Stimulants in the Treatment of Depression

almost- · Nov 14, 2006

Utilization of Stimulants in the Treatment of Atypical Depression and
Dysthymic Disorder

One of the underlying symptom profiles that characterizes patients who
respond to stimulants is anhedonia, lack of energy, easy fatigability,
and low self-esteem. Examples include dysthymic disorder (12), "atypical
depression" associated with medical illness [especially post-stroke
depression] (185), and more recently HIV-related neuropsychiatric
symptoms, including depression (8, 92). Frequently in these patients,
the symptomatology is pervasively anergic and apathetic, without
sadness, guilt, or more severe depressive mood. Thus, depressed,
hospitalized cancer patients, and those with neurological disorders
(especially post-stroke) or significant cardiac disorders, all often
suffer from difficulties with anergia and easy fatigability and are
candidates for stimulant treatment. These syndromes are all similar to
the psychiatric diagnosis of atypical depressive mood disorders, which
as Quitkin and colleagues (168) have demonstrated in a series of
studies, respond to either psychomotor stimulants or monoamine oxidase
inhibitors rather than tricyclic antidepressants.

In psychiatric patients, Rickels et al. (171, 172), found that
methylphenidate and pemoline mildly to moderately improved depressed
individuals with target symptoms of fatigue, listlessness, apathy, and
anorexia. Substantial positive response to methylphenidate has been
noted in pathological fatigue or neurasthenia (31, 225). In many of
these studies, a positive response was maintained over periods as long
as several months. Chiarello & Cole (31) reviewed studies on the use of
stimulants in withdrawn, apathetic geriatric patients and concluded that
pure senile organic brain syndrome is not improved by stimulant
treatment, but those who do not have prominent organic syndromes but
were apathetic, mildly depressed, or poorly motivated, did improve
significantly.

Willner (229) makes the case that a hypodopaminergic state underlies
many of these dysthymic states. Questions are frequently raised as to
whether one of the significant side effects of antidopaminergic
neuroleptic therapy in schizophrenia is a form of depression. It is
difficult to test this directly, but the evidence in normal volunteers
indicates that neuroleptics induce feelings of dysphoria, paralysis of
volition, and fatigue (17). Based on a series of reports in the 1950s,
it was widely accepted that the DA and norepinephrine-depleting drug
reserpine induced depression. (Note: the DA depletion from chronic-high
dose amphetamine abuse and associated depression will be discussed
later). However, Goodwin et al. (80) re-analyzed these data and
demonstrated that reserpine-induced depression was a misdiagnosis. The
actual syndrome was a ‘pseudodepression' characterized by psychomotor
slowing, fatigue and anhedonia but lacking the cognitive features of
depression such as hopelessness or guilt (this symptom constellation is
similar to that of amphetamine withdrawal). Only 5–10% showed symptoms
of major depression, and there was a strong possibility that these
patients actually had a prior history of the illness. Similarly,
Parkinsonism or pre-Parkinsonism depressions, which respond to treatment
with DA agonists, are characterized by decreased motivation and drive
but not by feelings of guilt, self-blame and worthlessness (26, 229).

http://www.acnp.org/G4/GN401000166/Default.htm

Underlying Distinguishing Features of Atypical vs. Endogenous Depression

Klein (120) makes an interesting argument that there are two main
hedonic systems in both humans and lower animals: 1) a series of
activities such as foraging, hunting, searching, other pursuit
activities and socializing, which generate positive feedback loops and
2) consummatory behaviors such as sexual orgasm, eating, drinking and
perhaps sleep, which generate a negative feedback loop, turning off
further activity. Klein (120) indicates that many of the feed-forward,
pursuit-acquisition behaviors are sublimated in humans and expressed as
the pleasures one might get from sports including running, jogging and
other types of play activities, which he sees as a mock hunting
activity. The author makes the obvious connection that endogenously
depressed patients have decreased consummatory pleasure, whereas
dysthymic or atypical depression patients have a loss of energy and
interest in pursuit-searching pleasures, yet have an intact consummatory
pleasure response. Indeed, the group defined by Quitkin et al. (168) as
definite atypical have a weighting of the following symptoms:
hyperphagia, hypersomnolence, reversed diurnal variation, and a leaden
muscle feeling.

