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Chapter 2. Antidepressives and Stimulants
Chapter 2.
Antidepressives and Stimulants
C a r l Kaiser and Charles L. Z i r k l e Smith Kline & French Laboratories, Philadelphia, Pa. 19101
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Introduction As i n p a s t years, this chapter reviews stimulants together with antidepressives. T h i s arrangement of t o p i c s seems not t o be j u s t i f i e d on c l i n i c a l grounds f o r t h e s p e c t r a of clinical u t i l i t y of t h e two c a t e g o r i e s of drugs are q u i t e d i f f e r e n t . Is t h e r e any reason f o r t r e a t i n g the two s u b j e c t s together o t h e r than one of convenience? Perhaps t h e answer i s yes i f t h e d e f i n i t i o n of *Istimulants" i s l i m i t e d to amphetamine and pharmacologically r e l a t e d agents. Most research reported i n the l a s t year supports t h e long held b e l i e f t h a t the antidepressives and t h e amphetamine-like drugs e x e r t many of t h e i r pharmacological and clinical effects by a c t i o n s on c e n t r a l monoaminergic, e s p e c i a l l y catecholaminergic, pathways. B u t t h e biochemical a c t i o n s of t h e t r i c y c l i c a n t i d e p r e s s i v e s are s t i l l poorly understood and t h e i r relevancy to t h e t h e r a p e u t i c effects has not been established. From the extensive s t u d i e s on amphetamine a more coherent, i f n o t clearer, p i c t u r e of i t s a c t i o n s is emerging. A sign of progress i s t h a t one can now with some assurance describe amphetamine a s a catecholaminergic agent w i t h a pronounced dopaminergic component o f action r a t h e r than a s a c e n t r a l l y - a c t i n g sympathomimetic amine. The 1971 l i t e r a t u r e describes t h e s y n t h e s i s and pharmacological evaluation of numerous p o t e n t i a l antidepressives, b u t p r e s e n t s no evidence t h a t new agents superior t o t h e e s t a b l i s h e d drugs are i n the offing.
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Tricvclic compounds w i t h antidepressive a c t i v i t y An a m i t r i p t y l i n e d e r i v a t i v e , S D 2202-01 (In),exhibited a pharmacological p r o f i l e similar t o t h a t o f the parent.' Antidepressive and anti-anxiety p r o p e r t i e s were Other a m i t r i p t y l i n e r e l a t i v e s , a l s o noted f o r a monomethyl analog (&I.* some 5-methylene-4-substituted dibenzocycloheptenes (21,had l i t t l e a c t i v i t y i n a mouse a n t i r e s e r p i n e test.' A dibenzthiepin, dothiepin (prothiadine), was superior t o a m i t r i p t y l i n e i n a double b l i n d comparison f o r t h e treatment of depression.' Amoxapine (3, cL-67772), a dibenzoxazepine, although devoid of a n t i c h o l i n e r g i c p r o p e r t i e s , produced imipramine-like a c t i v i t y i n animals. C l i n i c a l l y , 3 was an e f f e c t i v e a n t i depressive agent; however, s i d e e f f e c t s (insomnia, d i f f i c u l t u r i n a t i o n ) were e n ~ o u n t e r e d . ~Several related dibenzodiazepines had antidepressive properties. SM-307 (41, an e t h y l s u l f o n y l analog of dibenzepin,6 produced
kCOCH, NRCH'
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R=CH3 R=H
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imipramine-like e f f e c t s i n animals.’ A r e l a t e d pyridobenzodiazepine, UP-106 (2), a l s o was a c t i v e i n various animal tests i n which most a n t i depressives a r e e f f e c t i v e and i t demonstrated clinical activity.’ The s t r u c t u r a l l y s i m i l a r U-17,660 (6)w a s t h e most potent a n t i a l l e r g i c and antianaphylactic compound i n a series of 5- and 10-aminoalkylated dibenzodiazepines
.’
Antidepressive a c t i v i t y was noted f o r s o m e t r i c y c l i c compounds having a six-rnembered c e n t r a l ring. A series of naphthyridones, C-29 c-42 (2). and C-45 (21, caused imipramine-like a c t i v i t y i n animals.’ The influence of 3 on c e n t r a l biogenic amine levels,’ as w e l l a s i t s absorption, d i s t r i b u t i o n and excretion,’ was investigated i n mice and rats, Several phenothiazine d e r i v a t i v e s had antidepressive a CF, analog of a c t i v i t y , III extensive clinical t r i a l s f l u o r a c i z i n e (&I, chloracizine,’ showed antidepressive e f f i c a c y equivalent to imipramine. It a l s o produced a n t i c h o l i n e r g i c effects,’ ” S t r u c t u r e versus antidepressive a c t i v i t y r e l a t i o n s h i p s were reported f o r a series of phenot h i a z i n e s and r e l a t e d compounds bearing a carbocyclic b a s i c s i d e chain. Che of these compounds (&) was considerably more potent than amitriptyOther l i n e i n preventing reserpine-induced p t o s i s i n mice and rats.” phenothiazines with antidepressive a c t i o n s included &, t h e l-chloroanalog of chlorpromazine, which produced imipramine-like a c t i o n s i n mice and r a t s , ’ and the azaphenothiazine-10-thiolcarboxylate 4 which induced antidepressive-like symptoms (mydriasis, increased s e n s i t i v i t y t o touch) i n mice.‘ The antidepressive e f f e c t s of phenothiazine d e r i v a t i v e s with 1- o r a-substituents may be associated with the steric influence of these groups i n i n t e r f e r i n g with attainment of a nearly f l a t conformation by the t r i c y c l i c system.’ 3
(A),
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b) X=OCH3
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Other t r i c y c l i c compounds with antidepressive a c t i v i t y w e r e maprotiline (10, Ciba 34276-Ba), which produced imipramine-like e f f e c t s
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and blocked r a t synaptoso.na1 uptake of norepinephrine’ (NE) which antagonized tetrabenazineI n mice, t h e phenanthinduced p t o s i s i n mice a t EL+o 20 mgkg, P , o . ~ O rene 12 had no a n t i r e s e r p i n e a c t i v i t g ’ and a 6,g-dihydro d e r i v a t i v e of imipramine f a i l e d t o antagonize tetrabenazine-induced depression .2 and t h e pyridobenzocyclooctane
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(a%)3NHcH3 10 -
(q13 N(CH3 1 2
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Several diphenylmethane d e r i v a t i v e s had antidepressive a c t i v i t y . Tofenacin (3) w a s well-tolerated and e f f e c t i v e i n p a t i e n t s with various kinds of d e p r e ~ s i o n ‘.2~4 ~ Like imipramine, s o m e aminopropenes reversed reserpine-induced hypothennia i n mice .2 The (-1 -isomer of 2 caused c l i n i c a l antidepressive a c t i o n s , b u t these were accompanied by unwanted side e f f e c t s . 2 6
14
X=H,j-F,LF; R=H,CH3
14 -
15
Other compounds with antidepressive a c t i v i t y - It has been suggested t h a t rubidium s a l t s ( s e e below) may have antidepressive a c t i v i t y and a remarkable therapeutic response was noted i n an open clinical C l i n i c a l antidepressive a c t i v i t y was produced by A-25794 .2 A molindone r e l a t i v e , EN-3022 ( 9 1 , was e f f e c t i v e i n s e v e r a l tests (antagonism of tetrabenazine-induced p t o s i s i n mice; p o t e n t i a t i o n of pressor response t o NE i n dogs)30 i n which most antidepressives are a c t i v e . Nomifensine w a s more potent than imipramine i n antagonizing reserpineinduced catalepsy i n rats.” Quipazine had a pharmacological p r o f i l e similar t o t h a t of t r i c y c l i c anti depressive^.^^ I n a series of phenacylthioimidazolines, 2 was the most potent antagonist of reserpine-induced hypothermia i n mice (12X imipramine) .l3
(16)
(18)
(a)
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0
