Amphetamines depression

Kokkinidis, Larry, Robert M. Zacharko, and Patrick A. Predy. 1980. "Post-Amphetamine Depression of Self-Stimulation Responding from the Substantia Nigra Reversal by Tricyclic Antidepressants." Plmmmcotogy Biochemistry and Behavior 13 379-83. 

Cocaine is usually legally classified as an addictive drug though withdrawal doesn t cause the abstinence syndrome seen in junkies. Cocaine withdrawal causes symptoms similar to those seen in withdrawal from amphetamines — depression, fetigue and listlessness. 

Incorporation of the phenethyl moiety into a carbocyclic ring was at first sight compatible with amphetamine-like activity. Clinical experience with one of these agents, tranylcypromine (79), revealed the interesting fact that this drug in fact possessed considerable activity as a monamine oxidase inhibitor and as such was useful in the treatment of depression. Decomposition of ethyl diazoacetate in the presence of styrene affords a mixture of cyclopropanes in which the trans isomer predominates. Saponification gives acid 77. Conversion to the acid chloride followed by treatment with sodium azide leads to the isocyanate, 78, via Curtius rearrangement. Saponification of 78 affords tranylcypromine (79). 

A thiazole derivative that incorporates a fragment of the amphetamine molecule shows some CNS stimulant activity more specifically, the compound antagonizes the depression caused by overdoses of barbiturates and narcotics. Reaction of benzalde-hyde with sodium cyanide and benzenesulfonyl chloride gives the toluenesulfony1 ester of the cyanohydrin (141). Reaction of this with thiourea leads directly to aminophenazole (143) It is probable the reaction proceeds by displacement of the tosylate by the thiourea sulfur to give 142 addition of the amino group to the nitrile followed by tautomerization affords the observed product. ... 

Antipsychotic medications are indicated in the treatment of acute and chronic psychotic disorders. These include schizophrenia, schizoaffective disorder, and manic states occurring as part of a bipolar disorder or schizoaffective disorder. The co-adminstration of antipsychotic medication with antidepressants has also been shown to increase the remission rate of severe depressive episodes that are accompanied by psychotic symptoms. Antipsychotic medications are frequently used in the management of agitation associated with delirium, dementia, and toxic effects of both prescribed medications (e.g. L-dopa used in Parkinson s disease) and illicit dtugs (e.g. cocaine, amphetamines, andPCP). They are also indicated in the management of tics that result from Gilles de la Tourette s syndrome, and widely used to control the motor and behavioural manifestations of Huntington s disease. 

Stimulants induce both tolerance and sensitization to their behavioral effects. Tolerance develops to the anorectic and euphoric effects of stimulants (Schuster 1981) however, chronic intermittent use of low doses of stimulants delays the development of tolerance. With the doses commonly used in clinical practice, patients treated for narcolepsy or for depressive or apathetic states find that the stimulant properties usually persist without development of tolerance however, the persistence of antidepressant effects remains a matter of controversy. Sensitization has been linked to the development of amphetamine-induced psychosis (Yui et al. 1999). Sensitization to the induction of psychosis is suggested because psychosis is induced by progressively lower doses and shorter periods of consumption of amphetamine following repeated use over time (Sato 1986). Sensitization for amphetamine-induced psychosis may persist despite long periods of abstinence. 

Sevarino KA, Oliveto A, Kosten TR Neurobiological adaptations to psychostimulants and opiates as a basis of treatment development. Ann N Y Acad Sci 909 51 —87,2000 Silberman EK, Reus VI, Jimerson DC, et al Heterogeneity of amphetamine response in depressed patients. AmJ Psychiatry 138 1302—1307, 1981 Sofuoglu M, Brown S, Babb DA, et al Depressive symptoms modulate the subjective and physiological response to cocaine in humans. Drug Alcohol Depend 63 131-137, 2001... 

Garden City, NY, Medical Examination Publishing, 1981 Snyder SH, Faillace L 2,3-Dimethoxy-4-methyl-amphetamine (STP) a new hallucinogenic drug. Science 1388 669-670, 1967 Spielewoy C, Markou A Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function. Neuropsychopharmacology 28 1106-1116,2003... 

Drawing all this evidence together, Schildkraut (1965) concluded that depression was caused by a functional deficit of noradrenergic transmission in the brain. He also thought that the rebound depression and fatigue, which are experienced after the arousing effects of amphetamine have worn off, were due to depletion of neuronal stores of noradrenaline. However, Schildkraut made a clear distinction between the effects of antidepressants and the arousal induced by amphetamine, describing the latter as stimulation and excitement . To this day, there is controversy over whether or not amphetamine has a beneficial effect in depression. 

In an attempt to simulate in rats the dosage regimen commonly employed by abusers of amphetamines, METH was administered (10 or 15 mg/kg every 6 hours four to six doses), after which the animals were killed (Koda and Gibb 1971 Koda and Gibb 1973). TH activity and catecholamine con-eentrations were measured in various brain regions and in the adrenal. Neostriatal TH aetivity was depressed in a dose-dependent manner and reaehed its nadir at 36 hours. Dopamine (DA) and norepinephrine concentrations were initially elevated, but then deereased in parallel with TH aetivity. Adrenal TH aetivity was elevated, presumably because of stress assoeiated with the toxie doses of METH. 

Van Praag, H.M. Schut, T. Bosma, E. and Van Den Bergh, R. A comparative study of the therapeutic effects of some 4-chlorinated amphetamine derivatives in depressive patients. Psychopharmacologia 20 66-76, 1971. 

The treatment goals for acute intoxication of ethanol, cocaine/amphetamines, and opioids include (1) management of psychological manifestations of intoxication, such as aggression, hostility, or psychosis, and (2) management of medical manifestations of intoxication such as respiratory depression, hyperthermia, hypertension, cardiac arrhythmias, or stroke. 

When Schildkraut introduced the monoamine theory of depression, he admitted that there was little direct evidence for it. Instead, it was based on the supposed effectiveness of antidepressant medication and the mistaken belief that reserpine makes people depressed. Schildkraut acknowledged that Most of this evidence is indirect, deriving from pharmacological studies with drugs such as reserpine, amphetamine and the monoamine oxidase inhibitor antidepressants which produce affective changes. 21 A half-century has passed since his chemical-imbalance theory of depression was introduced, and the presumed effectiveness of antidepressants remains the primary evidence in its support. But as we have seen, the therapeutic effects of antidepressants are largely due to the placebo effect, and this pretty much knocks the legs out from under the biochemical theory. 

Amphetamine (53) is the prototype drug in this group. One significant objective of molecular manipulation in this group is to retain the appetite depressant activity without significant central stimulation. This is as yet unrealized. Some of the drugs prepared with this purpose in mind are discussed in this section. Reductive alkylation of the nitrogen... 

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