ACTIVATING CNS DRUGS: analeptics, antidepressants, metabolic cerebral protectors and adaptogens (Imisinum, Amitriptillinum, Pyrazidolum, Fluoxetinum, Sydnocarbum Coffeinum-natrii benzoas, Piracetamum, Cavintonum, Pentoxyphylline, Natrii oxybutiras, Cinarisinum, Vinpocetinum, Nicergolin, Pentoxiphyllini, papaverini hydrochloridum, Sermionum, Tinctura Ginseng, Tinctura Schisandrae, Extract Eleuterococci, Pantocrinum, Bemetilum, Cordiaminum, Sulfocamphocainum, Camphora, Bemegridum, Aethymisolum)

 

Activating CNS drugs: analeptics, antidepressants, metabolic cerebral protectors and adaptogens

The central nervous system (CNS) represents the largest part of the nervous system, including the brain and the spinal cord. Together with the peripheral nervous system, it has a fundamental role in the control of behavior. The CNS is contained within the dorsal cavity, with the brain within the cranial subcavity, and the spinal cord in the spinal cavity.

Since the strong theoretical influence of cybernetics in the fifties, the CNS is conceived as a system devoted to information processing, where an appropriate motor output is computed as a response to a sensory input. Yet, many threads of research suggest that motor activity exists well before the maturation of the sensory systems and then, that the senses only influence behavior without dictating it. This has brought the conception of the CNS as an autonomous system.

In the developing fetus, the CNS originates from the neural plate, a specialised region of the ectoderm, the most external of the three embryonic layers. During embryonic development, the neural plate folds and forms the neural tube. The internal cavity of the neural tube will give rise to the ventricular system. The regions of the neural tube will differentiate progressively into transversal systems. First, the whole neural tube will differentiate into its two major subdivisions: spinal cord (caudal) and brain (rostral/cephalic). Consecutively, the brain will differentiate into brainstem and prosencephalon. Later, the brainstem will subdivide into rhombencephalon and mesencephalon, and the prosencephalon into diencephalon and telencephalon.

The CNS is covered by the meninges, the brain is protected by the skull and the spinal cord by the vertebrae. The rhombencephalon gives rise to the pons, the cerebellum and the medulla oblongata, its cavity becomes the fourth ventricle. The mesencephalon gives rise to the tectum, pretectum, cerebral peduncle and its cavity develops into the mesencephalic duct or cerebral aqueduct. The diencephalon give rise to the subthalamus, hypothalamus, thalamus and epithalamus, its cavity to the third ventricle. Finally, the telencephalon gives rise to the striatum (caudate nucleus and putamen), the hippocampus and the neocortex, its cavity becomes the lateral (first and second) ventricles.

Neuroanatomy

The basic pattern of the CNS is highly conserved throughout the different species of vertebrates and during evolution. The major trend that can be observed is towards a progressive telencephalisation: while in the reptilian brain that region is only an appendix to the large olfactory bulb, it represent most of the volume of the mammalian CNS. In the human brain, the telencephalon covers most of the diencephalon and the mesencephalon. Indeed, the allometric study of brain size among different species shows a striking continuity from rats to whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts.

 

Therapy of Manic-Depressive Illness

Manic-depressive illness connotes a psychotic disorder of affect that occurs episodically without external cause. In endogenous depression (melancholia), mood is persistently low. Mania refers to the opposite condition. Patients may oscillate between these two extremes with interludes of normal mood. Depending on the type of disorder, mood swings may alternate between the two directions (bipolar depression, cyclothymia) or occur in only one direction (unipolar depression).

Proposed mechanism of action of selective serotonin/norepinephrine re-uptake inhibitor antidepressant drugs.

 

I. Endogenous Depression

In this condition, the patient experiences profound misery (beyond the observer’s empathy) and feelings of severe guilt because of imaginary misconduct. The drive to act or move is inhibited. In addition, there are disturbances mostly of a somatic nature (insomnia, loss of appetite, constipation, palpitations, loss of libido, impotence, etc.). Although the patient may have suicidal thoughts, psychomotor retardation prevents suicidal impulses from being carried out. In A, endogenous depression is illustrated by the layers of somber colors; psychomotor drive, symbolized by a sine oscillation, is strongly reduced. Therapeutic agents fall into two groups:

_       Thymoleptics, possessing a pronounced ability to re-elevate depressed mood e.g., the tricyclic antidepressants;

_       Thymeretics, having a predominant activating effect on psychomotor drive, e g., monoamine oxidase inhibitors.