M p r a m i n e - l i ke phannaco logica 1 a c t i v i t y , without a n t i cho l i n e r g ic properties, was noted f o r LG 152 i t also prevented synaptosomal reuptake of NE.35 Potent antitetrabenazine-induced p t o s i s a c t i v i t y , without anticholinergic effects, w a s produced by some e t h e r s of hexanophenone oxime, e.g. 2 3 3 6 The piperidinecarboxamide was equipotent with amitriptyl i n e i n a test f o r dopa-potentiation i n mice.)' A series o f phthalan derivatives having a pharmacological spectrum similar t o t h e tric y c l i c a n t i d e p r e s s i v e s was studied f o r i n h i b i t i o n of mitochondrial activity i n i n t a c t yeast cells a test which c o r r e l a t e s with c l i n i c a l antidepressive potency. Most potent a c t i v i t y was noted f o r Lu 3-04" (2&) , Lu 3-009 (24b) , Lu 3-074 3 X impramine))* and Lu 3-049 4.3X imipramine) C l i n i c a l antidepressive a c t i o n s were noted f o r HT 3261 (3)" and t h e choline d e r i v a t i v e panclar which was an e f f e c t i v e psychostimulant i n p a t i e n t s with schizophrenia, depression and neuroses." Other compounds with c l i n i c a l antidepressive a c t i v i t y included W I N 27,147-2 (271, which w a s devoid of s i d e effects a t e f f e c t i v e dose levels.42 and 8 14.368 (g>,53 which w a s o f doubtful value i n humans and caused untoward s i d e effects although i t produced antidepressive-like a c t i o n s i n animals. Short-lived antidepressive a c t i v i t y w a s observed with ~40pa.'~
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ss
=NO(CH2)2N% 22 -
3 HOPO) (% >,N(CH3
26
pcs
a) b) c) d)
24 -
X=CH,; R=CH3 X 4 ; R=CH3 X-S; R = C b X=C%; R=H OH
Several amphetamine d e r i v a t i v e s displayed antidepressive properties. Fenfluramine, an a n o r e c t i c drug which depresses motor a c t i v i t y , showed an imipramine-like p r o f i l e of a c t i v i t i n various phamacological tests i n mice.'5 p3loroamphetamine (*IY6 and i t s N-methyl d e r i v a t i v e ,
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RO-4-6861 (29b) ,47 produced c l i n i c a l a c t i v i t y resembling t h a t of the t r i c y c l i c a x d e p r e s s i v e s . BW 65-54 (2) e l i c i t e d antidepressive effects i n animals; i t potentiated responses to amphetamine, apparently by i n t e r f e r i n g with metabolic inactivation,'8 A number of new MA0 i n h i b i t o r s were described i n 1971; however, because of the l i m i t e d c l i n i c a l u t i l i t y of these agents i n t h e treatment of depression, they w i l l not be reviewed i n d e t a i l . Nonetheless, several of these substances a r e noteworthy. Sydnophene (2)'9 was included i n a series of sydnonimines examined f o r MAO-inhibitory a c t i v i t y . It demons t r a t e d m i l d stimulant and antidepressive a c t i o n s i n extensive c l i n i c a l s t u d i e s i n Russia.50 Another MAO-inhibitor, c l o r g i l i n e M&B 9302) had antidepressive a c t i v i t y ; i t s c l i n i c a l effects were s i m i l a r to those of i m i ~ r a m i n e . ~ ' Proportions of two forms of MA0 (Type A, B) were found to vary i n d i f f e r e n t a r e a s of r a t b r a i n . The type A enzyme, predominant i n sympathetic nerves, acted on both 5-HT and tyramine and was inhibited by and acted on tyramine, b u t 32, whereas type B-MA0 was i n s e n s i t i v e t o not 5-HT." I n humans, 32, tranylcypromine and isocarboxazid increased 5HT, NE and dopamine l e v e l s i n various b r a i n a r e a s ; however, t h e effect of tranylcypromine was s i g n i f i c a n t l y g r e a t e r than t h a t of the o t h e r two on dopamine i n t h e caudate nucleus and h y p o t h a l a m u ~ . ~In ~ vitro, Lilly 51641 (21, l i k e harmaline, p r e f e r e n t i a l l y blocked M A 0 oxidation of 5-HT, whereas tranylcypromine and pargyline s e l e c t i v e l y i n h i b i t e d the oxidation of tyramine .5'
(z,
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S t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s o f c e n t r a l stimuCentral Stimulants l a n t s were reviewed i n 1971.55 '56 The use of central stimulants, notably dextroamphetamine and methylphenidate, i n t h e therapy of hyperkinetic disorders i n children has increased, According t o NIMH estimates more than 200,000, o r about 1 s of hyperactive children, received amphetamine treatment i n 1969?' These agents reduce d i s t r a c t i b i l i t y and promote the c h i l d ' s a b i l i t y to focus on meaningful s t i m u l i and t o organize his bodily movements more purposefully.5 8 ' 5 9 Similar effects w e r e e l i c i t e d by treatment of untrainable hyperkinetic and aggressive dogs with dextroamphetamine."
(21,
N e w e r amphetamine r e l a t i v e s included pyrovalerone which w a s b e n e f i c i a l i n therapy of c h r o n i c a l l y fatigued patients," U-30,405A ( a) and U-28,926~ which caused CNS stimulation i n rhesus monkeys. 6% Amantadine produces amphetamine-like a c t i o n ( see below). An aminot e t r a l i n , ADT ( 6) afforded amphetamine-like e f f e c t s b u t decreased motor a c t i v i t y i n m i c S 3 Adenosine had a psychoanaleptic effect i n a mouse maze test.64 Exploratory a c t i v i t y of mice was enhanced by P1961 (2) .65 Other compounds f o r which CNS-stimulating a c t i v i t y was observed i n mice
(z),
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included 4864 ( 8) ,66 a benzocyclobutene % 1-69 and GYI 20238 (j
23 thiolactams,6 *
Kaiser, Z i r k l e
(2) ,6 several
a
c1
2
38
Several s t u d i e s r e l a t e d t o physical p r o p e r t i e s and metabolism of amphetamines. "he b a s i c i t y , t i s s u e d i s t r i b u t i o n and metabolism of p-f luoro-, p, p-dif luoroamphetamine, and amphetamine w e r e s t r i k i n g l y d i f f e r e n t i n rats.70 N m r studies of t h e conformational properties7' of amphetamine and r e l a t e d phenethylamines revealed a preference f o r trans phenylamino rotomers i n aqueous although s u b s t i t u e n t groups, steric and electronic f a c t o r s influence rotomer p o ~ u l a t i o n s . ~A~ quantum mechanical study indicated the folded form of amphetamine i s s l i g h t l y favored.72 Metabolism of amphetamine t o an oxime and subsequent hydrolys i s t o benzyl methyl ketone was shown t o c o n s t i t u t e a route of deaminat i ~ n . ~ ' In a r a b b i t l i v e r oxygenase system this conversion involves an intermediate a-hydroxyamine .75
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-theses. Biochemistry and Pharmacoloqy of the various i d e a s about biochemical causes of a f f e c t i v e disorders,76 '77 the Vatecholamine (CAI hypothesis" is s t i l l t h e most frequently c i t e d . According to this p o s t u l a t e depression may be r e l a t e d t o a deficiency of CA (usually NE) a t functionally important c e n t r a l CA receptors, w h i l e mania r e s u l t s from excess CA. Perhaps an equally p l a u s i b l e case can be made f o r a "serotonin hypothesis of a f f e c t i v e disorders." Consistent with t h e CA hypothesis a r e the observations t h a t when a-methyltyrosine, an i n h i b i t o r of CA biosynthesis, was given to 7 m a n i c and 3 depressed p a t i e n t s under double b l i n d conditions, 5 of t h e m a n i c p a t i e n t s became less manic and t h e 3 depressed p a t i e n t s became more d e p r e s ~ e d . ~ " ~However, ~ attempts t o overcome t h e postulated deficits of CA o r serotonin (5-HT) by administration of t h e amino acid precursors, Gdopa, tryptophan, o r 5-hydroxytryptophan- a s t r a t e g y successful i n the treatment of parkinsonism have given genera l l y disappointing r e s u l t s i n depressed patient^.^"^^ '13' Even i n l a r g e doses equivalent t o those found t o be e f f e c t i v e i n parkinsonism, M o p a produced an antidepressive effect i n Only 4 of 16 p a t i e n t s . A l l of the p a t i e n t s who responded had retarded depressions; none of the 5 p a t i e n t s with a g i t a t e d depression improved. Five depressed p a t i e n t s who had p r i o r