Hyperphagia and hypersomnolence are features of amphetamine withdrawal,
along with the loss of energy and pursuit pleasures. Klein (120) points
out that the atypical depressed patients respond to amphetamine and to
monoamine oxidase inhibitors (including deprenyl) and have only a
partial response to tricyclic antidepressants. In contrast, endogenously
depressed patients have little, if any, continuing positive response to
stimulants but do respond to tricyclic antidepressants. Nunes et al.
(157) reported that some subgroups of 113 cocaine abusers had a
significant response to imipramine (decreased craving, cocaine euphoria,
depression, and, to a lesser extent, cocaine use), with other subgroups
having no response. Unfortunately, an MAOI treatment group was not
included for comparison. In summary, subtyping of stimulant abusers may,
in the future, provide for more selective drug treatment for the earlier
phases of stimulant withdrawal in a manner similar to the current
treatment of depression.

http://www.acnp.org/G4/GN401000166/Default.htm

Treatment-Resistant Depression (TRD):
The use of stimulant agents, such as dextroamphetamine and
methylphenidate, in TRD has a long history but little empirical support
(4). Some patients refractory to MAOI and tricyclic combinations may be
treated successfully with the addition of methylphenidate or
Damphetamine (30, 32). Safety concerns often dictate that patients
treated with this rather heroic combination be started as inpatients.
Unfortunately, no controlled studies of stimulant augmentation therapy
have been conducted. Moreover, the abuse potential of these substances
certainly places their role in TRD at a lower priority level.

Interested in other research studies? Find more drug studies.

Ness · Nov 14, 2006

^I skimmed it, but I can tell you that (at least for me) stimulants make my depression MUCH worse. Although, to be fair mine is a special case. I suffer from irregular serotonin levels as a complication of ADD, so my brain is a bit funky in the way it responds to stimulants.

Jamshyd · Nov 14, 2006

I am severely depressive, with occasional manic episodes. Amphetamine did not cure depression - it would always trigger a manic episode followed by a long, helpless depressive ones.

It simply doesn't work.

nuke · Nov 14, 2006

Sometimes psychiatrists will prescribe an SSRI with a dopaminergic stimulant in the cast that all else has failed (called the 'heroic combo'). But generally it's avoided.

I have bad anxiety with depression occasionally (but not usually) stemming from that. I consider amphetamine in a low dose occasionally to generally be a positive thing for me (SSRIs/SNRIs never helped me much with anxiety). I'm starting to think I might be ADHD too.

almost- · Nov 14, 2006

Stimulants with MAOIs

Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication.
Feinberg SS.
J Clin Psychiatry. 2004 Nov;65(11):1520-4.

BACKGROUND: Among antidepressant augmentation strategies, the addition of a stimulant to a monoamine oxidase inhibitor (MAOI) has received little attention in the literature in recent years because of the diminished clinical use of the latter and concerns of precipitating a hypertensive crisis or other serious complication. Despite that fact, experienced clinicians continue to use this combination for a variety of indications after other options have failed. This article reviews these reported uses and presents a case suggesting another possible indication. METHOD: A MEDLINE search was conducted for articles published from 1962 to December 2003 using relevant search terms (psychostimulant, stimulant, amphetamine, dextroamphetamine, pemoline or methylphenidate, atomoxetine, bupropion, monoamine oxidase inhibitor, and selegiline). A manual search was conducted of cross-references and other relevant recent psychiatric sources). RESULTS: The described uses of the MAOI-stimulant combination have included treatment of refractory depression and the MAOI-related side effects of orthostatic hypotension and daytime sedation. No documented reports were found in the recent literature of hypertensive crises or fatalities occurring when the stimulant was cautiously added to the MAOI. Also presented here is another possible indication for this therapeutic regimen: treatment of attention-deficit/hyperactivity disorder in an adult patient whose major depression had uniquely responded to the MAOI tranylcypromine. CONCLUSION: As in other fields of medicine, potentially hazardous medication combinations are utilized in psychiatry after cautiously weighing the danger of the treatment against the morbidity and risk of not adequately addressing the illness. Particularly, as the potential arrival of the apparently safer transdermal selegiline may increase the use of MAOIs, we feel this combination deserves additional controlled study.

Full text: https://rikki.fi/tajkor/bl/Combinin...es_and_one_possible_additional_indication.pdf

fastandbulbous · Nov 14, 2006

I understand that mild, long lasting psychomotor stmulants (such as pipradrol, pemoline etc) can have positive effects in getting withdrawn depressives out of 'the dark hole' and possibly help with later motivation, but any strong stimulant such as amphetamine will not cure depression because the rebound comedown adds more to the depression compared with what it takes away

HeaT · Nov 15, 2006

methamphetamine use is what really amplified my depression. not fun...

almost- · Nov 16, 2006

fastandbulbous said:
I understand that mild, long lasting psychomotor stmulants (such as pipradrol, pemoline etc) can have positive effects in getting withdrawn depressives out of 'the dark hole' and possibly help with later motivation, but any strong stimulant such as amphetamine will not cure depression because the rebound comedown adds more to the depression compared with what it takes away

I agree.