It would be wrong to administer  drive-enhancing drugs, such as amphetamines,to a patient with endogenous depression. Because this therapy fails to elevate mood but removes psychomotor inhibition (A), the danger of suicide increases.

History: Imipramine is considered the prototype tricyclic antidepressant. The tricyclic antidepressants are chemically derived from a three-ring aromatic nucleus that has three forms: dibenzazepine (imipramine), dibenzocycloheptene (amitriptyline), or dibenzoxepin (doxepin).

Imipramine was first synthesized in the late 1940s and was approved for use for depression in 1959 and for enuresis in 1973. Recently, clomipramine was introduced, but it is indicated for treatment of obsessive-compulsive disorder, not depression. Since the introduction of the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (see Heterocyclic Antidepressants Overview), the use of tricyclic antidepressants has decreased. The SSRIs have a more well-tolerated adverse effect profile than the tricyclic type antidepressants in depression and obsessive-compulsive disorder. Fluoxetine, and presumably other serotonin-specific agents, appear to be inferior, however, to desipramine and other norepinephrine-active drugs in the treatment of diabetic neuropathy.

 

Tricyclic antidepressants (TCA; prototype: imipramine)

have had the longest and most extensive therapeutic use; however, in the past decade, they have been increasingly superseded by the serotonin-selective reuptake inhibitors (SSRI; prototype: fluoxetine). The central seven-membered ring of the TCAs imposes a 120° angle between the two flanking aromatic rings, in contradistinction to the flat ring system present in phenothiazine type neuroleptics. The side chain nitrogen is predominantly protonated at physiological pH. The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal reuptake of norepinephrine  and serotonin is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, б-adrenoceptors, and certain 5-HT and histamine (H1) receptors are blocked. Interference with the dopamine system is relatively minor. How interference with these transmitter/ modulator substances translates into an antidepressant effect is still hypothetical. The clinical effect emerges only after prolonged intake, i.e., 2–3 wk, as evidenced by an elevation of mood and drive. However, the alteration in monoamine metabolism occurs as soon as therapy is started. Conceivably, adaptive processes (such as downregulation of cortical serotonin and в-adrenoceptors) are ultimately responsible. In healthy subjects, the TCAs do not improve mood (no euphoria). Apart from the antidepressant effect, acute effects occur that are evident also in healthy individuals. These vary in degree among individual substances and thus provide a rationale for differentiated clinical use, based upon the divergent patterns of interference with amine transmitters/modulators.

Tricyclic Antidepressants (TCAs) for the Treatment of Neuropathic Pain

One of the mainstays in the treatment of painful neuropathies has been the use of tricyclic antidepressants. And tricyclic antidepressants are divided into 2 major groups: tertiary amines, drugs such as imipramine and amitriptyline and secondary amines, drugs such as nortriptyline and desipramine.

The [putative antineuralgic] mechanism of action of the tricyclic antidepressants (TCAs) is that they inhibit the reuptake of the biogenic amines, mostly norepinephrine (NE), as well as serotonin (5HT). I talked about the 2 important descending inhibitory pathways originating from the brainstem to the spinal cord with 5HTand NE being their major neurotransmitters. So, basically the tricyclic works by enhancing inhibition from the brainstem to the spinal cord.

The tertiary amines inhibit the reuptake of NE as well as 5HT, whereas the secondary amines are relatively selective NE reuptake inhibitors.

The tricyclic antidepressants were tested in a number of clinical trials in patients with painful diabetic neuropathy. This one was published by Mitchell Max in the New England Journal of Medicine back in 1982. It was a double-blind, placebo-controlled, cross-over, [trial] and it compared the efficacy of a tertiary amine, amitriptyline, to that of a secondary amine, desipramine, to a selective serotonin reuptake inhibitor (SSRI), fluoxetine. The doses that were used were pretty appropriate, about 100 mg each for amitriptyline and desipramine, and 40 mg for fluoxetine. And when the data was analyzed, it was found that while on amitriptyline, 74% of patients experienced moderate or significant pain relief compared to 61% while on desipramine and 48% while on fluoxetine. And if you saw that data alone without an internal control you might conclude that patients on [fluoxetine] did pretty well since approximately half of them had moderate or significant improvement in their pain.

It's only when you compare it to the placebo response that you realize that 41% of placebo-treated patients also had moderate or significant pain relief. And perhaps, the most important message of this particular trial, is the importance of placebo-controlled clinical trials in any condition, but especially in pain, because unless you have that internal control, you are not going to be able to [scientifically] judge the efficacy of a particular drug.