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h i s t o r i e s o f mania developed hypomania o r mania without a r e v e r s a l o f depression. It i s suggested t h a t CA, p a r t i c u l a r l y dopamine (DA), may be involved i n t h e genesis o f mania i n susceptible i n d i v i d u a l s b u t t h a t depression and mania are not opposite poles of the same entity." These r e s u l t s do not support t h e CA theory of depression b u t n e i t h e r do they rule i t out. Although L-dopa i n c r e a s e s DA i n b r a i n , i t may not i n c r e a s e NE. It also produces o t h e r c e n t r a l biochemical a c t i o n s , e.g., effects suggesting t h a t i t causes a decrease i n turnover o f b r a i n 5-HT i n depressed patients." However, t h e mostly negative clinical r e s u l t s with L a o p a seem t o cast f u r t h e r doubt on the v a l i d i t y of t h e behavioral syndrome and amine depletion induced by r e s e r p i n e (which i s reversed by L-dopa) a s a model of depression. The catechol theory of depression i s based i n p a r t on evidence t h a t the t r i c y c l i c antidepressives and ampheramine a f f e c t CA m e t a b o l i s m i n ways t h a t r e s u l t i n an increased a v a i l a b i l i t y o f t h e t r a n s m i t t e r s a t t h e i r receptor sites. It has been thought f o r s o m e t i m e t h a t t h e w e l l known i n h i b i t o r y a c t i o n o f t h e t r i c y c l i c a n t i d e p r e s s i v e s upon t h e uptake o f NE i n central noradrenergic (NA) neurons r e s u l t s i n an i n c r e a s e of t h e monoarnine a t t h e r e c e p t o r s and may account f o r antidepressive a c t i v i t y . Several observations may not be i n accord with this view. I n d i r e c t evidence has been adduced t h a t some t r i c y c l i c agents with t e r t i a r y amino groups (imipramine, chlorimipramine and a m i t r i p t y l i n e ) p r e f e r e n t i a l l y block 5-HT uptake i n 5-HT neumns w h i l e c e r t a i n secondary amines (desmethylimipramine , n o r t r i p t y l i n e and p r o t r i p t y l i n e ) p r e f e r e n t i a l l y i n h i b i t uptake o f NE. Recent s t u d i e s i n which i n vivo uptake o f NE and 5-HT was d i r e c t l y measured histochemically confirm t h e e a r l i e r data a s d i d funct i o n a l s t u d i e s using the extensor and f l e x o r r e f l e x e s t o assess t h e influence of t h e various drugs on 5-HT and NA receptor a c t i v i t y , respect i ~ e l y . ' ~ I n a d d i t i o n t h e antihistamine drugs, chlorpheniramine and e s p e c i a l l y brompheniramine were found t o be very potent blockers o f 5-HT uptake. However, these drugs, u n l i k e t h e t e r t i a r y amino t r i c y c l i c s , also showed a potent blocking a c t i o n on NE uptake. The questions arise whether t h e c l i n i c a l a c t i v i t y o f these drugs i s more c l o s e l y related t o effects on 5-HT o r on NE neurons o r whether t h e r e are two classes o f antidepressives a c t i n g by d i f f e r e n t mechanisms. Some clinicians feel t h a t t h e c l i n i c a l a c t i o n s of t h e t r i c y c l i c a n t i d e p r e s s i v e s can be divided i n t o a mood-elevating component and a psychomotor-activating component. They b e l i e v e t h e t e r t i a r y amines are more e f f e c t i v e i n brightening of mood, suggesting involvement of 5-HT neurons w h i l e t h e secondary amines are more e f f e c t i v e i n i n c r e a s i n g d r i v e o r producing psychomotor a c t i v a t i o n , suggesting t h a t NE neurons a r e mainly Seemingly a t odds with t h e blockade of amine-uptake hypotheses are the p r o p e r t i e s of one of t h e newer t r i c y c l i c s , iprindole. This drug produces c l i n i c a l effects resembling those of imipramine-like agents y e t i n s o m e pharmacological tests, e.g., r e v e r s a l o f reserpine-induced p t o s i s and hypothermia i n mice, i t i s considerably less potent than i~nipramine.'~ It i s a very weak i n h i b i t o r of uptake of NE and 5-HT &-I v i t r o and i n vivo i n mice and rats.86 Despite i t s weak uptake blocking a c t i v i t y , i t potentiated t h e awakening effect of Gdopa i n r e s e w z e d mice a s
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25
imipramine does. Unlike the a n t i d e p r e s s i v e s which block amine uptake, i p r i n d o l e does not augment the pressor response t o NE o r block t h e blood pressure response t o tyramine i n man,'7 Differences i n t h e e f f e c t s of acute and chronic treatment with imipramine and p r o t r i p t y l i n e on c e n t r a l NE metabolism i n t h e r a t have been observed." The turnover of NE was decreased a f t e r acute administration but increased during chronic administration of these drugs. The i n c r e a s e i n NE turnover occurred sooner when thyroxine was administered with imipramine. It i s suggested t h a t these observations may help t o explain t h e delayed o n s e t of c l i n i c a l antidepressive effects and t h e a c c e l e r a t i n g and enhancing effects o f thyroid hormone on the c l i n i c a l e f f e c t s of imipramine. It has been suggested t h a t thyroxine may e x e r t s o m e o f i t s action by f a c i l i t a t i n g the action of NE i n c e n t r a l NA pathways.e9 Rats t r e a t e d with thyroxine became hyperactive and showed increased s e n s i t i v i t y t o the behaviorally a c t i v a t i n g e f f e c t s o f NE administered i n t r a v e n t r i c u l a r l y . Possibly r e l e v a n t t o the v a r i a t i o n i n effects on NE turnover noted under varied conditions of administration of t h e t r i c y c l i c s i s t h e observation t h a t spontaneous a c t i v i t y i n r a t s w a s decreased s h o r t l y after administration of imipramine but w a s increased over t h a t of c o n t r o l animals one day a f t e r a d m i n i s t r a t i ~ n . ~Much ~ more d a t a o f t h e kinds c i t e d above must be obtained f r o m s t u d i e s o f a v a r i e t y of t r i c y c l i c antidepressives, including i p r i n d o l e , before any conclusions about a r e l a t i o n s h i p between t h e clinical a c t i o n of t h e s e drugs and t h e i r effects on monoamine metabolism can be drawn. A study o f t h e effects of L-dopa and Li,CO, on u r i n a r y excretion o f c y c l i c AMP i n depression and mania has been r e p ~ r t e d . ~ ' Manic p a t i e n t s excreted t h e most c y c l i c AMP and severely depressed p a t i e n t s excreted t h e l e a s t ; c o n t r o l s and moderately depressed p a t i e n t s showed intermediate values. Depressed p a t i e n t s t r e a t e d with L-dopa showed marked i n c r e a s e s i n urinary c y c l i c AMP excretion. P a t i e n t s treated with U 2 C 9 showed changes i n c y c l i c AMP excretion i n t h e d i r e c t i o n o f clinical change; a s depression improved, c y c l i c AMP e x c r e t i o n increased and as mania improved i t diminished. It i s not possible t o a t t r i b u t e these changes i n excretion of c y c l i c AMP t o e i t h e r c e n t r a l o r peripheral mechanisms o r both.
Rubidium i o n seems t o have opposite effects from l i t h i u m i o n on CA metabolism and it has been suggested t h a t i t may have c l i n i c a l antidepressive a c t i v i t y . It produces an i n c r e a s e i n t h e r e l e a s e and turnover o f b r a i n stem NE and, u n l i k e l i t h i u m ion, i t induces an increase i n s t e a d of a decrease i n shock-elicited aggression i n rats.92 Further comparisons of rubidium and l i t h i u m i o n s may shed considerable l i g h t on t h e biochemistry of t h e a f f e c t i v e disorders i f t h e i n i t i a l c l i n i c a l observations t h a t rubidium has antidepressive a c t i v i t y a r e confirmed by c o n t r o l l e d studies?' Although t h e r o l e s o f NE and 5-HT i n t h e antidepressive a c t i o n o f the t r i c y c l i c s have n o t been e s t a b l i s h e d , t h e r e i s l i t t l e doubt b u t t h a t the stimulatory a c t i o n of amphetamine i s t o a l a r g e e x t e n t mediated through CA pathways. Early experiments emphasized effects of t h e drug on NA systems. Now t h e evidence i s stronger f o r a DA mechanism of central
26 -
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Engelhardt, Ed.
