THE HISTORY OF
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Rebecca Martin
Selective Serotonin Reuptake Inhibitors, also referred to as
second generation antidepressants, are of a different class than
antidepressants used prior to their clinical introduction in the
1980s. The earlier, first generation antidepressants include
Monoamine Oxidase Inhibitors (MAOIs) (which affect not only the
serotonergic system, they also affect norepinephrine and dopamine)
and tricyclics (which affect the levels of norepinephrine and
serotonin). The implications of the involvement of serotonin in
depression were made in the 1960s in response to the effect of the
first generation antidepressant s on the serotonergic system
(Palfai & Jankiewicz, 1997). SSRIs were then developed to isolate
their effect to serotonin activity specifically. This limited drug
action makes SSRIs less toxic and less costly in overdose, and a
safer alternative to MAO Inhibitors and tricyclics (Stoner, et
al., 1997), and they are also safe for cardiac patients, causing
fewer cardiac side effects than tricyclics (Roose et al., 1998).
Four of the SSRIs available today are Luvox (fluvoxamine),
Paxil (paroxetine), Prozac (fluoxetine), and Zoloft (sertraline).
Luvox, patented in 1975 and 1978 by Philips-Duphar, has mainly
been used in Europe, but has recently been made available in the
U.S. Paxil, patented in 1974,1975 and 1977 by Ferrosan, is the
most potent of the SSRIs. Prozac (patented in 1975 and 1982) was
the first SSRI to be made clinically available in 1987, and by
1988, it had made quite an impact on the world of
psychopharmacology. The effectiveness and scarcity of side
effects associated with the drug made it very popular with
clinicians and patients alike. Zoloft, patented in 1981 and 1985
by Pfizer, is of a different chemical class from fluoxetine and
and is more potent and more specific in its inhibition of
serotonin reuptake (Palfai & Jankiewicz, 1997).
Although the action of these drugs and the system they affect
is limited, the uses of this type of reuptake inhibitor has a vast
range of uses. In addition to treating major depression, Luvox
was shown to be successful in treating Mixed Anxiety-Depression
(Huock, 1998); Paxil has been effective in a treating a case
sexual disinhibition in dementia (Stewart & Shin, 1997); Prozac
has been used in treating dysthemic disorder (Vanelle et al.,
1996); and Zoloft is successful in treating both dysthemia and
social dysfunction (Kocsis et al., 1997).
The specificity and efficiency in the action of SSRIs make
them an attractive option in the treatment of pediatric cases of
depression and atypical depression. Luvox was effective in
treating a case of selective mutism in a 6.5 year old girl in a
study conducted by Lafferty & Constantino (1998). Sanchez &
Guittierez-Casares (1977) found Paxil to be well tolerated and
effective in treating major depressive disorder in children under
14. Prozac, as well was shown to be beneficial in the treatment
of body dysmorphic disorder in an adolescent girl (Himann, 1997).
Ozbayrak (1997), found Zoloft to be successful in treating a 6
year old and a 13 year old with anxiety and pervasive development
disorder. Paxil and Zoloft have also been successful in treating
pediatric obsessive compulsive disorder (Moore et al., 1998;
Alderman et al., 1998). Prozac and Zoloft have also been found to
treat adolescent eneuresis (Sprenger, 1997; Feeny & Klykylo,
1997).
The milder side effects associated with SSRIs make them very
popular with regard to their range of possible applications.
Because SSRIs are less toxic than other antidepressant
medications, they are safe for use in the elderly, who are often
vulnerable to cardiac complications with the use of first
generation antidepressants. SSRIs are also safe for use with
children, for the treatment of a wide variety of symptoms. The
relative recency of their development leaves much in the way of
research to be performed on the long term effects of SSRIs.
Despite this fact, however, SSRIs are the most commonly prescribed
antidepressant medications today.
The attractiveness of SSRIs is not only due to their mild
side effects. The wide range of symptoms treated by the SSRIs
including anxiety disorders, obsessive compulsive disorder, and
major depressive disorder, provide many uses for these
medications. The mild physiological effects of SSRIs make
maintenance therapy easier for therapists and clients by reducing
the risk of toxicity, and thereby requiring less strictly
monitored therapy than first generation antidepressants. SSRIs
also generally are taken once a day, but larger amounts are taken
in two doses. SSRIs are an important addition to pharmacological
therapy, and warrant further study, with regard to long term
effects. Their limited physiological effects and unpleasant side
effects make them invaluable to those they have helped.
The Physiological Effects of
Selective Serotonin Reuptake Inhibitors
Rebecca Martin
The antidepressant, antiobsessive compulsive, and
antibulimic effects of Luvox, Paxil, Prozac, and Zoloft are
attributed to potentiation of serotonergic activity in the CNS
resulting from inhibition of neuronal uptake of serotonin (PDR,
1998). These drugs also block the uptake of serotonin into human
platelets and have a weak effect on norepinephrine and dopamine
neuronal systems, unlike first generation antidepressants like
Monoamine Oxidase Inhibitors and Tricyclics. It is the highly
selective process of the inhibition of the reuptake of serotonin
that make SSRIs so unique in their effectiveness with a vast array
of disorders and limited side effects.
In adult patients with Major Depressive Disorder (MDD), there
is evidence of diminished levels of 5HTPR, a serotonin transporter
protein in the brain (Perry, et al., 1998). Decreases in the
ability of blood platelets to bind with 5HT (serotonin) were found
to be clinically indicative of potential for nonresponsiveness to
Zoloft, and hypersuicidality in a study conducted on children and
adolescents with (MDD) by Sallee et al.(1998). This study
establishes that 5HTPR, present in blood platelets as well as the
brain, is the major pathway for the antidepressant action of
SSRIs. Also established is the potential advantage to monitoring
platelet 5HTPR in identifying patient subgroups such as
nonresponders and suicidal patients.
Plasma concentration of fluoxetine (Prozac) and
norfluoxetine (fluoxetine's metabolite) are not predictors of
clinical responsiveness in treatment of major depression
(Amsterdam et al. 1997). Knutson, et al. (1998) suggest blood
platelet levels of 5HTPR to be a clear indicator of functional
changes and not necessarily antidepressant effects; their control
subjects exhibited changes in negative affect in accordance with
blood platelet levels, regardless of their lack of depressive
symptoms. Treatment with Luvox and measurement of physiological
reactivity with d-fenfluramine indicates the responsiveness of the
serotonergic system, which is a predictor of clinical
responsiveness (Monteleone 1996).
Another effect of SSRIs is evident in the successful
treatment of Obsessive Compulsive Disorder (OCD). One observed
effect of OCD is an increase in the activity within the caudate
nucleus in accordance with OCD symptom severity (Baxter, et al.,
1992). In a case study of a 9 year old with OCD by Moore et
al.(1998), a 40 percent reduction in the amount of
glutamate/glutamine present in the caudate nucleus was discovered
as a result of treatment with Paxil. The findings of this study
are consistent with the hypothesis that an increase in serotonin,
induced by an SSRI, may have an inhibitory effect on the excess
release of the excitatory neurotransmitter glutamate, which is why
it is successful in the treatment of OCD.
