n d r e m o v i n g t h e e n t i r e p a t h o l o g y k n o w n to us as a g i v e n m e n t a l illness. We t h e r e f o r e n e e d e d a m a p to s p o t topical c h a n g e s a n d a s s e s s t h e i r r e l a t i o n s h i p to the regula~tory s y s t e m s o f the C N S . In e s s e n c e , t h e n , this a p p r o a c h a t t e m p t e d to e x p l o r e the q u e s t i o n , " ' W h a t d o t h e t r e a t m e n t s t r e a t ? " W H A T D O THE T R E A T M E N T S TREAT?.
T o find out w h a t the t r e a t m e n t a c t s u p o n r e q u i r e d first a b a s e l i n e profile o f s y m p t o m s defined in the f o l l o w i n g c a t e g o r i e s : (!) b e h a v i o r a l , i.e., o b s e r v a b l e s y m p t o m s : (2) e x p e r i e n t i a l , i.e., s u b j e c t i v e s y m p t o m s a s v e r b a l i z e d b y the p a t i e n t : (3) s o m a t i c s y m p t o m s i n d i c a t i v e o f i l l n e s s - a s s o c i a t e d r e g u l a t o r y d y s functions. T h e first c a t e g o r y , b e h a v i o r a l s y m p t o m s , i n c l u d e s p s y c h o m o t i l i t y p a t t e r n s , a f f e c t i v e c o n t a c t , s t a t e o f vigilance, m a n n e r i s m s , social a t t i t u d e s , and a p p e a r a n c e . T h e s e c o n d c a t e g o r y p e r t a i n s to feelings a n d t h o u g h t s . H e r e b e l o n g e x p r e s s i o n s o f s a d n e s s , d e s p o n d e n c y , suicidal ideas, feelings o f l o w e r e d vitality, a n x i e t i e s , d e l u s i o n s , a n d o b s e s s i o n s . T h e third c a t e g o r y i n c l u d e s c h a n g e s in s l e e p p a t t e r n s , eating b e h a v i o r , s e x u a l i t y , a n d a u t o n o m i c a n d e n d o c r i n e functions. A f t e r t r e a t m e n t h a s s t a r t e d , clinical s t u d i e s r e v e a l w h i c h s y m p t o m s , or c o n s t e l l a t i o n s o f s y m p t o m s , are in fact modified o r e l i m i n a t e d . O p t i m a l l y , all s y m p t o m s d i s a p p e a r . In the face o f clinical r e a l i t y , h o w e v e r , f e w t h e r a p e u t i c m e t h o d s can a c c o m p l i s h this, a n d c e r t a i n l y not in o n e s w e e p . M o r e o v e r , different t r e a t m e n t s , a n d in the c a s e o f p s y c h o p h a r m a c o l o g y , different d r u g s , p r o d u c e different effects. T h i s k n o w l e d g e is vital f o r the c l i n i c i a n ' s d e c i s i o n in o r d e r to m a k e t h e right c h o i c e in t r e a t i n g p r e s e n t i n g p s y c h o p a t h o l o g y . F o c u s i n g n o w on t h e t r e a t m e n t w i t h a n t i d e p r e s s a n t d r u g s , the m o s t impor-
TARGET SYMPTOMS FOR TREATMENT OF ,DEPRESSION
497
tant question t h a n was, and still is today, our understanding o f what constitutes drug-treatable depressive pathology. When, in 1957, imipramine was the o n l y available antidepressant, its mode o f action was classified as being t h y m o l e p t i c in character. B y this was meant a p r e d o m i n a n t l y mood-brightening effect that could be o b s e r v e d in changes o f b e h a v i o r as well as in patient's self-awareness. In contrast to a m p h e t a m i n e s , which were t h e n frequently used to i m p r o v e d y s p h o r i a and anergia, imipramine does not p r o d u c e e u p h o r i a or i apid increase o f energy. Thus, when imipramine w o r k e d , d e p r e s s i v e s y m p t o m a t o l o g y gradually diminished; w h e n it failed, there were no drug-induced mood changes as in the case o f p s y c h o s t i m u l a n t s . The s u b s e q u e n t discovery o f o t h e r tricyclic drugs and o f the m o n o a m i n e oxidase (MAO) inhibitors revealed p r o n o u n c e d differential effects on depressive symptoms and syndromes, In contrast to imipramine, amitryptiline"s mode o f action proved strong in altering agitated and anxious feelings o f d e p r e s s i o n , but was less potent in modifying depressive inhibitions and anergia. This discover), presented the first clue that affective p s y c h o m o t i l i t y patterns and their associated mental s y m p t o m s presented specific criteria for selecting the a p p r o p r i a t e antidepressant. My own investigations o f antidepressants began in 1957 with imipramine and continued with w h a t e v e r new drugs b e c a m e available for clinical trials o f their hoped-for efficacy as antidepressants. A f t e r 3 years o f clinical t r i a l s with tricyclics, MAO; inhibitors, and o t h e r investigational drugs, I reached the preliminary c o n c l u s i o n that not o n l y did the different groups o f antidepressant s v a r y in overall effectiveness, but that some forms o f depression appeared.to be more drug-treatable than others. Depressions