a c t i o n than f o r a NA mechanism. Although t h e r e is some disagreement, most authors believe t h a t amphetamine produces i t s c e n t r a l e f f e c t s by r e l e a s i n g dopamine and NE a t nerve endings from labile i n t r a n e u r o n a l pools of newlysynthesized amines. Amphetamine i s thought t o induce stereotyped behavior by r e l e a s i n g DA whereas apomorphine produces this behavioral effect by a direct a c t i o n on DA receptors. The increase i n locomotor a c t i v i t y e l i c i t e d by amphetamine appears t o be mediated a t l e a s t i n p a r t by a NA action. Other behavioral effects of amphetamine may also involve NA and/or DA actions. The experimental b a s i s f o r t h e s e statements h a s been extensively reviewed.53 A f e w of the observations may be b r i e f l y summarized a s follows. Depletion of CA i n t h e i n t r a n e u r o n a l storage granules by r e s e r p i n e does not prevent t h e i n c r e a s e i n motor a c t i v i t y o r s t e r e o t y p i c a l behavior produced by amphetamine o r apomorphine. I n h i b i t i o n of CA s y n t h e s i s by a-methyltyrosine blocks the effects o f amphetamine b u t not those of apomorphine. I n h i b i t o r s of dopamine P-hydroxylase (e.g., d i e t h y l dithiocarbamate), which i n h i b i t t h e s y n t h e s i s o f NE but n o t DA, decrease amphetamine-stimulated motor a c t i v i t y , b u t do n o t i n h i b i t and even may enhance amphetamine-induced stereotypies. Recent s t u d i e s confirm these r e s u ~ t s . ~'9'J '95
"'
b s t evidence suggests t h a t amphetamine- and apomorphine-induced s t e r e o t y p i e s a r e t h e r e s u l t of enhanced DA a c t i v i t y i n t h e neostriatum. Consistent with this view i s t h e e f f e c t of amphetamine i n rats with u n i l a t e r a l l e s i o n s of t h e n i g r o s t r i a t a l DA pathway ( s e e Chapter 1, p 19. The drug causes i p s i l a t e r a l turning i n t h e s e animals, presumably as a consequence of release o f DA i n t h e neostriatum from t h e i n t a c t DA neurons of the c o n t r a l a t e r a l (non-lesioned) side. T h i s effect of amphetamine i s attenuated by pretreatment with a m e t h y l t y r o s i n e b u t n o t with reserpine.96 19' I n c o n t r a s t , apomorphine, which i s believed t o be a d i r e c t a c t i n g DA agent, induces c o n t r a l a t e r a l turning behavior, an e f f e c t a t t r i b u t e d t o denervation s u p e r s e n s i t i v i t y o f s t r i a t a l DA r e c e p t o r s i n t h e neostriatum on the lesioned side. T h i s e f f e c t of apomorphine i s not antagonized by e i t h e r r e s e r p i n e o r a-methyltyrosine. I n r a t s with u n i l a t e r a l l e s i o n s i n t h e neostriatum, amphetamine and apomorphine both e l i c i t i p s i l a t e r a l turning. Similar effects are observed i n mice with u n i l a t e r a l l e s i o n s o f t h e caudate nucleus. This preparation provides a simple and rapid model f o r studying effects of drugs on c e n t r a l DA systems.9e Possibly a t odds with t h e hypothesis t h a t drug-induced stereotyped behavior involves a DA mechanism are observations on t h e effects of s o m e stimulants on t h e turnover o f b r a i n CA i n the r a t . cJ-Amphetamine, aminorex and p-chloramphetamine a t doses which increased motor a c t i v i t y , but d i d not induce s t e r e o t y p i e s , caused an i n c r e a s e i n turnover o f DA b u t not of NE. These r e s u l t s a r e d i f f i c u l t to i n t e r p r e t , however, because phenmetrazine did n o t a l t e r turnover of DA o r NE a t a dose t h a t increased motor a c t i v i t y . 9 9 Although t h e c e n t r a l a c t i o n s of amphetamine may r e q u i r e an uninterrupted s y n t h e s i s of CA r a t h e r than reserpine-sensitive s t o r e s of the amines, this does n o t seem t o be true f o r a l l amphetamine-like stimulants.
Chap. 2
Antidepressives, Stimulants
Kaiser, Z i r k l e
27
A r e c e n t study, together with e a r l i e r d a t a , suggests that amphetamine-like
stimulants can be divided i n t o two groups according t o t h e ways i n which they i n t e r a c t with r e s e r p i n e and a-methyltyrosine. The e f f e c t s of members of one group - amphetamine, methamphetamine, ephedrine,phenmetrazine and phentermine - are i n h i b i t e d by a-methyltyrosine b u t not by reserpine; those of members of t h e second group benzphetamine, methylphenidate, pipradrol, cocaine and amfonelic acid ( 7-benzyl-1-ethyl-1, It-dihydro-bxo-1,anaphthyridine-3-carboxylic acid) are i n h i b i t e d by r e s e r p i n e b u t n o t by m e t h y l t y r o s i n e , a t least i n moderate doses.”’ Although, a s t h e s e results suggest, stimulants may d i f f e r i n t h e i r a c t i o n s on i n t r a n e u r o n a l pools of CA, no d i f f e r e n c e i n t h e i r c l i n i c a l e f f e c t s has been observed. b t h y l p h e n i d a t e produced physiologic, s u b j e c t i v e and behavior effects t h a t w e r e not s i g n i f i c a n t l y d i f f e r e n t from those of amphetamine, methamphetamine, ephedrine and phenmetrazine.‘
-
-
’‘
Further s t u d i e s of t h e metabolism o f amphetamine and o f t h e effects of t h e drug and i t s metabolites on CA metabolism have n o t defined t h e biochemical e f f e c t s underlying t o l e r a n c e development t o t h e drug.102-104 A thorough study was made o f t h e psychomotor and anorexigenic effects of d-amphetamine upon chronic dosing.’ Tolerance development t o t h e drug occurred i n r a t s which w e r e dosed d a i l y s h o r t l y before t e s t i n g . Tolerance d i d not occur i n rats which received t h e same d a i l y doses o f amphetamine but were dosed a f t e r each d a i l y t e s t session. Subsequent dosing of t h e l a t t e r group with amphetamine p r i o r t o t e s t i n g produced psychornotor stimulation and anorexigenic e f f e c t s a s l a r g e a s those i n i t i a l l y observed i n t h e r a t s t h a t had always been dosed d a i l y p r i o r to t e s t i n g . The r e s u l t s suggest t h a t tolerance t o t h e s e effects of amphetamine r e p r e s e n t s a behavioral adaptation of the r a t s t o the. “drugged” state.
-
Several reports described effects of t h e methylxanthines and amantadine on b r a i n monoamine m e t a b o l i s m which may be involved i n t h e i r pharmacological actions. Caffeine and theophylline release b r a i n NE i n r a t s and guinea pigs.’o6 The i n c r e a s e i n c y c l i c AMP produced by these drugs, u s u a l l y a t t r i b u t e d t o i n h i b i t i o n of phosphodiesterase, could be I n mice due t o stimulation of adenyl cyclase by t h e released NE. c a f f e i n e and aminophylline appear t o i n c r e a s e turnover of b r a i n DA and NE.lo7 Other d a t a suggest t h a t t h e methylxanthines e i t h e r prevent t h e The antiparkinsonisn release o f b r a i n 5-HT o r i n c r e a s e 5-HT synthesis.”* e f f e c t s of amantadine have stimulated s t u d i e s o f i t s c e n t r a l actions. Extensive biochemical and pharmacological d a t a from s t u d i e s i n r a t s and mice i n d i c a t e t h a t this drug produces i t s effects, e.g. i n c r e a s e i n r o t a t i o n a l behavior i n t h e r a t turning model and i n c r e a s e i n motor a c t i v i t y , by r e l e a s i n g CA, e s p e c i a l l y DA, f r o m e x t r a g r a n u l a r (reserpiner e s i s t a n t ) s t o r e s . Thus amantadine appears t o have an amphetamine-like action b u t i t i s much less potent than However, unlike amphetamine, amantadine-induced i n c r e a s e i n motor a c t i v i t y i n mice was not a l t e r e d by a-rnethyltyrosine.l
’’
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CNS Agents
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A. Berkowitz, J. H. Tarver and S. Spector, Eur. J. Pharmacol., 2, 64 (1970). Waldeck, J. Pham. hamacol., 23, 824 (1971). A. Berkowitz and S. Spector, Eur. J. h a m c o l . , 322 (1971). U. Stramberg and T. H. Svensson, Acta Phamcol. Todcol., 161 (1971). L.-0. Farnebo, K. Fuxe, M. Goldstein, B. Hamberger and U. Ungerstedt, Eur. J. Fhamacol., (1971). 111. J. E. Thornburg and K. E. Moore, Pharmacologist, 2,202 (1971).
106. 107. 108. 109. 110.