Sargent, et al. (1997) discuss the effect of Paxil on the
increase of serotonin (5HT) induced release of cortisol in
relation to the treatment of depression. An increase of serotonin
mediated cortisol release was apparent 8 weeks into treatment,
well after antidepressant effects had been established. This
suggests that in depressed patients, SSRIs produce an enduring
increase in 5HT neurotransmission and subsequent increased release
of cortisol. SSRIs, like many other drugs produce the enzyme
cytochrome P450 in the liver (Palfai & Jankiewicz, 1997). This
makes it necessary to use caution when taking more than one
medication at a time; combining antidepressant medications, such
as SSRIs and Monoamine Oxidase Inhibitors, can cause an excess of
serotonin in the system, causing serotonergic syndrome.
An important aspect in the study of the physiological effects
of SSRIs is the effects that they have on children exposed
prenatally. Some research has been done on the aspect of the use
of SSRIs by pregnant and nursing women. The use of Prozac in the
third trimester of pregnancy doesn't appear to have any effect on
infants (Chambers et al. 1996); and Prozac does not appear to
alter the neurodevelopment of preschoolers as a result of maternal
antidepressant treatment (Nulman et al. 1997). Despite high
levels of fluoxetine and norfluoxetine in the breastmilk and urine
of nursing mothers, infants appear to be unaffected by their
mothers' continued use of Prozac while nursing and their urine and
plasma levels of fluoxetine and norfluoxetine were below
detectable levels (Yoshida et al. 1997).
Analysis of the breastmilk of nursing mothers treated with Zoloft
revealed the presence of sertraline and its metabolite
desmethylsertraline; despite this fact, nursing infants do not
show any notable effects as a result of being exposed to the drug
through breast milk (Stowe et al. 1997).
Although the future of the use of these drugs in pregnant
women looks promising, Dahl, et al. (1998) have reported a case of
withdrawal symptoms in a neonate whose mother was treated with
Paxil prenatally. Aside from the specific effect of inhibiting
serotinin reuptake selectively, the reported physiological effects
of SSRIs thus far are few. Hopefully, continued research will
aid in our better understanding the functions of SSRIs and the
processes involved in depression and many other mood disorders.
BIBLIOGRAPHY
Alderman, J., Wolkow, R., Chung, M., & Johnston, H.E. (1998).
Sertraline treatment of children and adolescents with obsessive
compulsive disorder or depression: Pharmacokinetics, tolerability,
and efficacy. Journal of the American Academy of Child and
Adolescent Psychiatry, 37, 386-394.
Amsterdam, J.D., Fawcett, J., Quitkin, F.M., Reimherr, F.W.,
Rosenbaum, J.F., Michelson, D., Hornig-Rohan, M., & Beasly, C.M.
(1997). Fluoxetine and norfluoxetine plasma concentrations in
major depression: A multicinter study. American Journal of
Psychiatry, 154, 963-969.
Baxter, L. R., Schwartz, J. M., Bergman, K. S., et al. (1992)
Caudate Glucose metabolic rate changes with both drug and behavior
therapy for obsessive compulsive disorder. Archives of General
Psychiatry. 49, 681-689.
Chambers, C., Johnson, K., Dick, L., Felix, R. & Lyons Jones, K.,
(1996). Birth outcomes in pregnant women taking fluoxetine. The
New England Journal of Medicine. 355(14) 1010-1015.
Dahl, M. L., Olhager, E., & Ahlner, J., (1997). Paroxetine
withdrawal syndrome in a neonate. The British Journal of
Psychiatry. 391-392.
Feeny, D.J., Klykylo, W.M. (1997). SSRI treatment of enuresis.
Journal of the American Academy of Child and Adolescent
Psychiatry, 36, 1326-1327.
Heimann, S.W. (1997). SSRI for body dysmorphic disorder. Journal
of the American Academy of Child and Adolescent Psychiatry, 36,
868.
Huock, C. (1998). An open label pilot study of fluvoxamine for
mixed anxiety depression. Psychopharmacology Bulletin, 34, 225-
227.
Knutson, B., Wolkowicz, O.M., Cole, S.W., Chan, T., Moore, E. A.,
Johnson, R.C., Terpstra, J., Turner, R.A., & Reus, V.L. (1998).
Selective alteration of personality and social behavior by
serotonergic intervention. American Journal of Psychiatry, 155,
373-379.
Kocsis, J.H., Zisook, S., Davidson, J., Shelton, R., Yonkers, K.,
Hellerstein, D.J., Rosenbaum, J., & Hallbreich, U. (1997). Double
blind comparison of sertraline, imipramine and placebo in the
treatment of dysthemia: Psychosocial outcomes. American Journal of
Psychiatry, 154, 390-396.
Lafferty, J.E., & Consantino, J.N. (1998). Fluvoxamine in
selective mutism. Journal of American Academy of Child and
Adolescent Psychiatry, 37, 12-13.
Monteleone, P., Catapano, F., Di Martino, S., Ferraro, C., & Maj,
M., (1996). Prolactin response to d-fenfluramine in obssessive
compulsive patients, and outcome of fluvoxamine treatment. British
Journal of Psychiatry. 554-557.
Moore, G.J., MacMaster, F.P., Stewart, C., & Rosenberg, D.R.
(1998). Case study: Caudate glutamatergic changes with paroxetine
therapy for pediatric obsessive compulsive disorder. Journal of
the American Academy of Child and Adolescent Psychiatry, 37, 663-
667.
Nulman, I., Rovet, J., Stewart, D. E., Wolpin, J., Gardner, H. A.,
Theis, J. G. W., Kulin, N., & Koren, G., (1997). Neurodevelopment
of children exposed in utero to antidepressant drugs. The New
England Journal of Medicine. 336(4)258-263.
Ozbayak, K.R. (1997). Sertraline in PPD. Journal of the American
Academy of Child and Adolescent Psychiatry, 36, 7-8.
Palfai, T., & Jankiewicz, H., 2nd ed. (1997). Drugs and Human
Behavior, Brown & Benchmark, Madison, WI. 262-288.
Physicians' Desk Reference, 52ed. (1998), Medical Economics Co.,
Montrali, N.J.
Rey-Sanchez, F., & Guitteirrez-Casares, J.R.(1997). Paroxetine in
children with major depressvie disorder: An open trial. Journal of
the American Academy of Child and Adolescent Psychiatry, 36, 1443-
1447.
Roose, S.P., Glassman, A.H., Attia, E., Woodring, S., Giardina,
E.V., & Bigger Jr., T. (1998). Cardiovascular effects of
fluoxetine in depressed patients with heart disease. American
Journal of Psychiatry, 155, 660-665.
Sallee, F.R., Hilal, R., Dougherty, D., Beach, K. & Nesbitt, L.
(1998). Platelet serotonin transporter in depressed children and
adolescents: 3H-Paroxetine platelet binding before and after
sertraline. Journal of the American Academy of Child and
Adolescent Psychiatry, 37, 777-784.