w i t h vital s y m p t o m s s u c h as s a d n e s s , anergia, i n h i b i t i o n o r thought processes, and somatic d y s f u n c t i o n s s e e m e d to respond more f a v o r a b l y than depressions associated with ideational s y m p t o m s , i.e,, h y p o c h o n d r i a s i s , phobias, and nihilistic delusions, n Although the use o f E C T declined shortly after the d i s c o v e r y o f the antidepressants, E C T remains the treatment o f choice in the United States for acutely ~suicidal and delusional tylJeS o f depressions: T h e d e v e l o p m e n t o f p s y c h o p h a r m a e o l o g i c r e s e a r c h methodologic p a t t e r n s , which began in the 1950s a f t e r the arrival o f neuroleptic d r u g s , p r o d u c e d instruments for both the qualitative and quantitative m e a s u r e m e n t o f psychopathologic s y m p t o m a t o l o g i e s . In quick succession, batteries o f rating scales became available that could be statistically analyzed. T h e y were needed to confirm the validity o f open clinical observations and to serve for c o m p a r a t i v e studies in double-blind fashion. I w i l l not - c o n c e r n m y s e l f here with m e t h o d o l o g i c researc'h problems. It is a m a t t e r o f historical fact in which clinical p s y c h i a t r y can take pride that the o b s e r v a t i o n a l discoveries o f the prototypical a c t i o n o f neuroleptics and a n t i d e p r e s s a n t s have stood t h e test o f time. T h i s is o f acute significance since practicing physicians c o n t i n u e to depend on their diagnostic capability to r e c o g n i z e the s y m p t o m s that ' l e n d t h e m s e l v e s t o t r e a t m e n t w i t h a given p s y c h o a c t i v e d r u g . T h e most instructive application o f the principal differential c r i t e r i a is the a n t i d e p r e s s a n t classification by Kielholz. 6 His classification has been periodically brought up to date to include all currently available antidepressants. In
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FRITZ A. FREYHAN
this classification, drugs fall into three groups of therapeutic properties, as shown in Fig. I: (1) depression-relieving and mood-brightening: (2) psyc h o m o t o r - a c t i v a t i n g : and (3) p s y c h o m o t o r - s e d a t i n g and anxiolytic. For the previously described type o f vital depression, the a n t i d e p r e s s a n t s in the center, i.e,, imipramine, n o r p r a m i n e , and c h l o m i p r a m i n e are the drugs o f choice. T h e y share to some extent all three property c o m p o n e n t s , T o the left are the antidepressants with p s y c h o m o t o r - a c t i v a t i n g properties. T h e y are most effective for depressions with p r o n o u n c e d s y m p t o m s of inhibition, retardation, and anergia. To the right are the a n t i d e p r e s s a n t s with strong sedative properties most suitable for the treatment o f agitated and anxious depressions. Pharmacologically, these drugs include tricyclics, MAO inhibitors and to the very right, neuroleptics. The latter are not truly a n t i d e p r e s s a n t s but may b e needed if anxious agitation does not yield to sedative a n t i d e p r e s s a n t s such as doxepine or ,,mytriptiline. DISPARITIES IN CLINICAL PRACTICE Recent studies in W e s t e r n E u r o p e a n countries (Austria, France, G e r m a n y , Italy, and SwitzerlandJ and in the United States have s h o w n that prescription patterns for t r e a t m e n t o f depression are not in keeping with scientifically ascertained indications, r T h e r e is widespread e v i d e n c e o f preference for anxiolytic drugs and, to a lesser degree, neuroleptics. Anxiolytic drugs a t t e n u a t e and control a n x i e t y , but they have no effect on the biologic processes a s s u m e d to be the pathogenetic factors o f depression. The same holds true for neuroleptics, which ihave only a limited place in the treatment for maximally agitated depressions. The most plausible explanation for the o v e r p r e s c r i p t i o n o f anxiolytic drugs like diazepam is twofold: (1) the low incidence o f side effects make anxiolytics safe in that patients will offer very few c o m p l a i n t s that would interfere with treatment, and (2) physicians seem to be disproportionately sensitive to s y m p t o m s o f anxiety and less aware o f the o t h e r m a j o r s y m p t o m s o f depression. This situation c o n s t i t u t e s a serious therapeutic problem, since the substitution o f anxiolytics and neuroleptics for potent a n t i d e p r e s s a n t s precludes in most instances satisfactory therapeutic results. SPECIFICITY ISSUE The cardiologist has no c o n c e p t u a l problems prescribing for a patient suffering from c