E,
2,
2, 27
Antidepressives and Stimulants
C a r l Kaiser and Charles L. Z i r k l e Smith Kline & French Laboratories, Philadelphia, Pa. 19101
-
Introduction As i n p a s t years, this chapter reviews stimulants together with antidepressives. T h i s arrangement of t o p i c s seems not t o be j u s t i f i e d on c l i n i c a l grounds f o r t h e s p e c t r a of clinical u t i l i t y of t h e two c a t e g o r i e s of drugs are q u i t e d i f f e r e n t . Is t h e r e any reason f o r t r e a t i n g the two s u b j e c t s together o t h e r than one of convenience? Perhaps t h e answer i s yes i f t h e d e f i n i t i o n of *Istimulants" i s l i m i t e d to amphetamine and pharmacologically r e l a t e d agents. Most research reported i n the l a s t year supports t h e long held b e l i e f t h a t the antidepressives and t h e amphetamine-like drugs e x e r t many of t h e i r pharmacological and clinical effects by a c t i o n s on c e n t r a l monoaminergic, e s p e c i a l l y catecholaminergic, pathways. B u t t h e biochemical a c t i o n s of t h e t r i c y c l i c a n t i d e p r e s s i v e s are s t i l l poorly understood and t h e i r relevancy to t h e t h e r a p e u t i c effects has not been established. From the extensive s t u d i e s on amphetamine a more coherent, i f n o t clearer, p i c t u r e of i t s a c t i o n s is emerging. A sign of progress i s t h a t one can now with some assurance describe amphetamine a s a catecholaminergic agent w i t h a pronounced dopaminergic component o f action r a t h e r than a s a c e n t r a l l y - a c t i n g sympathomimetic amine. The 1971 l i t e r a t u r e describes t h e s y n t h e s i s and pharmacological evaluation of numerous p o t e n t i a l antidepressives, b u t p r e s e n t s no evidence t h a t new agents superior t o t h e e s t a b l i s h e d drugs are i n the offing.
-
Tricvclic compounds w i t h antidepressive a c t i v i t y An a m i t r i p t y l i n e d e r i v a t i v e , S D 2202-01 (In),exhibited a pharmacological p r o f i l e similar t o t h a t o f the parent.' Antidepressive and anti-anxiety p r o p e r t i e s were Other a m i t r i p t y l i n e r e l a t i v e s , a l s o noted f o r a monomethyl analog (&I.* some 5-methylene-4-substituted dibenzocycloheptenes (21,had l i t t l e a c t i v i t y i n a mouse a n t i r e s e r p i n e test.' A dibenzthiepin, dothiepin (prothiadine), was superior t o a m i t r i p t y l i n e i n a double b l i n d comparison f o r t h e treatment of depression.' Amoxapine (3, cL-67772), a dibenzoxazepine, although devoid of a n t i c h o l i n e r g i c p r o p e r t i e s , produced imipramine-like a c t i v i t y i n animals. C l i n i c a l l y , 3 was an e f f e c t i v e a n t i depressive agent; however, s i d e e f f e c t s (insomnia, d i f f i c u l t u r i n a t i o n ) were e n ~ o u n t e r e d . ~Several related dibenzodiazepines had antidepressive properties. SM-307 (41, an e t h y l s u l f o n y l analog of dibenzepin,6 produced
kCOCH, NRCH'
la:
lb: -
R=CH3 R=H
-2
Antidepressives, S t i m u l a n t s
Chap. 2
19 -
Kaiser, Z i r k l e
imipramine-like e f f e c t s i n animals.’ A r e l a t e d pyridobenzodiazepine, UP-106 (2), a l s o was a c t i v e i n various animal tests i n which most a n t i depressives a r e e f f e c t i v e and i t demonstrated clinical activity.’ The s t r u c t u r a l l y s i m i l a r U-17,660 (6)w a s t h e most potent a n t i a l l e r g i c and antianaphylactic compound i n a series of 5- and 10-aminoalkylated dibenzodiazepines
.’
Antidepressive a c t i v i t y was noted f o r s o m e t r i c y c l i c compounds having a six-rnembered c e n t r a l ring. A series of naphthyridones, C-29 c-42 (2). and C-45 (21, caused imipramine-like a c t i v i t y i n animals.’ The influence of 3 on c e n t r a l biogenic amine levels,’ as w e l l a s i t s absorption, d i s t r i b u t i o n and excretion,’ was investigated i n mice and rats, Several phenothiazine d e r i v a t i v e s had antidepressive a CF, analog of a c t i v i t y , III extensive clinical t r i a l s f l u o r a c i z i n e (&I, chloracizine,’ showed antidepressive e f f i c a c y equivalent to imipramine. It a l s o produced a n t i c h o l i n e r g i c effects,’ ” S t r u c t u r e versus antidepressive a c t i v i t y r e l a t i o n s h i p s were reported f o r a series of phenot h i a z i n e s and r e l a t e d compounds bearing a carbocyclic b a s i c s i d e chain. Che of these compounds (&) was considerably more potent than amitriptyOther l i n e i n preventing reserpine-induced p t o s i s i n mice and rats.” phenothiazines with antidepressive a c t i o n s included &, t h e l-chloroanalog of chlorpromazine, which produced imipramine-like a c t i o n s i n mice and r a t s , ’ and the azaphenothiazine-10-thiolcarboxylate 4 which induced antidepressive-like symptoms (mydriasis, increased s e n s i t i v i t y t o touch) i n mice.‘ The antidepressive e f f e c t s of phenothiazine d e r i v a t i v e s with 1- o r a-substituents may be associated with the steric influence of these groups i n i n t e r f e r i n g with attainment of a nearly f l a t conformation by the t r i c y c l i c system.’ 3
(A),
’
‘
’
0
a> X=H
b) X=OCH3
c> x 4 1
-7
-a
2
a ) X=2-CF3 ; R=CO(CY N(C, H, l 2 b) X=Z-Cl; R = t r a n s - T C % N(CH, C > X-1-C1; R = m 3 N(CH3 1 2
Other t r i c y c l i c compounds with antidepressive a c t i v i t y w e r e maprotiline (10, Ciba 34276-Ba), which produced imipramine-like e f f e c t s
20 -
Sec t. I
i n dogs’
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CNS Agents
E n g e l h a r d t , Ed.
,
and blocked r a t synaptoso.na1 uptake of norepinephrine’ (NE) which antagonized tetrabenazineI n mice, t h e phenanthinduced p t o s i s i n mice a t EL+o 20 mgkg, P , o . ~ O rene 12 had no a n t i r e s e r p i n e a c t i v i t g ’ and a 6,g-dihydro d e r i v a t i v e of imipramine f a i l e d t o antagonize tetrabenazine-induced depression .2 and t h e pyridobenzocyclooctane
(z),
7
@cH(q)2N(a3)2
\
(a%)3NHcH3 10 -
(q13 N(CH3 1 2
11 -
((33 1 2
12 -
Several diphenylmethane d e r i v a t i v e s had antidepressive a c t i v i t y . Tofenacin (3) w a s well-tolerated and e f f e c t i v e i n p a t i e n t s with various kinds of d e p r e ~ s i o n ‘.2~4 ~ Like imipramine, s o m e aminopropenes reversed reserpine-induced hypothennia i n mice .2 The (-1 -isomer of 2 caused c l i n i c a l antidepressive a c t i o n s , b u t these were accompanied by unwanted side e f f e c t s . 2 6
14
X=H,j-F,LF; R=H,CH3
14 -
15
Other compounds with antidepressive a c t i v i t y - It has been suggested t h a t rubidium s a l t s ( s e e below) may have antidepressive a c t i v i t y and a remarkable therapeutic response was noted i n an open clinical C l i n i c a l antidepressive a c t i v i t y was produced by A-25794 .2 A molindone r e l a t i v e , EN-3022 ( 9 1 , was e f f e c t i v e i n s e v e r a l tests (antagonism of tetrabenazine-induced p t o s i s i n mice; p o t e n t i a t i o n of pressor response t o NE i n dogs)30 i n which most antidepressives are a c t i v e . Nomifensine w a s more potent than imipramine i n antagonizing reserpineinduced catalepsy i n rats.” Quipazine had a pharmacological p r o f i l e similar t o t h a t of t r i c y c l i c anti depressive^.^^ I n a series of phenacylthioimidazolines, 2 was the most potent antagonist of reserpine-induced hypothermia i n mice (12X imipramine) .l3
(16)
(18)
(a)
Chap. 2
Antidepressives, Stimulants
21 -
Kaiser, Z i r k l e
0
M p r a m i n e - l i ke phannaco logica 1 a c t i v i t y , without a n t i cho l i n e r g ic properties, was noted f o r LG 152 i t also prevented synaptosomal reuptake of NE.35 Potent antitetrabenazine-induced p t o s i s a c t i v i t y , without anticholinergic effects, w a s produced by some e t h e r s of hexanophenone oxime, e.g. 2 3 3 6 The piperidinecarboxamide was equipotent with amitriptyl i n e i n a test f o r dopa-potentiation i n mice.)' A series o f phthalan derivatives having a pharmacological spectrum similar t o t h e tric y c l i c a n t i d e p r e s s i v e s was studied f o r i n h i b i t i o n of mitochondrial activity i n i n t a c t yeast cells a test which c o r r e l a t e s with c l i n i c a l antidepressive potency. Most potent a c t i v i t y was noted f o r Lu 3-04" (2&) , Lu 3-009 (24b) , Lu 3-074 3 X impramine))* and Lu 3-049 4.3X imipramine) C l i n i c a l antidepressive a c t i o n s were noted f o r HT 3261 (3)" and t h e choline d e r i v a t i v e panclar which was an e f f e c t i v e psychostimulant i n p a t i e n t s with schizophrenia, depression and neuroses." Other compounds with c l i n i c a l antidepressive a c t i v i t y included W I N 27,147-2 (271, which w a s devoid of s i d e effects a t e f f e c t i v e dose levels.42 and 8 14.368 (g>,53 which w a s o f doubtful value i n humans and caused untoward s i d e effects although i t produced antidepressive-like a c t i o n s i n animals. Short-lived antidepressive a c t i v i t y w a s observed with ~40pa.'~
(a
(2)
-
.r
c
(a,
(a,
(261,
(c4L C H 3
ss
=NO(CH2)2N% 22 -
3 HOPO) (% >,N(CH3
26
pcs
a) b) c) d)
24 -
X=CH,; R=CH3 X 4 ; R=CH3 X-S; R = C b X=C%; R=H OH
Several amphetamine d e r i v a t i v e s displayed antidepressive properties. Fenfluramine, an a n o r e c t i c drug which depresses motor a c t i v i t y , showed an imipramine-like p r o f i l e of a c t i v i t i n various phamacological tests i n mice.'5 p3loroamphetamine (*IY6 and i t s N-methyl d e r i v a t i v e ,
22 -
Sect.