BTW 4-methylaminorex is a really good antidepressant and smart drug, and it has a little anxiolytic properties as well.

Dr.Heckyll · Nov 17, 2006

As I speak, I'm on 100mg pemoline taken 4 hours ago and 50mg taken 20 minutes ago. It really does help a lot with depression. I've also tried menthylphenidate 10mg orally, but it didn't do me any good.

nuke · Nov 17, 2006

Dr.Heckyll said:
As I speak, I'm on 100mg pemoline taken 4 hours ago and 50mg taken 20 minutes ago. It really does help a lot with depression. I've also tried menthylphenidate 10mg orally, but it didn't do me any good.

how pemoline like? if it weren't for the liver issues i'd consider it.

uacvax · Nov 17, 2006

fastandbulbous said:
I understand that mild, long lasting psychomotor stmulants (such as pipradrol, pemoline etc) can have positive effects in getting withdrawn depressives out of 'the dark hole' and possibly help with later motivation, but any strong stimulant such as amphetamine will not cure depression because the rebound comedown adds more to the depression compared with what it takes away

none of those drugs "cure" depression. western medicine isn't involved with curing, it treats.

i can't speak for others but when my tolerance to amphetamines (adderall) was low, I did not experience significant comedowns with my prescribed dose (10mg ir, or 20mgXR) however great care should be taken to make sure that the depressed individual doesn't become dependent on it. speaking from personal experience, when your productivity goes from nil and skyrockets, it's a pretty huge incentive to continue using. i agree that it's a good kickstart for withdrawn depressives, but like I said even if drugs ameliorate the situation it's not curing.

I haven't cured myself yet but I imagine that to do so a ton of work needs to be done in the areas of support of friends/family, absolving social anxiety and other things. i've used adderall for what it was worth and now amphetamine tolerance sucks ass and takes too damn long to die down

Dr.Heckyll · Nov 17, 2006

nuke said:
how pemoline like? if it weren't for the liver issues i'd consider it.

It doesn't give a "high" and has pretty much zero abuse potential. It comes on smooth and slow, lasts the whole day, and there is no crash. But it significantly increases my drive, normalizes my mood and gererally helps me have a normal day rather than a rotten depresssed day.

Here are some details on it from Clarke's Analysis of Drugs and Poisons:

Disposition in the Body.Slowly absorbed after oral administration. About 50% of a dose is excreted in the urine as unchanged drug in 48 h and about 4% as 5–phenyloxazolidine–2,4–dione; the remainder is excreted in the urine as conjugated pemoline and unidentified polar metabolites; mandelic acid is also a metabolite of pemoline. Less than 1% of a dose is eliminated in the faeces.

Therapeutic concentration
After a single oral dose of 50 mg given to 3 subjects, peak plasma concentrations of 0.77 to 1.22 mg/L (mean 1.0) were attained in about 2 to 3 h; peak concentrations in saliva of 0.47 to 0.75 mg/L (mean 0.59) were reported after 2 to 4 h; following administration of 37.5 mg to 1 subject, peak plasma and saliva concentrations of 0.89 and 0.58 mg/L, respectively, were attained in about 4 h [N. P. E. Vermeulen et al.,Br. J. Clin. Pharmacol.,1979, 8, 459–463.]

After daily oral doses of 37.5 and 75 mg to 28 hyperactive children for seven days, mean plasma concentrations of about 2 and 4 mg/L respectively, were reported 3 h after the last dose [C. P. Tomkins et al.,Ther. Drug Monit.,1980, 2, 255–260.]

Peak plasma concentrations of 4.3 (± 1.0) mg/L were attained in 2.8 (±1.8) h after a single 2 mg/kg oral dose of pemoline to 7 prepubescent boys [F. Sallee et al.,Clin. Pharmacol. Ther.,1985, 37, 606–609.]

Toxicity.Estimated minimum lethal dose, 2 g for an adult, 0.2 g for children up to 2 years, although recovery has occurred following the ingestion of up to 1.8 g by young children.

Half–life.Plasma half–life, about 10 to 18 h.

Protein binding.In plasma, about 30%.

Dose.Usually 40 mg daily; maximum of 120 mg daily.

Stimulants in the Treatment of Depression

almost-

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