Sargent, P.A., Williamson, D.J., & Cowen, P.J. (1997). Brain 5-HT
neurotransmision during paroxetine treatment. British Journal of
Psychiatry, 49-52.
Sprenger, D. (1997). Sertraline for nocturnal enuresis. Journal of
the American Academy of Child and Adolescent Psychiatry, 36, 304-
305.
Stewart, J.T., & Shin, K.J. (1997). Paroxetine treatment of sexual
disinhibition in dimentia. American Journal of Psychiatry, 154.
Stoner, S.C., Marken, P.A., Watson, W.A., Switzer, J.L., Barber,
M.F., Meyer, V.L., Sommi Jr., R.W., & Steele, M.T. (1997).
Antidepressant overdoses and resultant emergency department
services: The impact of SSRIs. Psychopharmacology Bulletin, 33-
667-670.
Stowe, Z. N., Owens, M. J., Landry, J. C., Kilts, C. D., Ely, T.,
Llewellyn, A., & Nemeroff, C. B., (1997). Sertraline and
Desmethylsertraline in human breast mild and nursing infants.
American Journal of Psychiatry. 154 (9) 1255-1260.
Vanelle, A., Attar-Levy, D., Porier, M., Bouhassira, L., Blin, P.,
and Olie, J., (1996). Controlled efficacy study of fluoxetine in
dysthmia. The British Journal of Psychiatry. 345-350.
Yoshida, K., Smith, B., Craggs, M., & Kumar, R. C., (1997)
Fluoxetine in breast milk and developmental outcome of breast fed
infants. British Journal of Psychiatry. 175-179.
SEROTONIN
By Jonathan Stickels
Serotonin(5-hydroxytyptryptamine, 5-HT) is widely distributed in
animals and plants, occurring in vertebrates, fruits, nuts, and
venom. An average human possess about 10mg of 5-HT. A number of
congeners of serotonin are also found in nature and have been
shown to possess a variety of peripheral and central nervous
system activities.
Of particular interest over the years is the psychotomimetic
activity displayed in several serotonin related compounds, such as
antidepressants. Although serotonin may be obtained from a
variety of dietary sources, endogenous 5-HT is synthesized in situ
from tryptophan through the actions of enzymes tryptophan
hydroxylase and aromatic L-amino acid decarboxylase(Borne, p1).
Both dietary and endogenous 5-HT are rapidly metabolized and
inactivated by monoamine oxidase and aldehyde dehydrogenase to the
major metabolite 5-hydroxyindoleacetic acid(5-HIAA)(Borne, p2).
Serotonin is perhaps the most implicated in the etiology of
treatment of various disorders, including depression, anxiety,
OCD, schizophrenia, and other CNS related disorders. Serotonin's
most widely studied features are those which effect the CNS.
Serotonin has been proven to have an astounding effect on sleep,
appetite, mood, behavior, memory, and learning. Peripherally,
serotonin appears to play a major role in platelet homeostasis,
motility of the GI tract, and carcinoid tumor secretion(Borne,
p2). This represents quite a large spectrum of pharmacological
and psychological effects.
Chemical neurotransmitters(CNT's) produce their effects as a
consequence of
interactions with appropriate receptors. As is the case with all
CNT's, serotonin is synthesized in brain neurons and stored in
vesicles. Upon a nerve impulse, it is released into the synaptic
cleft, where it interacts with various postsynaptic receptors.
LUVOX
Fluvoxamine maleate is an aralkyketone-derivative antidepressant
agent. The drug differs structurally from serotonin-reuptake
inhibitors, and tricyclic antidepressant agents. The exact
mechanism of action of fluvoxamine has not been fully elucidated
but appears to involve inhibition of reuptake of serotonin (5-
hydroxytryptamine [5-HT] ) at the presynaptic membrane. Data from
in vitro studies suggest that fluvoxamine is more potent than
clomipramine, fluoxetine, and desipramine as a serotonin-reuptake
inhibitor(AHFS, 1997). Although not clearly established, it has
been suggested that the mechanism of action of fluvoxamine and
other drugs used in the management of obsessive compulsive
disorder may be related to their serotonergic activity(AHFS,
1997). Fluvoxamine appears to have little or no effect on
reuptake or other neurotransmitters such as norepinephrine and
dopamine. In addition, the selectivity of fluvoxamine in
inhibiting serotonin versus norepinephrine reuptake appears to be
substantially greater than that of other selective serotonin-
reuptake inhibitors and tricyclic antidepressants, including
clomipramine.
Fluvoxamine maleate is a selective serotonin ( 5-HT ) reuptake
inhibitor (SSRI ) belonging to a new chemical series, the 2-
aminoethyl oxime ethers of aralkylketones. It is chemically
unrelated to other SSRI's and clomipramine. It is chemically
designated as 5-methoxy-4'-( trifluoromethyl ) valerophenone-(E)-
O-( 2-aminoethyl )oxime maleate
( 1: 1 ) and has the empirical formula C16H21O2N2F3C4H4O4. Its
molecular weight is 434.4(PDR,1998).
Fluvoxamine maleate is a white or off white, odorless,
crystalline powder which is sparingly soluble in water, freely
soluble in ethanol and chloroform and practically insoluble in
diethyl ether
Luvox, fluvoxamine maleare, tablets are for oral administration.
In addition to the active ingredient, fluvoxamine maleate, each
tablet contains the following inactive ingredients: carnauba wax,
hydroxpropyl methylcellulose, mannitol, polyethylene glycol,
polysorbate 80, pregelatinized starch ( potato ), silicon dioxide,
sodium stearyl fumarate, starch ( corn ), and titanium dioxide.
The 50 mg and 100 mg tablets also contain synthetic iron
oxides(PDR, 1998).
In vitro studies fluvoxamine maleate had no significant
affinity for histaminergic, alpha or beta adrenergec, muscarinic,
or dopaminergic receptors. Antagonism of some of these receptors
is thought to be associated with various sedative, cardiovascular,
anticholinergic, and extrapyramidal effects of some psychotropic
drugs. There is minimum interference with noradrenergic
processes, and, in common with several other specific inhibitors
of serotonin uptake, fluvoxamine has very little in vitro affinity
for alpha 1, alpha 2, beta 1, dopamine 2, histamine 1, serotonin
1, serotonin 2 or muscarinic receptors(PDR, 1998).
PAXIL
Paroxetine, brand name Paxil, is a potent SSRI. The activity of
this drug on brain neurons is thought to be responsible for its
antidepressant effects. Paroxetine hydrochloride is a
phenylpiperidine-derivative antidepressant agent. While the
structure of paroxetine includes 3 benzene rings, the drug differs
structurally from classic tricyclic antidepressants and is
structurally unrelated to other currently available
antidepressants. Paroxetine also differs from other SSRI's.
Paxil is an orally administered antidepressant unrelated to any
other SSRI's or tricyclic antidepressants. It is the
hydrochloride salt of phenylpiperidine compound:
(-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy)
methyl] piperdine hydrochloride hemihydrate and has the empirical
formula of C19H20FNO3 HCI 1/2H2O. The molecular weight is 347.8
(329.4 as free base). The structural formula is:
cols, polysorbate 80, sodium starch glycolate, titanium dioxide
and one or more of the following: D&C Red No. 30, D&C Yellow No.