o r o n a r y heart disease on the basis o f s y m p t o m s . T h e r e are drugs for anginal pain, h y p e r t e n s i o n , a r r h y t h m i a s , and d e c o m p e n s a t i o n . The underlying illness may be arteriosclerosis, but we have no m e d i c a t i o n to normalize systemic c a r d i o v a s c u l a r pathology. In p s y c h i a t r y there have traditionally been arguments as to w h e t h e r a t r e a t m e n t is "'only s y m p t o m a t i c " or attacking the "'underlying c a u s e s . " For the present, the u n d e r l y i n g c a u s e s o f mood disorders remain in the realm o f h y p o t h e s e s . C o n s e q u e n t l y , there c a n be no specific treatments. T h e search for the "'Grundst6rung'" o f depressive illness c o n t i n u e s . But we have to resist the t e m p t a t i o n to r e d u c e the c o m p l e x i t y o f affective
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disorders to deficits in n e u r o t r a n s m i t t e r c h e m i s t r y . Some researchers n o w distinguish rigidly between noradrenaline- and s e r o t o n i n - s y s t e m d e p r e s s i o n s , as if d y s f u n c t i o n in both systems or, for that matter, in Still o t h e r s y s t e m s , were incompatible. ~ When lithium entered the therapeutic a r e n a in t h e 1960s, there was new and vigorous talk about iithium's therapeutic specificity. Genetic and clinical studies changed the focus from s y m p t o m - o r i e n t e d therapeutic criteria to course-of-the-illness factors. Bipolar, i.e., manic-depressive, disorders were considered specifically lithium-responsive. T h e case for unipolar depression s e e m e d more problematic, since c o m p a r a t i v e studies showed no superiority o f lithium o v e r tricyclic antidepressants. The most important argument in f a v o r o f lithium specificity c o n c e r n s the evidence o f the effectiveness o f lithium in the prophylactic m a n a g e m e n t of bipolar affective disorders. H o w e v e r , when the first c o m p a r a t i v e studies of the prophylactic efficacy o f lithium versus imipramine were u n d e r t a k e n , both seemed c o m p a r a b l e in p r o p h y l a c t i c effectiveness. ~' To clarify this matter, the National Institute o f Mental Health is n o w c o n d u c t i n g a multihospital study. The therapeutic effects of lithium are clinically impressive. T h e question of specificity, h o w e v e r , must be regarded a s p r e m a t u r e . In a study by A l e x a n d e r van K a m m e n , and B u n n e y t" executed at t h e National Institute of Mental Health u n d e r rigorous placebo-controlled double-blind c o n d i t i o n s , the a u t h o r s concluded that their "'findings suggest that the clinical efficacy o f lithium is not disease-specific for manic-depressive illness, as others have s u g g e s t e d . " The day may c o m e when we have biochemical tests to determine psychiatric diagnosis o f depressive disorders. In that e v e n t , we m a y k n o w the exact process o f the biological disturbance on which to base a truly c o r r e c t i v e treatment. Meanwhile, we can only assume that the clinical e v i d e n c e o f therapeutic efficacy is p r o o f o f the interaction o f a n t i d e p r e s s a n t s with C N S subsystems that c o n t r i b u t e s to the pathogenesis o f depressions. S u m m i n g up, revisiting the target s y m p t o m s provides e v i d e n c e o f their undiminished value as therapeutic guideposts, A glimpse, at r a n d o m as it w e r e , in two current publications would seem to support this view. T h e first quotation is from a report o f the Task F o r c e on P s y c h o p h a r m a c o l o g i c a l Criteria Dev e l o p m e n t o f the American Psychiatric A s s o c i a t i o n , W a s h i n g t o n , D.C. tl T h e authors state that "'children suffering from c h i l d h o o d p s y c h o s e s m a y r e s p o n d to a n t i p s y c h o t i c medication. Generally the usefulness of this medication is limited to specific target s y m p t o m s , such as aggressiveness, h y p e r a c t i v i t y , or sleep disorder, r a t h e r than to the general t r e a t m e n t o f this p r i m a r y d i s o r d e r . " The second q u o t a t i o n is by van Praag, t:~ and states that c o m p o u n d s do not "'respect the boundaries o f the c o n v e n t i o n a l nosological e n t i t i e s " and that "'the s y n d r o m e o r s y m p t o m s determine the i n d i c a t i o n . " In e v e r y d a y clinical practice, then, the c o n c e p t u a l i z a t i o n o f what r e p r e s e n t s treatable p a t h o l o g y remains our c h i e f c o n c e r n . In this e n d e a v o r , the formulation o f target s y m p t o m s remains an important step towards successful treatment.