1
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CNS Agents
E n g e l h a r d t , Ed.
RO-4-6861 (29b) ,47 produced c l i n i c a l a c t i v i t y resembling t h a t of the t r i c y c l i c a x d e p r e s s i v e s . BW 65-54 (2) e l i c i t e d antidepressive effects i n animals; i t potentiated responses to amphetamine, apparently by i n t e r f e r i n g with metabolic inactivation,'8 A number of new MA0 i n h i b i t o r s were described i n 1971; however, because of the l i m i t e d c l i n i c a l u t i l i t y of these agents i n t h e treatment of depression, they w i l l not be reviewed i n d e t a i l . Nonetheless, several of these substances a r e noteworthy. Sydnophene (2)'9 was included i n a series of sydnonimines examined f o r MAO-inhibitory a c t i v i t y . It demons t r a t e d m i l d stimulant and antidepressive a c t i o n s i n extensive c l i n i c a l s t u d i e s i n Russia.50 Another MAO-inhibitor, c l o r g i l i n e M&B 9302) had antidepressive a c t i v i t y ; i t s c l i n i c a l effects were s i m i l a r to those of i m i ~ r a m i n e . ~ ' Proportions of two forms of MA0 (Type A, B) were found to vary i n d i f f e r e n t a r e a s of r a t b r a i n . The type A enzyme, predominant i n sympathetic nerves, acted on both 5-HT and tyramine and was inhibited by and acted on tyramine, b u t 32, whereas type B-MA0 was i n s e n s i t i v e t o not 5-HT." I n humans, 32, tranylcypromine and isocarboxazid increased 5HT, NE and dopamine l e v e l s i n various b r a i n a r e a s ; however, t h e effect of tranylcypromine was s i g n i f i c a n t l y g r e a t e r than t h a t of the o t h e r two on dopamine i n t h e caudate nucleus and h y p o t h a l a m u ~ . ~In ~ vitro, Lilly 51641 (21, l i k e harmaline, p r e f e r e n t i a l l y blocked M A 0 oxidation of 5-HT, whereas tranylcypromine and pargyline s e l e c t i v e l y i n h i b i t e d the oxidation of tyramine .5'
(z,
-
S t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s o f c e n t r a l stimuCentral Stimulants l a n t s were reviewed i n 1971.55 '56 The use of central stimulants, notably dextroamphetamine and methylphenidate, i n t h e therapy of hyperkinetic disorders i n children has increased, According t o NIMH estimates more than 200,000, o r about 1 s of hyperactive children, received amphetamine treatment i n 1969?' These agents reduce d i s t r a c t i b i l i t y and promote the c h i l d ' s a b i l i t y to focus on meaningful s t i m u l i and t o organize his bodily movements more purposefully.5 8 ' 5 9 Similar effects w e r e e l i c i t e d by treatment of untrainable hyperkinetic and aggressive dogs with dextroamphetamine."
(21,
N e w e r amphetamine r e l a t i v e s included pyrovalerone which w a s b e n e f i c i a l i n therapy of c h r o n i c a l l y fatigued patients," U-30,405A ( a) and U-28,926~ which caused CNS stimulation i n rhesus monkeys. 6% Amantadine produces amphetamine-like a c t i o n ( see below). An aminot e t r a l i n , ADT ( 6) afforded amphetamine-like e f f e c t s b u t decreased motor a c t i v i t y i n m i c S 3 Adenosine had a psychoanaleptic effect i n a mouse maze test.64 Exploratory a c t i v i t y of mice was enhanced by P1961 (2) .65 Other compounds f o r which CNS-stimulating a c t i v i t y was observed i n mice
(z),
Chap. 2
Ant idepress ives, S t i m u l a n t s
included 4864 ( 8) ,66 a benzocyclobutene % 1-69 and GYI 20238 (j
23 thiolactams,6 *
Kaiser, Z i r k l e
(2) ,6 several
a
c1
2
38
Several s t u d i e s r e l a t e d t o physical p r o p e r t i e s and metabolism of amphetamines. "he b a s i c i t y , t i s s u e d i s t r i b u t i o n and metabolism of p-f luoro-, p, p-dif luoroamphetamine, and amphetamine w e r e s t r i k i n g l y d i f f e r e n t i n rats.70 N m r studies of t h e conformational properties7' of amphetamine and r e l a t e d phenethylamines revealed a preference f o r trans phenylamino rotomers i n aqueous although s u b s t i t u e n t groups, steric and electronic f a c t o r s influence rotomer p o ~ u l a t i o n s . ~A~ quantum mechanical study indicated the folded form of amphetamine i s s l i g h t l y favored.72 Metabolism of amphetamine t o an oxime and subsequent hydrolys i s t o benzyl methyl ketone was shown t o c o n s t i t u t e a route of deaminat i ~ n . ~ ' In a r a b b i t l i v e r oxygenase system this conversion involves an intermediate a-hydroxyamine .75
-
-theses. Biochemistry and Pharmacoloqy of the various i d e a s about biochemical causes of a f f e c t i v e disorders,76 '77 the Vatecholamine (CAI hypothesis" is s t i l l t h e most frequently c i t e d . According to this p o s t u l a t e depression may be r e l a t e d t o a deficiency of CA (usually NE) a t functionally important c e n t r a l CA receptors, w h i l e mania r e s u l t s from excess CA. Perhaps an equally p l a u s i b l e case can be made f o r a "serotonin hypothesis of a f f e c t i v e disorders." Consistent with t h e CA hypothesis a r e the observations t h a t when a-methyltyrosine, an i n h i b i t o r of CA biosynthesis, was given to 7 m a n i c and 3 depressed p a t i e n t s under double b l i n d conditions, 5 of t h e m a n i c p a t i e n t s became less manic and t h e 3 depressed p a t i e n t s became more d e p r e s ~ e d . ~ " ~However, ~ attempts t o overcome t h e postulated deficits of CA o r serotonin (5-HT) by administration of t h e amino acid precursors, Gdopa, tryptophan, o r 5-hydroxytryptophan- a s t r a t e g y successful i n the treatment of parkinsonism have given genera l l y disappointing r e s u l t s i n depressed patient^.^"^^ '13' Even i n l a r g e doses equivalent t o those found t o be e f f e c t i v e i n parkinsonism, M o p a produced an antidepressive effect i n Only 4 of 16 p a t i e n t s . A l l of the p a t i e n t s who responded had retarded depressions; none of the 5 p a t i e n t s with a g i t a t e d depression improved. Five depressed p a t i e n t s who had p r i o r
-
24 -
Sect. 1
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CNS Agents
Engelhardt, Ed.