10, FD&C Blue No. 2, FD&C Yellow No. 6(PDR, 1998).
The antidepressant action of paroxetine and its efficacy in
the treatment of obsessive compulsive disorder and panic disorder
is presumed to be linked to the potentiation of serotonergic
activity in the CNS resulting from the inhibition of the neuronal
reuptake of serotonin(5-hydroxy-tryptamine, HT-5). Studies at
clinically relevant doses in humans have demonstrated that
paroxetine blocks the reuptake of serotonin into human
platelets(PDR, 1998). In vitro studies in animals also suggest
that paroxetine is a potent and highly selective inhibitor of
neuronal serotonin reuptake and has only very weak effects on
norepinephrine and dopamine neuronal reuptake. In virto
radioligand binding studies indicate that paroxetine has little
affinity for muscarinic, alpha 1, alpha 2, beta-adrenergic,
dopamine(D2), 5HT 1, 5HT 2, and histamine(H1)-receptors;
antagonism of muscarinic, histaminergic and alpha 1-adrenergic
receptors has been associated with various anticholinergic,
sedative, and cardiovascular effects for other psychotropic drugs.
Because of the relative potencies of paroxetine's major
metabolites are at most 1/50 of the parent compound, they are
essentially inactive(PDR, 1998).
PROZAC
The antidepressant, antiobsessional, and antibolimic actions of
fluoxetine is presumed to be linked to its ability to inhibit the
neuronal reuptake of serotonin. Prozac, fluoxetine hydrochloride,
is an antidepressant for oral administration; it is chemically
unrelated to tricyclic, tetracyclic, or other antidepressants.
Its empirical formula is C17H18F3NO HCI and has a molecular
weight of 345.79. Fluoxetine hydrochloride is a white to off-
white crystalline solid with a solubility of 14 mg/mL in
water(PDR, 1998).
Fluoxetine is a phenylpropylamine-derivitive antidepressant. The
drug is a bicyclic antidepressant that differs structurally and
pharmacologically from other available antidepressants. The
presence of the p-trifluoromethyl substitute on the molecule
appears to contribute to the drugs high selectivity and potency
for inhibiting serotonin reuptake, possibly as a result of its
electron-withholding effect and lipophilicity. Prozac is a
racemic mixture of two optical insomers. Limited to vivo and in
vitro data suggests that the pharmacologic activities of the
optical insomers do not differ substantially, although the
dextrorotatory insomer appears to have slightly greater serotonin
reuptake inhibiting activity and a longer duration of action than
the levorotatory insomer(AHFS, 1997).
Fluoxetine inhibits the reuptake of serotonin into brain
synaptosomes and platelets in rats and humans. In receptor
binding studies, fluoxetine was shown to have only weak affinity
for various receptor systems namely opiate, serotonergic 5-HT 1,
muscarinic, and serotonergic 5HT 2 receptors(Mental Health, p30-
p05 html). Unlike most clinically effective antidepressants,
fluoxetine did not down-regulate beta-adrenergic receptors;
however, like all tested antidepressants, it causes up-regulation
of GABA-B receptors. Mixed effects have been observed on
serotonergic receptor sensitivity. Antagonism of muscarinic,
histaminergic, and alpha 1-adrenergic receptors has been
hypothesized to be associated with various anticholinergic,
sedative, and cardiovascular effects in classical tricyclic
antidepressants(PDR, 1998). Fluoxetine binds to these and other
membrane receptors from brain tissue much less potently than do
the tryciclic drugs.
The pharmacology of fluoxetine is complex and in some ways
resembles that of other antidepressant agents, particularly those
that potentiate the effects of serotonin. Unlike other serotonin
facilitators, fluoxetine is a highly selective reuptake inhibitor
and has little or no effect on other neurotransmitters.
The precise mechanism of antidepressant action of fluoxetine
is unclear, but has been shown to selectively inhibit the reuptake
of serotonin(5-HT) at the presynaptic neuronal membrane.
Fluoxetine-induced inhibition of serotonin reuptake causes
increased synaptic concentrations of serotonin in the CNS,
resulting in numerous functional changes associated with enhanced
serotonergic neurotransmission. Unlike other antidepressants,
prozac has little or no effect on other neurotransmitters such as
norepinephrine or dopamine, and does not exhibit clinically
important anticholinergic, antihistaminic, or alpha 1-adrenergic
blocking activity at usual therapeutic dosages(AHFS, 1997).
Although the mechanism of antidepressant action of
antidepressant medication may involve inhibition of the reuptake
of various neurotransmitters at the presynaptic neuronal membrane,
it has been suggested that postsynaptic receptor modification is
mainly responsible for the antidepressant action observed during
long-term administration of antidepressant agents(AHFS, 1997).
Some antidepressants reportedly decrease the number of 5-HT
binding sites following chronic administration. However
fluoxetine may exert activity by somewhat different mechanisms
than those of other antidepressants. Some evidence shows that
prozac does not substantially reduce the number of beta-adrenergic
binding sites, nor does effect beta-adrenergic sensitivity.
Although data on the effects of fluoxetine on 5-HT binding sites
has been conflicting and further studies are needed to determine
the effect of these binding sites(AHFS, 1997).
Fluoxetine is a highly selective inhibitor of serotonin
reuptake at the presynaptic neuronal membrane. In addition, the
potency and selectivity of serotonin-reuptake inhibition exhibited
by fluoxetine's principal metabolite, norfluoxetine, appear to be
similar to those of the parent drug. Fluoxetine and
norfluoxetine-induced inhibition of serotonin reuptake causes
increased synaptic concentrations of serotonin, resulting in
numerous functional changes associated with enhanced serotonergic
neurotransmission. Fluoxetine appears to decrease the turnover of
serotonin in the CNS, probably as a result of a decrease in the
rate of serotonin synthesis. The drug reportedly decreases brain
concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the
principal metabolite of serotonin; reduces the uptake of
radiolabeled tryptophan by synaptosomes; and reduces the rate of
conversion of tryptophan to serotonin. Fluoxetine also inhibits
spontaneous firing of serotonergic neurons in the dorsal raphe
nucleus(AHFS, 1997).
ZOLOFT
Zoloft, sertraline hydrochloride, is a SSRI for oral
administration. Sertraline hydrochloride is a naphthalenamine-
derivitive antidepressant agent. While the structure of
sertraline includes three rings, the drug differs structurally
from classic tricyclics and is structurally unrelated to other
antidepressants. Sertraline differs also from other SSRI's. It
has a molecular weight of 342.7. Sertraline has the following
chemical name:
(1S-cis)-4-(3,4-dichloophenyl)-1,2,3,4-tetrahydro-N-methyl-1-
naphthalemine hydrochloride. The empirical formula is C17H17NCI2
HC1. Sertraline is a white crystalline powder that is slightly
soluble in water and isopropyl alcohol, and sparingly soluble in
ethanol(PDR, 1998).