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REFERENCES 6. Kielholz P: Personal communication 1. Freyhan FA: Rationale and-indications for 7. Kielholz P (ed): Depression in Everyday biological treatment of psychiatric disorders, in Rinkel M (ed): Biological Treatment of Mental Practice. Berne, Hans Huber, I974, pp 121-184 8. Ackenheil M, Hippius H, Matussek N: Illness. New York, Page, 1966, pp 460-,462 2. Freyhan FA: Observations on the clinical Ergebnisse der biochemischen Forschung auf use of tranquilizing agents, Delaware Med J dem Schizophrenie-GebieL Nervenarzt 49. 1978; pp 634-649 29: t91, 1957 9. Freyhan FA: On the Controversy of 3. Freyhaa FA: The neuroleptic action and effectiveness of proclorperazine in psychiatric Prophylactic Antidepressants. Compr Psychiadisorders, in Psychiatric Research Reports 9, try 16:1-5, 1975 10. Alexander PE, van Kammen DP. Bunney Washington, D.C., Amer/can Psychiatric AsWE Jr: Antipsychotic Effects of Lithium in sociation, March 1958 4. Freyhan FA: Clinical techniques f o r Schizophrenia. Am J Psychiatry 136:283-287, 1979 evaluating antipsychotic drugs, in Nodine JH, I 1. Dorsey R, Ayd FJ, Cole J, et al: PSySiegler PE (eds): Animal and Clinical Pharchopharmacological screening criteria demacologic Techniques in Drug Evaluation. Chicago, Year Book Medical Publishers, 1964, velopment project. JAMA 24 I: 102 i - 1031, 1979 12. van Praag, HM: Psychotropic Drugs: A pp 310-316 5. Freyhan FA: The influence of specific -Guide for the Practitioner. New York. Brunner and non-specific factors on the clinical effects of MazeL 1978 psychotropic drugs. Neuro-Psychopharmacology 2:189-203, 1961
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~RIOR T O T H E A D V E N T O F m o d e r n p s y c h o p h a r m a c o l o g y , p s y c h i a t r y in t h e U n i t e d States w a s d e p l o r a b l y d i v i d e d into t w o c a m p s , t h e o n e psyc h o a n a l y t i c a l , t h e o t h e r s o m a t i c . B o t h differ f u n d a m e n t a l l y in regard to t h e r a p y and t r e a t m e n t o f m e n t a l d i s o r d e r s . T h e n e u r o s e s w e r e c o n c e d e d to be the territory o f the p s y c h o a n a l y s t , while t h e p s y c h o s e s w e r e the d o m a i n o f the so-called biologically o r i e n t e d psychiatrist. W h e n I e n t e r e d the stage o f clinical psychiatric r e s e a r c h , t h e m a j o r s o m a t i c t r e a t m e n t s w e r e insulin c o m a , electroconvulsive treatment (ECT), and leukotomies. T h e average patient suffering from s c h i z o p h r e n i c a n d affective illness was t r e a t e d with insulin c o m a a n d / o r ECT, d e p e n d i n g on t h e p r i m a r y diagnosis. Patients w h o b e c a m e c h r o n i c and a p p e a r e d resistant to t h e s e t r e a t m e n t s w e r e c a n d i d a t e s f o r prefrontal or subs e q u e n t l y o t h e r l e u k o t o m y p r o c e d u r e s . Clinical results i n d i c a t e d the effectiven e s s o f t h e s e s o m a t i c t r e a t m e n t s , e s p e c i a l l y E C T , for p a t i e n t s with serfous depressions. While t h e r e w a s a clinical c o n s e n s u s r e g a r d i n g the use o f t h e s e t r e a t m e n t s . clinical r e s e a r c h p r o d u c e d w i d e l y conflicting data o n the e v a l u a t i o n o f therapeutic results. In t h e c a s e o f insulin c o m a , f e w p u b l i s h e d s t u d i e s a g r e e d on the statistically a s c e r t a i n e d f r e q u e n c i e s o f i m p r o , , ; e m e n t , let a l o n e r e c o v e r i e s . Similarly, statistics o n E C T - i n d u c e d r e m i s s i o n o f d e p r e s s i o n s varied b e t w e e n 51)% a n d 90%. t T h e s e a m a z i n g d i s c r e p a n c i e s on claims for t h e r a p e u t i c results w e r e in large m e a s u r e attributable to t h e simplistic a p p l i c a t i o n o f diagnostic entities. Alt h o u g h a n y k n o w l e d g e r e g a r d i n g the etiology o f the m a j o r m e n t a l d i s o r d e r s w a s c o n j e c t u r a