h i s t o r i e s o f mania developed hypomania o r mania without a r e v e r s a l o f depression. It i s suggested t h a t CA, p a r t i c u l a r l y dopamine (DA), may be involved i n t h e genesis o f mania i n susceptible i n d i v i d u a l s b u t t h a t depression and mania are not opposite poles of the same entity." These r e s u l t s do not support t h e CA theory of depression b u t n e i t h e r do they rule i t out. Although L-dopa i n c r e a s e s DA i n b r a i n , i t may not i n c r e a s e NE. It also produces o t h e r c e n t r a l biochemical a c t i o n s , e.g., effects suggesting t h a t i t causes a decrease i n turnover o f b r a i n 5-HT i n depressed patients." However, t h e mostly negative clinical r e s u l t s with L a o p a seem t o cast f u r t h e r doubt on the v a l i d i t y of t h e behavioral syndrome and amine depletion induced by r e s e r p i n e (which i s reversed by L-dopa) a s a model of depression. The catechol theory of depression i s based i n p a r t on evidence t h a t the t r i c y c l i c antidepressives and ampheramine a f f e c t CA m e t a b o l i s m i n ways t h a t r e s u l t i n an increased a v a i l a b i l i t y o f t h e t r a n s m i t t e r s a t t h e i r receptor sites. It has been thought f o r s o m e t i m e t h a t t h e w e l l known i n h i b i t o r y a c t i o n o f t h e t r i c y c l i c a n t i d e p r e s s i v e s upon t h e uptake o f NE i n central noradrenergic (NA) neurons r e s u l t s i n an i n c r e a s e of t h e monoarnine a t t h e r e c e p t o r s and may account f o r antidepressive a c t i v i t y . Several observations may not be i n accord with this view. I n d i r e c t evidence has been adduced t h a t some t r i c y c l i c agents with t e r t i a r y amino groups (imipramine, chlorimipramine and a m i t r i p t y l i n e ) p r e f e r e n t i a l l y block 5-HT uptake i n 5-HT neumns w h i l e c e r t a i n secondary amines (desmethylimipramine , n o r t r i p t y l i n e and p r o t r i p t y l i n e ) p r e f e r e n t i a l l y i n h i b i t uptake o f NE. Recent s t u d i e s i n which i n vivo uptake o f NE and 5-HT was d i r e c t l y measured histochemically confirm t h e e a r l i e r data a s d i d funct i o n a l s t u d i e s using the extensor and f l e x o r r e f l e x e s t o assess t h e influence of t h e various drugs on 5-HT and NA receptor a c t i v i t y , respect i ~ e l y . ' ~ I n a d d i t i o n t h e antihistamine drugs, chlorpheniramine and e s p e c i a l l y brompheniramine were found t o be very potent blockers o f 5-HT uptake. However, these drugs, u n l i k e t h e t e r t i a r y amino t r i c y c l i c s , also showed a potent blocking a c t i o n on NE uptake. The questions arise whether t h e c l i n i c a l a c t i v i t y o f these drugs i s more c l o s e l y related t o effects on 5-HT o r on NE neurons o r whether t h e r e are two classes o f antidepressives a c t i n g by d i f f e r e n t mechanisms. Some clinicians feel t h a t t h e c l i n i c a l a c t i o n s of t h e t r i c y c l i c a n t i d e p r e s s i v e s can be divided i n t o a mood-elevating component and a psychomotor-activating component. They b e l i e v e t h e t e r t i a r y amines are more e f f e c t i v e i n brightening of mood, suggesting involvement of 5-HT neurons w h i l e t h e secondary amines are more e f f e c t i v e i n i n c r e a s i n g d r i v e o r producing psychomotor a c t i v a t i o n , suggesting t h a t NE neurons a r e mainly Seemingly a t odds with t h e blockade of amine-uptake hypotheses are the p r o p e r t i e s of one of t h e newer t r i c y c l i c s , iprindole. This drug produces c l i n i c a l effects resembling those of imipramine-like agents y e t i n s o m e pharmacological tests, e.g., r e v e r s a l o f reserpine-induced p t o s i s and hypothermia i n mice, i t i s considerably less potent than i~nipramine.'~ It i s a very weak i n h i b i t o r of uptake of NE and 5-HT &-I v i t r o and i n vivo i n mice and rats.86 Despite i t s weak uptake blocking a c t i v i t y , i t potentiated t h e awakening effect of Gdopa i n r e s e w z e d mice a s
Chap. 2
Antidepressives, Stimulants
Kaiser, Z i r k l e
25
imipramine does. Unlike the a n t i d e p r e s s i v e s which block amine uptake, i p r i n d o l e does not augment the pressor response t o NE o r block t h e blood pressure response t o tyramine i n man,'7 Differences i n t h e e f f e c t s of acute and chronic treatment with imipramine and p r o t r i p t y l i n e on c e n t r a l NE metabolism i n t h e r a t have been observed." The turnover of NE was decreased a f t e r acute administration but increased during chronic administration of these drugs. The i n c r e a s e i n NE turnover occurred sooner when thyroxine was administered with imipramine. It i s suggested t h a t these observations may help t o explain t h e delayed o n s e t of c l i n i c a l antidepressive effects and t h e a c c e l e r a t i n g and enhancing effects o f thyroid hormone on the c l i n i c a l e f f e c t s of imipramine. It has been suggested t h a t thyroxine may e x e r t s o m e o f i t s action by f a c i l i t a t i n g the action of NE i n c e n t r a l NA pathways.e9 Rats t r e a t e d with thyroxine became hyperactive and showed increased s e n s i t i v i t y t o the behaviorally a c t i v a t i n g e f f e c t s o f NE administered i n t r a v e n t r i c u l a r l y . Possibly r e l e v a n t t o the v a r i a t i o n i n effects on NE turnover noted under varied conditions of administration of t h e t r i c y c l i c s i s t h e observation t h a t spontaneous a c t i v i t y i n r a t s w a s decreased s h o r t l y after administration of imipramine but w a s increased over t h a t of c o n t r o l animals one day a f t e r a d m i n i s t r a t i ~ n . ~Much ~ more d a t a o f t h e kinds c i t e d above must be obtained f r o m s t u d i e s o f a v a r i e t y of t r i c y c l i c antidepressives, including i p r i n d o l e , before any conclusions about a r e l a t i o n s h i p between t h e clinical a c t i o n of t h e s e drugs and t h e i r effects on monoamine metabolism can be drawn. A study o f t h e effects of L-dopa and Li,CO, on u r i n a r y excretion o f c y c l i c AMP i n depression and mania has been r e p ~ r t e d . ~ ' Manic p a t i e n t s excreted t h e most c y c l i c AMP and severely depressed p a t i e n t s excreted t h e l e a s t ; c o n t r o l s and moderately depressed p a t i e n t s showed intermediate values. Depressed p a t i e n t s t r e a t e d with L-dopa showed marked i n c r e a s e s i n urinary c y c l i c AMP excretion. P a t i e n t s treated with U 2 C 9 showed changes i n c y c l i c AMP excretion i n t h e d i r e c t i o n o f clinical change; a s depression improved, c y c l i c AMP e x c r e t i o n increased and as mania improved i t diminished. It i s not possible t o a t t r i b u t e these changes i n excretion of c y c l i c AMP t o e i t h e r c e n t r a l o r peripheral mechanisms o r both.