The mechanism action of sertraline is presumed to be linked
to its inhibition of CNS neuronal uptake of serotonin(5-HT).
Studies at clinical relevant doses in humans has demonstrated that
sertraline blocks uptake of serotonin into human platelets. In
vitro studies in animals also suggests that sertraline is a potent
and selective inhibitor of neuronal serotonin reuptake and has
only weak effect on other neurotransmitters. In vitro studies
also conclude that sertraline has no significant affinity
adrenergic, cholinergic, GABA, dopaminergic, seratonergic(5-
HT(1A), 5-HT(1b), 5-HT 2, or benzodiazepine receptors; antagonism
of such receptors has been hypothesized to be associated with
various anticholinergic, sedative, and cardiovascular effects for
other psychotropic drugs. The chronic administration of
sertraline was found in animals to down-regulate brain
norepinephrine receptors, and has been observed with other
clinically effective antidepressants(PDR, 1998).
BIBLIOGRAPHY
Borne, Ronald F. Ph.D., Serotonin: The Neurotransmitter for the
90's. http:www.fairline.com
Internet Mental Health. http:www.mentalhealth.com. p30-105, p30-
p02, p30-p05,
p30-z02 html.
McEvoy, Gerald K. Pharm.D. ed. American Hospital Formulary
Service, 1997., Society of Health-System Pharmacology., Bethesda,
MD, 1997
Physicians Deck Reference, 1998, Pfizer Inc.
Primary effects of SSRI's
By Sandra Nine
The primary effect of any antidepressant is the reduction of the
symptoms of depression. The onset of relief may take from one to
four weeks. If there is no relief of any symptoms at this point,
it is recommended that dosage or medication choice be re-evaluated
and changed at this time (Skidmore-Roth, L., 1997). At
therapeutic doses, antidepressants elevate the mood of the
depressed and seems to simply excite them into normalcy. At this,
the second generation antidepressants known as SSRI's have proved
especially successful (Palfai, T. & Jankiewicz, H., 1997). While
the effectiveness of these new drugs is not in question, it is
important to remember that antidepressants are still one of the
most used drugs of choice for suicide. Practitioners should take
care to limit availability of large amounts of SSRI's to those at
risk for suicide. The possibility of suicide may persist until
significant remission of depressive symptoms occurs, and patients
should be supervised closely (Kozlak, 1998).
With each of the medications discussed here, Luvox (fluvoxamine),
Paxil (paroxetine), Prozac (fluoxetine), and Zoloft (sertraline),
sleep and appetite disturbances are usually the first symptoms to
be relieved (Sargeant, M., 1998). A series of antidepressant
treatment, usually four to six months, often reduces symptoms to a
quite tolerable level, but continued therapy may be warranted to
maintain the relief (D/ART, 1998). The biochemical imbalance is
not cured, but it can be treated as long as the depressive illness
persists (Bloomfield, H. H. & McWilliams, P., 1996a). These
medications have been shown to be non-habit forming and to have
none of the lasting side effects of some earlier antidepressants
(Anderson, K. N., Anderson, L. E., & Glanze, W. D., 1998). As
such, the primary, and often only, listed therapeutic effect of
SSRI's for treatment of moderate to mild depression is listed in
many texts as simply: relief of the symptoms of depression
(Skidmore-Roth, L., 1997).
Secondary and adverse effects of SSRI's
SSRI's are known as second generation or atypical antidepressants
because users of the drug do not suffer from the sometimes harsh
side effects of their pharmaceutical predecessors (Karch, A.,
1992). Among those side effects reduced or eliminated by the
selective nature of these drugs are antihistaminergic and
anticholinergic outcomes (Anderson, K. N., Anderson, L. E., &
Glanze, W. D., 1998). However, as a rule, one should never take
any SSRI's with monoamine oxidase inhibitors due to the adverse
cardiac effects that may transpire (Long, P. W., 1998b); In fact,
there should be at least a two week separation between the
therapies when there is a transition from one to the other (D/ART,
1998). This is the point where the secondary effects of the four
common SSRI's part. Each is very individual. Following is a
presentation and discussion of the various side effects of Luvox,
Paxil, Prozac, and Zoloft.
Luvox
Seizures have rarely been reported during use of this drug,
however, caution should be used in those with a history of
seizure. Combination of Luvox with alcohol may increase the level
of psychomotor impairment. In spite of the controlled clinical
trials on this drug, not enough is known about its combination
with electroconvulsive therapy for it to be advised (Long, P. W.,
1998b).
Of the most commonly observed adverse effects associated with
Luvox are nausea, constipation, anorexia, diarrhea, dyspepsia,
somnolence, dry mouth, nervousness, insomnia, dizziness, tremor,
agitation, asthenia, and delayed ejaculation (Long, P. W., 1998b).
Per body system, other less frequent but still significant and
noteworthy are:
Nervous system: vertigo, abnormal thinking, anxiety, amnesia, and
further depression;
Cardiovascular: palpitations, syncope, tachycardia, postural
hypotension, and migraine;
Body as a whole: headache, abdominal pain, malaise, chills, and
chest pain;
Skin: increased sweating and pruritis;
Respiratory: dyspnea, pharyngitis, and rhinitis;
Special senses: taste perversion, tinnitus, amblyopia, abnormal
vision, and hyperacusis;
Musculoskeletal: myalgia, arthralgia, myasthenia, and tetany;
Metabolic: weight loss or gain and peripheral edema.
All of the above secondary physical effects were reported in at
least 1% of participants in early clinical trials (Long, P. W.,
1998b). Other sources reported an increase in frequency of
urination and painful menstruation as well (Anderson, K. N.,
Anderson, L. E., & Glanze, W. D., 1998).
Since early 1998, there have been over 300 reported cases of
overdose with Luvox. There were only 15 deaths from all of those
cases, and 14 of those were attributed to Luvox only in
combination with other drugs. It is recommended that immediate
treatment be initiated in case of overdose with therapy to include
administration of medicinal charcoal and having the stomach
pumped(Long, P. W., 1998b).
Paxil
While most effective with mild to moderate depression,
clinical trials have shown effectiveness for up to six months for
moderate to severe depressed clients. However, sixteen percent of
patients given Paxil stop treatment with this medication due to an
adverse experience (Long, P. W., 1998c). Adverse events leading
to patient requested discontinuation of treatment include
asthenia, headache, nausea, somnolence, insomnia, and abnormal
ejaculation. The most frequently reported secondary effects
(minimum of 1%) are nausea, somnolence, sweating, tremor,
asthenia, dizziness, dry mouth, insomnia, and male sexual
dysfunction (Long, P. W., 1998c). The citation of 1% occurrence
in clinical trials cannot be necessarily predictive of patient
outcome, but can provide the physician with a basis for estimating
drug or non-drug causes of adverse effects. Other reported
secondary effects attributed to antidepressant therapy with Paxil
are listed below by body system.