l at b e s t , the n o t i o n p r e v a i l e d that t h e t r e a t m e n t s w e r e d i r e c t e d at unitary diseases. Therapeutic evaluations were therefore based on such entities as s c h i z o p h r e n i c or a f f e c t i v e d i s o r d e r s , b r o k e n d o w n into c o n v e n t i o n a l subg r o u p s s u c h as c a t a t o n i c o r p a r a n o i d s c h i z o p h r e n i a ; a n d r e a c t i v e , m a n i c d e p r e s s i v e , o r involutional t y p e o f affective illness. O t h e r qualifying factors i n c l u d e d age, d u r a t i o n o f illness, and sex. W h e n in "1954 c h l o r p r o m a z i n e and, later, m a n y o t h e r p s y c h o a c t i v e drugs w e r e i n t r o d u c e d , patient s e l e c t i o n for P r e s e n t e d at the Depression S y m p o s i u m , Utrecht, The Netherlatzds, Alarch 30, 1979. A d d r e s s reprint requests t o Fritz A . Freyhan. M . D . , 2015 R Street. ~I. ~V., IJ,'ashington. D.C. 20009. © 1979 b v G r u n e & Stratton, Inc. 0010-440)(179.r2006-0001501.0010
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drug t r e a t m e n t f o l l o w e d this n o s o l o g i c a l l y i n a d e q u a t e p r o c e d u r e . I f clinical p s y c h o p h a r m a c o l o g y h a d a c h i e v e d n o t h i n g else, w e w o u l d h a v e to p a y t r i b u t e to the role that it had p l a y e d in the r e d i s c o v e r y o f clinical p s y c h o p a t h o l o g y . T h e n e u r o l e p t i c as well as the a n t i d e p r e s s a n t drugs c l e a r l y s h o w e d s e l e c t i v e effects o n the clinical s y m p t o m a t o l o g y o f p s y c h i a t r i c d i s o r d e r s . It t h e r e f o r e n o longer s e e m e d r e a s o n a b l e to e x p e c t t h a t the m o s a i c a n d p o l a r i t y o f s y m p t o m s c o n v e n t i o n a l l y s u b s u m e d w i t h i n b : o a d d i a g n o s t i c c a t e g o r i e s could r e s p o n d in an identical m a n n e r to the s a m e d r u g ' s m o d e o f a c t i o n . M e t h o d o l o g i c a l l y , t h e idea o f t h e r a p e u t i c t a r g e t s r e p r e s e n t i n g s y m p t o m a t o l o g i e s w i t h i n the f r a m e w o r k o f nosological entities s e e m e d to me a logical c o n c e p t u a l requirem e n t . Clinical observatio~ls s t r o n g l y s u g g e s t e d that p s y c h o a c t i v e drugs act s e l e c t i v e l y o n definable f u n c t i o n a l a r e a s . Different c e r e b r a l s y s t e m s a p p e a r to be i n v o l v e d in p r o d u c i n g c a t a t o n i c s t u p o r o r e x c i t e m e n t , d e p r e s s i v e a n e r g i a o r a n x i o u s agitation, nihilistic d e l u s i o n s o r p a r a n o i d h a l l u c i n a t i o n s . B a s e d o n earlier s t u d i e s o f the effect o f c h l o r p r o m a z i n e a n d p r o c h l o r p e r a z i n e , I dev e l o p e d in 1955 a n i n v e s t i g a t i o n a t m e t h o d b a s e d o n "'target s y m p t o m s " in o r d e r to i d e n t i f y the a r e a s o f d r u g - t r e a t a b l e p s y c h o p a t h o l o g y . T M T h e s e target s y m p t o m s w e r e not c o n c e i v e d as isolated islands in a n o s o l o g i c v a c u u m , but on the c o n t r a r y w e r e i n t e n d e d to lend s u b s t a n c e to individual p s y c h o p a t h o l o g i c d i f f e r e n t i a t i o n within d i a g n o s t i c entities. N e i t h e r on clinical n o r on pharm a c o l o g i c g r o u n d s did it s e e m likely t h a t d r u g s w o u l d act like b u l l d o z e r s digging up a n d r e m o v i n g t h e e n t i r e p a t h o l o g y k n o w n to us as a g i v e n m e n t a l illness. We t h e r e f o r e n e e d e d a m a p to s p o t topical c h a n g e s a n d a s s e s s t h e i r r e l a t i o n s h i p to the regula~tory s y s t e m s o f the C N S . In e s s e n c e , t h e n , this a p p r o a c h a t t e m p t e d to e x p l o r e the q u e s t i o n , " ' W h a t d o t h e t r e a t m e n t s t r e a t ? " W H A T D O THE T R E A T M E N T S TREAT?.