Rubidium i o n seems t o have opposite effects from l i t h i u m i o n on CA metabolism and it has been suggested t h a t i t may have c l i n i c a l antidepressive a c t i v i t y . It produces an i n c r e a s e i n t h e r e l e a s e and turnover o f b r a i n stem NE and, u n l i k e l i t h i u m ion, i t induces an increase i n s t e a d of a decrease i n shock-elicited aggression i n rats.92 Further comparisons of rubidium and l i t h i u m i o n s may shed considerable l i g h t on t h e biochemistry of t h e a f f e c t i v e disorders i f t h e i n i t i a l c l i n i c a l observations t h a t rubidium has antidepressive a c t i v i t y a r e confirmed by c o n t r o l l e d studies?' Although t h e r o l e s o f NE and 5-HT i n t h e antidepressive a c t i o n o f the t r i c y c l i c s have n o t been e s t a b l i s h e d , t h e r e i s l i t t l e doubt b u t t h a t the stimulatory a c t i o n of amphetamine i s t o a l a r g e e x t e n t mediated through CA pathways. Early experiments emphasized effects of t h e drug on NA systems. Now t h e evidence i s stronger f o r a DA mechanism of central
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a c t i o n than f o r a NA mechanism. Although t h e r e is some disagreement, most authors believe t h a t amphetamine produces i t s c e n t r a l e f f e c t s by r e l e a s i n g dopamine and NE a t nerve endings from labile i n t r a n e u r o n a l pools of newlysynthesized amines. Amphetamine i s thought t o induce stereotyped behavior by r e l e a s i n g DA whereas apomorphine produces this behavioral effect by a direct a c t i o n on DA receptors. The increase i n locomotor a c t i v i t y e l i c i t e d by amphetamine appears t o be mediated a t l e a s t i n p a r t by a NA action. Other behavioral effects of amphetamine may also involve NA and/or DA actions. The experimental b a s i s f o r t h e s e statements h a s been extensively reviewed.53 A f e w of the observations may be b r i e f l y summarized a s follows. Depletion of CA i n t h e i n t r a n e u r o n a l storage granules by r e s e r p i n e does not prevent t h e i n c r e a s e i n motor a c t i v i t y o r s t e r e o t y p i c a l behavior produced by amphetamine o r apomorphine. I n h i b i t i o n of CA s y n t h e s i s by a-methyltyrosine blocks the effects o f amphetamine b u t not those of apomorphine. I n h i b i t o r s of dopamine P-hydroxylase (e.g., d i e t h y l dithiocarbamate), which i n h i b i t t h e s y n t h e s i s o f NE but n o t DA, decrease amphetamine-stimulated motor a c t i v i t y , b u t do n o t i n h i b i t and even may enhance amphetamine-induced stereotypies. Recent s t u d i e s confirm these r e s u ~ t s . ~'9'J '95
"'
b s t evidence suggests t h a t amphetamine- and apomorphine-induced s t e r e o t y p i e s a r e t h e r e s u l t of enhanced DA a c t i v i t y i n t h e neostriatum. Consistent with this view i s t h e e f f e c t of amphetamine i n rats with u n i l a t e r a l l e s i o n s of t h e n i g r o s t r i a t a l DA pathway ( s e e Chapter 1, p 19. The drug causes i p s i l a t e r a l turning i n t h e s e animals, presumably as a consequence of release o f DA i n t h e neostriatum from t h e i n t a c t DA neurons of the c o n t r a l a t e r a l (non-lesioned) side. T h i s effect of amphetamine i s attenuated by pretreatment with a m e t h y l t y r o s i n e b u t n o t with reserpine.96 19' I n c o n t r a s t , apomorphine, which i s believed t o be a d i r e c t a c t i n g DA agent, induces c o n t r a l a t e r a l turning behavior, an e f f e c t a t t r i b u t e d t o denervation s u p e r s e n s i t i v i t y o f s t r i a t a l DA r e c e p t o r s i n t h e neostriatum on the lesioned side. T h i s e f f e c t of apomorphine i s not antagonized by e i t h e r r e s e r p i n e o r a-methyltyrosine. I n r a t s with u n i l a t e r a l l e s i o n s i n t h e neostriatum, amphetamine and apomorphine both e l i c i t i p s i l a t e r a l turning. Similar effects are observed i n mice with u n i l a t e r a l l e s i o n s o f t h e caudate nucleus. This preparation provides a simple and rapid model f o r studying effects of drugs on c e n t r a l DA systems.9e Possibly a t odds with t h e hypothesis t h a t drug-induced stereotyped behavior involves a DA mechanism are observations on t h e effects of s o m e stimulants on t h e turnover o f b r a i n CA i n the r a t . cJ-Amphetamine, aminorex and p-chloramphetamine a t doses which increased motor a c t i v i t y , but d i d not induce s t e r e o t y p i e s , caused an i n c r e a s e i n turnover o f DA b u t not of NE. These r e s u l t s a r e d i f f i c u l t to i n t e r p r e t , however, because phenmetrazine did n o t a l t e r turnover of DA o r NE a t a dose t h a t increased motor a c t i v i t y . 9 9 Although t h e c e n t r a l a c t i o n s of amphetamine may r e q u i r e an uninterrupted s y n t h e s i s of CA r a t h e r than reserpine-sensitive s t o r e s of the amines, this does n o t seem t o be true f o r a l l amphetamine-like stimulants.
Chap. 2
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Kaiser, Z i r k l e
27
A r e c e n t study, together with e a r l i e r d a t a , suggests that amphetamine-like
stimulants can be divided i n t o two groups according t o t h e ways i n which they i n t e r a c t with r e s e r p i n e and a-methyltyrosine. The e f f e c t s of members of one group - amphetamine, methamphetamine, ephedrine,phenmetrazine and phentermine - are i n h i b i t e d by a-methyltyrosine b u t not by reserpine; those of members of t h e second group benzphetamine, methylphenidate, pipradrol, cocaine and amfonelic acid ( 7-benzyl-1-ethyl-1, It-dihydro-bxo-1,anaphthyridine-3-carboxylic acid) are i n h i b i t e d by r e s e r p i n e b u t n o t by m e t h y l t y r o s i n e , a t least i n moderate doses.”’ Although, a s t h e s e results suggest, stimulants may d i f f e r i n t h e i r a c t i o n s on i n t r a n e u r o n a l pools of CA, no d i f f e r e n c e i n t h e i r c l i n i c a l e f f e c t s has been observed. b t h y l p h e n i d a t e produced physiologic, s u b j e c t i v e and behavior effects t h a t w e r e not s i g n i f i c a n t l y d i f f e r e n t from those of amphetamine, methamphetamine, ephedrine and phenmetrazine.‘
-
-
’‘
Further s t u d i e s of t h e metabolism o f amphetamine and o f t h e effects of t h e drug and i t s metabolites on CA metabolism have n o t defined t h e biochemical e f f e c t s underlying t o l e r a n c e development t o t h e drug.102-104 A thorough study was made o f t h e psychomotor and anorexigenic effects of d-amphetamine upon chronic dosing.’ Tolerance development t o t h e drug occurred i n r a t s which w e r e dosed d a i l y s h o r t l y before t e s t i n g . Tolerance d i d not occur i n rats which received t h e same d a i l y doses o f amphetamine but were dosed a f t e r each d a i l y t e s t session. Subsequent dosing of t h e l a t t e r group with amphetamine p r i o r t o t e s t i n g produced psychornotor stimulation and anorexigenic e f f e c t s a s l a r g e a s those i n i t i a l l y observed i n t h e r a t s t h a t had always been dosed d a i l y p r i o r to t e s t i n g . The r e s u l t s suggest t h a t tolerance t o t h e s e effects of amphetamine r e p r e s e n t s a behavioral adaptation of the r a t s t o the. “drugged” state.
-
Several reports described effects of t h e methylxanthines and amantadine on b r a i n monoamine m e t a b o l i s m which may be involved i n t h e i r pharmacological actions. Caffeine and theophylline release b r a i n NE i n r a t s and guinea pigs.’o6 The i n c r e a s e i n c y c l i c AMP produced by these drugs, u s u a l l y a t t r i b u t e d t o i n h i b i t i o n of phosphodiesterase, could be I n mice due t o stimulation of adenyl cyclase by t h e released NE. c a f f e i n e and aminophylline appear t o i n c r e a s e turnover of b r a i n DA and NE.lo7 Other d a t a suggest t h a t t h e methylxanthines e i t h e r prevent t h e The antiparkinsonisn release o f b r a i n 5-HT o r i n c r e a s e 5-HT synthesis.”* e f f e c t s of amantadine have stimulated s t u d i e s o f i t s c e n t r a l actions. Extensive biochemical and pharmacological d a t a from s t u d i e s i n r a t s and mice i n d i c a t e t h a t this drug produces i t s effects, e.g. i n c r e a s e i n r o t a t i o n a l behavior i n t h e r a t turning model and i n c r e a s e i n motor a c t i v i t y , by r e l e a s i n g CA, e s p e c i a l l y DA, f r o m e x t r a g r a n u l a r (reserpiner e s i s t a n t ) s t o r e s . Thus amantadine appears t o have an amphetamine-like action b u t i t i s much less potent than However, unlike amphetamine, amantadine-induced i n c r e a s e i n motor a c t i v i t y i n mice was not a l t e r e d by a-rnethyltyrosine.l
’’
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