Body as a whole: malaise, pain
Cardiovascular: hypertension, syncope, tachycardia
Dermatologic: pruritis, acne, alopecia, ecchymosis
Metabolic: weight gain or loss
Musculoskeletal: arthralgia, traumatic fracture
Nervous system: CNS stimulation, concentration impaired,
depression, emotional lability, and vertigo
Respiratory: cough increased and rhinitis
Special senses: abnormality of accommodation, conjunctivitis, ear
and eye pain, mydriasis, otitis media
Overdoses with Paxil have occurred with as little as 850 mg
(usual daily does is 20mg), but recovery has been medically
uneventful. There were no ECG abnormalities, coma, or convulsion
if Paxil was the only drug taken (Long, P. W., 1998c).
Prozac
Use of this drug for treatment of depression for longer than
five or six weeks has not been explored in controlled studies, so
it is at the discretion of the physician to continue therapy(Long,
P. W., 1998a). During clinical trials four percent of subjects
discontinued treatment due to allergic reactions. These reactions
subsided easily either with termination of drug therapy or with
adjunctive use of antihistamines. 10-15% of patients experienced
increased anxiety, nervousness, and insomnia. Notable weight loss
also occurred in a significant number of patients and this can be
undesirable in those already underweight (Long, P. W., 1998a).
Overall, 15% of patients discontinue use of Prozac for any of the
following reasons: nervousness, anxiety, insomnia, nausea,
dizziness, asthenia, headaches, rash and pruritis. Emergence of
suicidal thoughts was reported in 1.2% of clients (Long, P. W.,
1998a). Other secondary effects related to the use of Prozac for
antidepressant treatment delineated by body system include:
Behavioral: abnormal dreams, drowsiness, fatigue, confusion
Autonomic: excessive sweating, urinary retention, vision
disturbances
Respiratory: bronchitis, rhinitis, excessive yawning
Hematologic: anemia, hemorrhage, lymphadenopathy
Dermatologic: acne, alopecia, dry skin, herpes simplex
Urogenital: painful menstruation, sexual dysfunction, urinary
tract infection, frequent micturation
Overdose resulting in death has only occurred in two people but it
was with 1800mg or more of Prozac in combination with other drugs.
Symptoms of overdose are limited to nausea and vomiting,
hypomania, and CNS excitation resulting in seizures (Long, P. W.,
1998a).
Zoloft
Zoloft is indicated to treat exacerbations of major
depressive episodes. Zoloft is not associated with any withdrawal
symptoms or drug seeking behaviors, but it is still suggested that
those with a history of drug misuse or abuse be monitored closely
(Sertraline, 1997).15% of patients in recent clinical trials
discontinued use of Zoloft due to the following symptoms:
agitation, insomnia, sexual dysfunction, somnolence, dizziness,
headache, tremor, anorexia, diarrhea, loose stools, nausea, and
fatigue (Sertraline, 1997). There have been no deaths reported
related to drug overdose of Zoloft taken alone (Sertraline, 1997).
Secondary or adverse effects associated with Zoloft therapy for
relief of depression are listed below by body system.
Autonomic: increased saliva and cold clammy skin
Cardiovascular: postural dizziness, dependent edema, syncope,
tachycardia
CNS and PNS: confusion, gait and coordination abnormalities,
migraine, and vertigo
Skin: acne, alopecia, rash, dry skin, and pruritis
Psychiatric: abnormal dreams, aggression, amnesia, apathy,
delusion, aggravated depression, suicide ideation, and teeth
grinding
Reproductive: dysmenorrhea, intermenstrual bleeding
Respiratory: bronchospasm and epistaxis
Special senses: vision disturbances, eye and ear pain,
conjunctivitis
Alternative therapies in the treatment of depression
Aside from traditional drug treatment, there are other
therapies available used to relieve the symptoms of depression.
Sometimes use is dictated by the severity or the illness (D/ART,
1998). These therapies include phototherapy, two types of talk
therapy, St. John's Wort, and electroconvulsive therapy (ECT).
Phototherapy exposes the patient to high luminous ultraviolet
light for a certain time period each day. This is believed to
help with serotonin levels for those who suffer depression
seasonally (D/ART, 1998). Usually people suffer during the winter
when there is little natural sunlight. Therapy must be done for a
certain amount of time each day and the eyes must be open. The
way it is believed to work is through the optic nerve channels,
although exact mechanisms have yet to be defined (Kozlak, 1998).
Phototherapy is used for seasonal disorders only and for those
with mild to moderate depression. Depressive symptoms are usually
relieved in a shirt amount of time which is an improvement over
the usual 4 week wait for drugs to be effective (Sargeant, M.,
1998).
Talk therapy is often used in conjunction with drug therapy.
In fact, this combination is 25% more effective than either
therapy alone, and serves to alleviate feelings of hopelessness
and loss of control until the medications can kick in (Sargeant,
M., 1998). Two commonly used approaches to talk therapy are
Interpersonal and Cognitive/Behavioral. Interpersonal therapists
focus on a patient's disturbed personal relationships that both
can cause and exacerbate depression. The verbal exchange between
the patient and therapist is believed to aid the patient in
finding insight into and resolutions to their problems (D/ART,
1998). Cognitive/Behavioral therapists attempt to change a
patient's negative styles of thinking and behaving that are known
to be associated with depression. They may also help a person
learn new behaviors that lead to more satisfaction in life and aid
cement the unlearning of the previous counter-productive behaviors
(Sargeant, 1998).
ECT while having a bad reputation in the past is certainly a
valid form of treatment for the severely depressed. It is viewed
as essential because of the immediate effects of the treatment.
Due to the immediacy of the relief of the depressive symptoms, ECT
is generally used for acute depressive episodes where patients are
gravely disabled, suicidal ideations are prominent, or there is
resistance to drug therapy. The electric current sent through a
patient is minimal and anticonvulsants are usually given before
treatment (leonard, B. E., 1992). Treatment is given twice weekly
over several weeks with a few shocks given at each session. The
main side effect is transient short term memory loss, but this can
be reduced by using unilateral ECT instead of bilateral. ECT
appears to affect GABA and 5-HT receptors (Leonard, B. E., 1992).
Another therapy controversial in the United States is the use
of St. John's Wort. It has been used for more than two thousand
years in Europe and is again gaining popularity there in the
treatment of mild to moderate depression (Bloomfield, H. H. &
McWilliams, P., 1996b). The active ingredient is hypericum, and
like the SSRI's, is believed to effect 5-HT. It also takes up to
four weeks to begin relief of symptoms, but is found to have fewer
side effects (Bloomfield, H. H. & McWilliams, P., 1996a). The
European clinical trials have been rejected by the NIH for lack of
controlled trials, but they are beginning their own studies and
expect conclusions to be published by late 1999 (NIHM, 1998).
Reference List
Bloomfield, H. H. & McWilliams, P. The side effects of hypericum.
Hypericum Homepage: 1996a. Available at
www.hypericum.com/hyp12.htm.
Bloomfield, H. H. & McWilliams, P. The treatment of depression.
Hypericum Homepage: 1996b. Available at
www.hypericum.com/hyp07.htm.