T o find out w h a t the t r e a t m e n t a c t s u p o n r e q u i r e d first a b a s e l i n e profile o f s y m p t o m s defined in the f o l l o w i n g c a t e g o r i e s : (!) b e h a v i o r a l , i.e., o b s e r v a b l e s y m p t o m s : (2) e x p e r i e n t i a l , i.e., s u b j e c t i v e s y m p t o m s a s v e r b a l i z e d b y the p a t i e n t : (3) s o m a t i c s y m p t o m s i n d i c a t i v e o f i l l n e s s - a s s o c i a t e d r e g u l a t o r y d y s functions. T h e first c a t e g o r y , b e h a v i o r a l s y m p t o m s , i n c l u d e s p s y c h o m o t i l i t y p a t t e r n s , a f f e c t i v e c o n t a c t , s t a t e o f vigilance, m a n n e r i s m s , social a t t i t u d e s , and a p p e a r a n c e . T h e s e c o n d c a t e g o r y p e r t a i n s to feelings a n d t h o u g h t s . H e r e b e l o n g e x p r e s s i o n s o f s a d n e s s , d e s p o n d e n c y , suicidal ideas, feelings o f l o w e r e d vitality, a n x i e t i e s , d e l u s i o n s , a n d o b s e s s i o n s . T h e third c a t e g o r y i n c l u d e s c h a n g e s in s l e e p p a t t e r n s , eating b e h a v i o r , s e x u a l i t y , a n d a u t o n o m i c a n d e n d o c r i n e functions. A f t e r t r e a t m e n t h a s s t a r t e d , clinical s t u d i e s r e v e a l w h i c h s y m p t o m s , or c o n s t e l l a t i o n s o f s y m p t o m s , are in fact modified o r e l i m i n a t e d . O p t i m a l l y , all s y m p t o m s d i s a p p e a r . In the face o f clinical r e a l i t y , h o w e v e r , f e w t h e r a p e u t i c m e t h o d s can a c c o m p l i s h this, a n d c e r t a i n l y not in o n e s w e e p . M o r e o v e r , different t r e a t m e n t s , a n d in the c a s e o f p s y c h o p h a r m a c o l o g y , different d r u g s , p r o d u c e different effects. T h i s k n o w l e d g e is vital f o r the c l i n i c i a n ' s d e c i s i o n in o r d e r to m a k e t h e right c h o i c e in t r e a t i n g p r e s e n t i n g p s y c h o p a t h o l o g y . F o c u s i n g n o w on t h e t r e a t m e n t w i t h a n t i d e p r e s s a n t d r u g s , the m o s t impor-
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tant question t h a n was, and still is today, our understanding o f what constitutes drug-treatable depressive pathology. When, in 1957, imipramine was the o n l y available antidepressant, its mode o f action was classified as being t h y m o l e p t i c in character. B y this was meant a p r e d o m i n a n t l y mood-brightening effect that could be o b s e r v e d in changes o f b e h a v i o r as well as in patient's self-awareness. In contrast to a m p h e t a m i n e s , which were t h e n frequently used to i m p r o v e d y s p h o r i a and anergia, imipramine does not p r o d u c e e u p h o r i a or i apid increase o f energy. Thus, when imipramine w o r k e d , d e p r e s s i v e s y m p t o m a t o l o g y gradually diminished; w h e n it failed, there were no drug-induced mood changes as in the case o f p s y c h o s t i m u l a n t s . The s u b s e q u e n t discovery o f o t h e r tricyclic drugs and o f the m o n o a m i n e oxidase (MAO) inhibitors revealed p r o n o u n c e d differential effects on depressive symptoms and syndromes, In contrast to imipramine, amitryptiline"s mode o f action proved strong in altering agitated and anxious feelings o f d e p r e s s i o n , but was less potent in modifying depressive inhibitions and anergia. This discover), presented the first clue that affective p s y c h o m o t i l i t y patterns and their associated mental s y m p t o m s presented specific criteria for selecting the a p p r o p r i a t e antidepressant. My own investigations o f antidepressants began in 1957 with imipramine and continued with w h a t e v e r new drugs b e c a m e available for clinical trials o f their hoped-for efficacy as antidepressants. A f t e r 3 years o f clinical t r i a l s with tricyclics, MAO; inhibitors, and o t h e r investigational drugs, I reached the preliminary c o n c l u s i o n that not o n l y did the different groups o f antidepressant s v a r y in overall effectiveness, but that some forms o f depression appeared.to be more drug-treatable than others. Depressions w i t h vital s y m p t o m s s u c h as s a d n e s s , anergia, i n h i b i t i o n o r thought processes, and somatic d y s f u n c t i o n s s e e m e d to respond more f a v o r a b l y than depressions associated with ideational s y m p t o m s , i.e,, h y p o c h o n d r i a s i s , phobias, and nihilistic delusions, n Although the use o f E C T declined shortly after the d i s c o v e r y o f the antidepressants, E C T remains the treatment o f choice in the United States for acutely ~suicidal and delusional tylJeS o f depressions: T h e d e v e l o p m e n t o f p s y c h o p h a r m a e o l o g i c r e s e a r c h methodologic p a t t e r n s , which began in the 1950s a f t e r the arrival o f neuroleptic d r u g s , p r o d u c e d instruments for both the qualitative and quantitative m e a s u r e m e n t o f psychopathologic s y m p t o m a t o l o g i e s . In quick succession, batteries o f rating scales became available that could be statistically analyzed. T h e y were needed to confirm the validity o f open clinical observations and to serve for c o m p a r a t i v e studies in double-blind fashion. I w i l l not - c o n c e r n m y s e l f here with m e t h o d o l o g i c researc'h problems. It is a m a t t e r o f historical fact in which clinical p s y c h i a t r y can take pride that the o b s e r v a t i o n a l discoveries o f the prototypical a c t i o n o f neuroleptics and a n t i d e p r e s s a n t s have stood t h e test o f time. T h i s is o f acute significance since practicing physicians c o n t i n u e to depend on their diagnostic capability to r e c o g n i z e the s y m p t o m s that ' l e n d t h e m s e l v e s t o t r e a t m e n t w i t h a given p s y c h o a c t i v e d r u g . T h e most instructive application o f the principal differential c r i t e r i a is the a n t i d e p r e s s a n t classification by Kielholz. 6 His classification has been periodically brought up to date to include all currently available antidepressants. In
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this classification, drugs fall into three groups of therapeutic properties, as shown in Fig. I: (1) depression-relieving and mood-brightening: (2) psyc h o m o t o r - a c t i v a t i n g : and (3) p s y c h o m o t o r - s e d a t i n g and anxiolytic. For the previously described type o f vital depression, the a n t i d e p r e s s a n t s in the center, i.e,, imipramine, n o r p r a m i n e , and c h l o m i p r a m i n e are the drugs o f choice. T h e y share to some extent all three property c o m p o n e n t s , T o the left are the antidepressants with p s y c h o m o t o r - a c t i v a t i n g properties. T h e y are most effective for depressions with p r o n o u n c e d s y m p t o m s of inhibition, retardation, and anergia. To the right are the a n t i d e p r e s s a n t s with strong sedative properties most suitable for the treatment o f agitated and anxious depressions. Pharmacologically, these drugs include tricyclics, MAO inhibitors and to the very right, neuroleptics. The latter are not truly a n t i d e p r e s s a n t s but may b e needed if anxious agitation does not yield to sedative a n t i d e p r e s s a n t s such as doxepine or ,,mytriptiline. DISPARITIES IN CLINICAL PRACTICE Recent studies in W e s t e r n E u r o p e a n countries (Austria, France, G e r m a n y , Italy, and SwitzerlandJ and in the United States have s h o w n that prescription patterns for t r e a t m e n t o f depression are not in keeping with scientifically ascertained indications, r T h e r e is widespread e v i d e n c e o f preference for anxiolytic drugs and, to a lesser degree, neuroleptics. Anxiolytic drugs a t t e n u a t e and control a n x i e t y , but they have no effect on the biologic processes a s s u m e d to be the pathogenetic factors o f depression. The same holds true for neuroleptics, which ihave only a limited place in the treatment for maximally agitated depressions. The most plausible explanation for the o v e r p r e s c r i p t i o n o f anxiolytic drugs like diazepam is twofold: (1) the low incidence o f side effects make anxiolytics safe in that patients will offer very few c o m p l a i n t s that would interfere with treatment, and (2) physicians seem to be disproportionately sensitive to s y m p t o m s o f anxiety and less aware o f the o t h e r m a j o r s y m p t o m s o f depression. This situation c o n s t i t u t e s a serious therapeutic problem, since the substitution o f anxiolytics and neuroleptics for potent a n t i d e p r e s s a n t s precludes in most instances satisfactory therapeutic results. SPECIFICITY ISSUE The cardiologist has no c o n c e p t u a l problems prescribing for a patient suffering from c o r o n a r y heart disease on the basis o f s y m p t o m s . T h e r e are drugs for anginal pain, h y p e r t e n s i o n , a r r h y t h m i a s , and d e c o m p e n s a t i o n . The underlying illness may be arteriosclerosis, but we have no m e d i c a t i o n to normalize systemic c a r d i o v a s c u l a r pathology. In p s y c h i a t r y there have traditionally been arguments as to w h e t h e r a t r e a t m e n t is "'only s y m p t o m a t i c " or attacking the "'underlying c a u s e s . " For the present, the u n d e r l y i n g c a u s e s o f mood disorders remain in the realm o f h y p o t h e s e s . C o n s e q u e n t l y , there c a n be no specific treatments. T h e search for the "'Grundst6rung'" o f depressive illness c o n t i n u e s . But we have to resist the t e m p t a t i o n to r e d u c e the c o m p l e x i t y o f affective