D/ART. Depression is more than the blues: Depression, what every
woman should know. National Institute of Mental Health: 1998.
Available at www.nimh.nih.gov/dart/wom_dep.htm.
Karch, A. M. Handbook of drugs and the nursing process. 2nd ed.
Lippincott. Philadelphia: 1992.
Kozlak, J. Course syllabus: Psychiatric nursing. Humboldt State
University. Arcata, CA: Spring 1998.
Leonard, B. E. Fundamentals of psychopharmacology. Wiley. New
York: 1992.
Long, P. W. Fluoxetine. Internet Mental Health: 1998a.
Available at www.mentalhealth.com/drug/.
Long, P. W. Fluvoxamine. Internet Mental Health: 1998b.
Available at www.mentalhealth.com/drug/.
Long, P. W. Paroxetine. Internet Mental Health: 1998c.
Available at www.mentalhealth.com/drug/.
NIHM. Questions and answers about the Hypericum Perforatum study.
National Institute of Mental Health: 1998. Available at
www.nimh.nih.gov/publicat/stjohnqa.htm.
Palfai, T. & Jankiewicz, H. Drugs and human behavior. 2nd ed.
Brown and Benchmark. Dubuque, IA: 1997.
Sargeant, M. Plain talk about...Depression. National Institutes
of Health: 1998. Available at www.nimh.gov/publicat/ptdep.htm.
Sertraline. Mosby, Inc.-Mosby GenRx: 1997. Available at
www.rxlist.com/cgi/generic/sertral/htm.
Skidmore-Roth, L. Mosby's drug guide for nurses. 2nd ed. Mosby.
St. Louis: 1997.
Ion Channels Affected by SSRIs
By Jeffery Craven
The neuron is encased by a boundary known as the membrane.
This membrane is made up of a double layer of lipid molecules; it
is this membrane that protects the cell and governs what goes in
and what goes out of the cell. One way in which specific
materials-ions-gain entrance into the cell is through ion
channels. Within the membrane are several different protein
molecules, which serve different purposes. Some of these detect
external substances and transmit information about them to the
interior of the cell. Other proteins regulate access to the
inside of the cell, permitting the entrance of some substances and
rejecting others. Other proteins actually act as a transporter of
substances into and out of the cell. It is this membrane upon
which the class of SSRIs might act in order to gain access into
the receptors of the terminal buttons and exhibit their effects.
There are several different types of ion channels which suggests
that signaling in the nervous system is quite varied and intricate
(Feldman, Jerrold, Quenzer, 1997).
The primary neurotransmitter receptors on which the SSRIs
work are serotonin, although norepinepherine does function in the
regulation of mood. Because serotonin is associated with several
different receptors, it is possible that the SSRIs work on several
different ion channels. Basic functioning implies that a
neurotransmitter binds to specific receptors located on the
membrane. The opening or closing of the ion channels that are
associated with this particular action follows this binding. The
opening or closing of the ion channels allows specific ions to
flow into or out of the cell, thus allowing the consequential
action to take place on the neuron.
Ions can be transported across the membrane in one of two
ways--either by diffusion along a concentration gradient through
water-filled pores or by actually being transported by carrier
proteins, a process called facilitation diffusion (Feldman, Meyer,
Quenzer, 1997). This facilitation diffusion works by an ion
binding to a protein located within the membrane, which has
charged or non-charged binding sites that are hydrophobic, and
able to interact and diffuse across the lipid membrane. This
protein essentially moves the ion from the extracellular fluid to
the intracellular fluid, where it then lets go. Ion transport
rates are much slower with the use of protein carriers as opposed
to channels.
Ion channels are made up of polypeptides that are soluble in
phospholipid membranes which come together to form specialized
proteins which cross the membrane around an aqueous pore. One
group of these types of channels is the gated channels. These are
channels that open or close as a result of electrical, mechanical,
or chemical actions upon them. Ultimately, the entrance of
particular ions into the membranes of neurons changes the membrane
potential which causes the onset of action potentials. One of
these gated channels is the ligand-gated channel. A ligand is a
molecule found in the extracellular fluid, which is a chemical
that attaches to a binding site. Ligands in their natural form
are neurotransmitters or hormones. Other chemicals found in
nature or synthetic products can serve as ligands as well
(Carlson, 1994). Another of these channels is the voltage-gated
channel, which opens or closes in response to changes in the
membrane potential. In this sense, if the resting potential of a
membrane goes from -70mV to -90mV, the channel will close and
restrict the flow of ions across the membrane. Mechanical-gated
channels open or close as a result of some mechanical force that
is caused by an interaction between the ion channel and the
cytoskeleton. Another ion channel that is more likely to be
affected by serotonin is the neurotransmitter dependent channel,
which opens in response to molecules of a neurotransmitter fitting
into the receptors on the postsynaptic membrane
Inhibitory and Excitatory Processes-
As the name of this class of drugs would suggest, it would
seem that their effects on the neurons, which they are specialized
for, would result in inhibitory effects. In fact, they do cause
inhibitory effects, but on the presynaptic as opposed to the
postsynaptic neuron. They inhibit the reuptake of serotonin.
Normally what occurs is a message, via a neurotransmitter, is sent
across the synapse, which connects the membrane of the terminal
buton of one neuron to another. One of these membranes is of the
presynaptic neuron from which the neurotransmitter is sent and the
other is the postsynaptic membrane, which accepts the message.
The postsynaptic membrane is said to have an action potential.
This means that the effect on that membrane, and hence, the
neuron, can be either excitatory or inhibitory.
An excitatory postsynaptic potential occurs as a result of
depolarization. This process takes place as a result of the
voltage of the postsynaptic neuron reaching its threshold. The
threshold is the level of voltage at which a large change in the
membrane potential, which may last for several milliseconds, can
be observed (Kaczmarek, Levitan, 1997). The threshold will vary
from neuron to neuron but seems to be constant in the range of
10mV-20mV depolarized from the negative resting potential of the
membrane, which is the charge of the membrane potential when the
axon of the neuron is not conducting nerve impulses. This resting
potential normally ranges from -40mV to -90mV. For the
postsynaptic neuron to become excited, the threshold must be
attained. One important property of this process is what is known
as the all or none law. This law governs, in a sense, the action
potential of the neuron and is used to describe the fact that
small depolarizations will not necessarily result in an action
potential. This also means to say that the if the size of a
stimulus is strong enough to cause an action potential, the
amplitude of the response is no longer representative of the
amplitude of the stimulus. The result is an all or none nerve
impulse; the nerve impulse either occurs or does not (Kaczmarek,
Levitan, 1997).