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disorders to deficits in n e u r o t r a n s m i t t e r c h e m i s t r y . Some researchers n o w distinguish rigidly between noradrenaline- and s e r o t o n i n - s y s t e m d e p r e s s i o n s , as if d y s f u n c t i o n in both systems or, for that matter, in Still o t h e r s y s t e m s , were incompatible. ~ When lithium entered the therapeutic a r e n a in t h e 1960s, there was new and vigorous talk about iithium's therapeutic specificity. Genetic and clinical studies changed the focus from s y m p t o m - o r i e n t e d therapeutic criteria to course-of-the-illness factors. Bipolar, i.e., manic-depressive, disorders were considered specifically lithium-responsive. T h e case for unipolar depression s e e m e d more problematic, since c o m p a r a t i v e studies showed no superiority o f lithium o v e r tricyclic antidepressants. The most important argument in f a v o r o f lithium specificity c o n c e r n s the evidence o f the effectiveness o f lithium in the prophylactic m a n a g e m e n t of bipolar affective disorders. H o w e v e r , when the first c o m p a r a t i v e studies of the prophylactic efficacy o f lithium versus imipramine were u n d e r t a k e n , both seemed c o m p a r a b l e in p r o p h y l a c t i c effectiveness. ~' To clarify this matter, the National Institute o f Mental Health is n o w c o n d u c t i n g a multihospital study. The therapeutic effects of lithium are clinically impressive. T h e question of specificity, h o w e v e r , must be regarded a s p r e m a t u r e . In a study by A l e x a n d e r van K a m m e n , and B u n n e y t" executed at t h e National Institute of Mental Health u n d e r rigorous placebo-controlled double-blind c o n d i t i o n s , the a u t h o r s concluded that their "'findings suggest that the clinical efficacy o f lithium is not disease-specific for manic-depressive illness, as others have s u g g e s t e d . " The day may c o m e when we have biochemical tests to determine psychiatric diagnosis o f depressive disorders. In that e v e n t , we m a y k n o w the exact process o f the biological disturbance on which to base a truly c o r r e c t i v e treatment. Meanwhile, we can only assume that the clinical e v i d e n c e o f therapeutic efficacy is p r o o f o f the interaction o f a n t i d e p r e s s a n t s with C N S subsystems that c o n t r i b u t e s to the pathogenesis o f depressions. S u m m i n g up, revisiting the target s y m p t o m s provides e v i d e n c e o f their undiminished value as therapeutic guideposts, A glimpse, at r a n d o m as it w e r e , in two current publications would seem to support this view. T h e first quotation is from a report o f the Task F o r c e on P s y c h o p h a r m a c o l o g i c a l Criteria Dev e l o p m e n t o f the American Psychiatric A s s o c i a t i o n , W a s h i n g t o n , D.C. tl T h e authors state that "'children suffering from c h i l d h o o d p s y c h o s e s m a y r e s p o n d to a n t i p s y c h o t i c medication. Generally the usefulness of this medication is limited to specific target s y m p t o m s , such as aggressiveness, h y p e r a c t i v i t y , or sleep disorder, r a t h e r than to the general t r e a t m e n t o f this p r i m a r y d i s o r d e r . " The second q u o t a t i o n is by van Praag, t:~ and states that c o m p o u n d s do not "'respect the boundaries o f the c o n v e n t i o n a l nosological e n t i t i e s " and that "'the s y n d r o m e o r s y m p t o m s determine the i n d i c a t i o n . " In e v e r y d a y clinical practice, then, the c o n c e p t u a l i z a t i o n o f what r e p r e s e n t s treatable p a t h o l o g y remains our c h i e f c o n c e r n . In this e n d e a v o r , the formulation o f target s y m p t o m s remains an important step towards successful treatment.
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REFERENCES 6. Kielholz P: Personal communication 1. Freyhan FA: Rationale and-indications for 7. Kielholz P (ed): Depression in Everyday biological treatment of psychiatric disorders, in Rinkel M (ed): Biological Treatment of Mental Practice. Berne, Hans Huber, I974, pp 121-184 8. Ackenheil M, Hippius H, Matussek N: Illness. New York, Page, 1966, pp 460-,462 2. Freyhan FA: Observations on the clinical Ergebnisse der biochemischen Forschung auf use of tranquilizing agents, Delaware Med J dem Schizophrenie-GebieL Nervenarzt 49. 1978; pp 634-649 29: t91, 1957 9. Freyhan FA: On the Controversy of 3. Freyhaa FA: The neuroleptic action and effectiveness of proclorperazine in psychiatric Prophylactic Antidepressants. Compr Psychiadisorders, in Psychiatric Research Reports 9, try 16:1-5, 1975 10. Alexander PE, van Kammen DP. Bunney Washington, D.C., Amer/can Psychiatric AsWE Jr: Antipsychotic Effects of Lithium in sociation, March 1958 4. Freyhan FA: Clinical techniques f o r Schizophrenia. Am J Psychiatry 136:283-287, 1979 evaluating antipsychotic drugs, in Nodine JH, I 1. Dorsey R, Ayd FJ, Cole J, et al: PSySiegler PE (eds): Animal and Clinical Pharchopharmacological screening criteria demacologic Techniques in Drug Evaluation. Chicago, Year Book Medical Publishers, 1964, velopment project. JAMA 24 I: 102 i - 1031, 1979 12. van Praag, HM: Psychotropic Drugs: A pp 310-316 5. Freyhan FA: The influence of specific -Guide for the Practitioner. New York. Brunner and non-specific factors on the clinical effects of MazeL 1978 psychotropic drugs. Neuro-Psychopharmacology 2:189-203, 1961