The movement of particular species of ions causes either
excitatory or inhibitory postsynaptic potentials across the
membrane of the neuron. This action occurs through the
stimulation of neurotransmitter-dependent ion channels
(Carlson,1994). The four major types of these channels are sodium
(Na+), potassium (K+), chloride(Cl-), and calcium (Ca2+). Most of
these ion-dependent channels are, in fact, stimulated by other
receptors called metabotropic receptors, which are aptly named as
they initiate a series of steps which causes the neuron to expend
stored energy. These receptors are located closely on the cell
membrane to G proteins, which play an important role in the
process. The process begins as a molecule of a neurotransmitter
binds with the appropriate receptor on the membrane. This binding
then stimulates the G protein. One subunit of the G protein, the
? subunit, breaks off and is what actually opens the ion channel
allowing in the ions that will cause some inhibitory or excitatory
potential in the neuron. There is a more complicated way, however
that the ion channels of a membrane can be opened, thus creating a
postsynaptic potential. This process involves the action of a
second messenger, which is a chemical located in the cytoplasm,
that is the result of the activation of an enzyme in the membrane
by the ? subunit of the G protein. Basically, it is the job of
this second messenger in this case, to open the appropriate ion
channel.
Excitatory postsynaptic potentials, or depolarization, are
most often caused by the action of neurotransmitter-dependent
sodium channel. Sodium is just one ion located mostly in the
extracellular fluid. Another is chloride. Potassium is one ion
that is located primarily in the intracellular fluid, while
organic anions are found only in the intracellular fluid. What
maintains the neuron's membrane potential is the fact that these
ions, whether positively or negatively charged, are kept in
balance according to the electrical charge of the intracellular
and extracellular fluids. The force of diffusion tends to
distribute molecules that are in areas of high concentration; this
would mean that diffusion would push ions that are highly
concentrated inside the cell out, and vice versa with ion that are
highly concentrated outside the cell. Along with diffusion is the
force of electrostatic pressure, which causes positive ions in a
positively charged environment and negatively charged ion in a
negatively charged environment to be pushed in the opposite
direction. For example, as diffusion would force positively
charged potassium ions outside the cell, the positively charged
extracellular fluid would push it back in.
The sodium-potassium pump is what causes the action
potential. This process is what causes the membrane potential to
change. The process begins with potassium inside the cell and
sodium outside. Sodium, in its high concentration is pushed
inside the cell and the electrostatic pressure with a positive
extracellular environment and negative intracellular environment
would force these ions inside as well. However the cell membrane
is very impermeable to sodium. Therefor, an influx of sodium into
the cell by way of open ion channels must occur. In this was, the
ion channels are stimulated in some way, and the rushing in of
sodium ion causes the membrane to change and possible initiate
hyperpolarization or a depolarization.
Effects Reported by Users-
The first thing to note about the effects reported by users
of this select group of drugs as well as any other psychotropic
drugs is that these individuals are the best references as to how
these drugs might make you feel. The second thing to note is that
not all individuals will experience the same effects. While one
person may call zoloft a miracle drug, another might call it an
evil drug. It is this that any individual who is about to begin
taking an antidepressant should consider. It is wise to get
several perspectives on any antidepressant in order to make a
personal decision as to what the expected benefits and side
effects might be. The Internet offers several chatrooms and
newsgroups whose main purpose is to allow individuals to share
experiences with different psychotropic drugs.
One prozac user reported that after the first few months on
prozac, she felt like Superman. Prozac enabled her to break the
mask, which limited her socially so that she could talk to people,
be witty with comebacks, and enjoy these moments. With prozac,
she was everything God had intended her to be-naturally happy.
She became full of life and was interested people. This was on a
20mg. dosage. A year and a half later, she took herself off
Prozac and began taking St. John's Wort. The effects did not
parallel those of prozac so she went back on the drug. She is now
at 40mg per day, seeing a therapist weekly, and wanting to be off
prozac; she does not want to rely on a drug to be happy and is
confident that one day she will not have to.
Others are in a different boat, having tried five different
antidepressants until stumbling upon one that worked. This isn't
a claim regarding a user's dependence or co-dependence, but may
say something about the desire to feel normal. A zoloft user
reported, "I have nothing but praise for zoloft. For me it has
reached the parts other anti-depressants have failed to reach."
Side effects in this user included bowel upsets at first as well
as a bit of mania, but nothing too drastic. It has also caused
fantastic dreams. Another zoloft user reports, "Zoloft has been a
life-saver for me. Only been on it for about six weeks, but its
effectiveness is like night-and day. The side effects were
worrisome at first, but worth the inconvenience." One person
noted that zoloft started working just a few days after starting
it and the effects were incredible. "It worked great for two
years and then just stopped working. A dosage increase didn't
help."
A user of paxil: "I took paxil for four weeks. Did nothing
to cure my social phobia still very paranoid, same anxieties, very
lethargic (at times, dizzy and lightheaded) and sometimes
nauseous." In response to this, another reported, "Paxil didn't
help me at all either," while one said that she is on paxil right
now and that it has given her her life back. Weight gain seems to
be somewhat common among paxil users.
Luvox users seem to experience somewhat common sleep
disturbances. One reported that, "I tried luvox for a couple
months but had to stop because I was so exhausted." Another said
that luvox is the most effective antidepressant the patient has
tried. Yet, it has caused drowsiness, although not that strong.
One report of luvox's overall effects, including side effects, by
one user was that the first week after taking luvox was scary.
The mind and heart were racing a lot. After three and a half
weeks, there was more calm, but sleeping had become problematic;
nicotine also hit a lot faster for this user. As for depression,
one person reported "Luvox made my depression and obsessive
compulsive disorder worse than they already were." Finally,
another stated that after four days, this user experienced a
racing heartbeat and panic attack-like symptoms. When the
pressure was on, such as driving, the user would begin to get very
upset.
Many users report, themselves, that drugs work differently
for everybody and that one cannot rely on the advice from only a
doctor. It might be important, in this case, to investigate the
experiences of others before diving into a relationship with an
antidepressant that might be very inaffective. This information
came from newsgroups on the World Wide and Web and is very
current.
References
Carlson, N.R. Physiology of Behavior. Needham Heights, MA:
Allyn and Bacon, 1994.
Feldman, R.S, Meyer, J.S., and Quenzer, L.F. Principle of
Neuroqsychopharmacolgy. Sunderland, Massachusettes:
Sinaur Associates, Inc., 1997.
Levitan, I.B. and L.K. Kazmarek. The Neuron. New York:
Oxford University Press, 1997.
Online (1998). Transport Across Cell Membranes. Available:
www.jkittredge.com/~jkimball/BiologyPages/D/Diffusion.html#direct [April 21,
1998].
Online (1998). Newsgroup: alt.support.depression.medication
[October 12, 1998].
Online (1998). Newsgroup: alt.support.anxiety-panic.
[October 12, 1998].
Online (1998). Newsgroup: alt.support.survivors.prozac.
[October 12, 1998].
Online (1998). Newsgroup: soc.support.depression.misc.
[October 12, 1998].
Online (1998). Newsgroup: alt. drugs.psychedelic.
[October 12, 1998].
Online (1998). Newsgroup: alt.support.mult-sclerosis.
[October 12, 1998].
Online (1998). Newsgroup: alt.support.ocd [October 12,
1998].
Return to the Project Table of Contents
Go back to the beginning
Copyright © 1995, Dr. John M. Morgan, All rights reserved -
This page last edited October 28, 1998
If you have any feedback for the author, E-mail me