And actually, when the data was statistically analyzed, it was found that while on amitriptyline or desipramine patients [fared] significantly better compared to placebo. But there was no statistically significant difference between the fluoxetine and the placebo phase of the trial. Virtually every clinical trial that was done using TCAs in the treatment of painful diabetic neuropathy replicated these results in the sense that there is a statistical trend favoring the tertiary amine over the secondary amine, but it rarely reaches statistical significance. And the other important point is that the SSRIs are not effective for the treatment of neuropathic pain except in patients with depression and pain. But if the patient is not depressed, the SSRIs are virtually useless.

A Medline search looking at the clinical trials done with TCAs in post-herpetic neuralgia yielded those 5 clinical trials. Three of them were placebo-controlled. Two of them were comparative trials. All of them were single-center, cross-over trials [that] randomized a relatively small number of patients - between 15 and 32 patients. But again, the results were concordant and showed the efficacy of the tertiary amine, amitriptyline, compared to placebo as well as the secondary amine, desipramine, compared to placebo and the fact that amitriptyline was significantly more efficacious than zimelidine, another SSRI

Although the tricyclic antidepressants are very effective for the treatment of neuropathic pain, they can be associated with a number of side effects. Because of their antihistaminic properties they can lead to sedation. Obviously you can have the anticholinergic side effect, postural hypotension, which, especially in elderly patients, when coupled with the sedative side effects, can lead to significant falls. Arrhythmia in patients with cardiac disease, seizures in patients with epilepsy and weight gain.

Again, as a general rule the tertiary amines, amitriptyline and clomipramine, are associated with significantly more sedative and postural hypotension as compared to secondary amines, desipramine and nortriptyline. So, even though the tertiary amines are slightly more efficacious for the treatment of neuropathic pain, they do so at the expense of significantly more side effects. And you might want to take that into consideration in deciding on the drug of choice for a particular patient.

The [most important] point is the third bullet, the fact that the antineuralgic properties of the TCAs are independent from their antidepressant effects. And the way this was proven was by taking a cohort of patients who participated in those clinical trials, classifying them according to who was and who wasn't depressed at baseline. And showing that both groups had comparable efficacy in addition, of course, to the fact the doses that we tend to use for the treatment of neuropathic pain are much lower than what is [typically] needed for the treatment of depression.

 

Mechanism of action antidepressants

The precise mechanism of action of tricyclic antidepressants is not fully understood. It is believed that these drugs interfere with the reuptake of various neurotransmitters at the neuronal membrane. This results in a potentiation of the neurotransmitter at the post-synaptic receptor. Imipramine, a tertiary amine, inhibits the reuptake of serotonin more than do secondary amines, which inhibit primarily norepinephrine. Because imipramine is metabolized to a secondary amine (desipramine), however, classification of tricyclic antidepressants according to type of neurotransmitter affected is problematic.

 The mechanism of action of noradrenergic and specific serotonergic antidepressants (NaSSAs)

Depression is associated with reduced levels of monoamines in the brain. Noradrenergic and specific serotonergic antidepressants (NaSSAs), such as mirtazapine, have a dual mechanism of action that increases the concentration of 5-HT and noradrenaline in the synaptic cleft to within the normal range. NaSSAs bind to and inhibit both noradrenaline a2-autoreceptors and noradrenaline a2-heteroeceptors. This action prevents the negative feedback effect of synaptic noradrenaline on 5-HT and noradrenaline neurotransmission, and neurotransmission sustained. NaSSAs also block 5-HT2 and 5-HT3 receptors on the post-synaptic membrane, which causes enhanced 5-HT1 mediated neurotransmission.

Click the image to view high resolution version

The mechanism of action of tricyclic antidepressants (adverse effects)

Mood elevation secondary to antidepressant therapy occurs only in depressed individuals and may require 2-3 weeks of therapy. Adverse effects, however, can be seen within a few hours. The delayed antidepressant effect has led to reconsideration of the reuptake theory because blockade of neurotransmitter reuptake occurs much more rapidly than the clinical antidepressant effect. Improvement in the depressive state might result from the correction of an abnormal neurotransmitter-receptor relationship.

Amitriptyline exerts anxiolytic, sedative and psychomotor dampening effects. These are useful in depressive patients who are anxious and agitated.

Effect of Amitriptyline

In contrast, desipramine produces psychomotor activation. Imipramine occupies an intermediate position. It should be noted that, in the organism, biotransformation of imipramine leads to desipramine (N-desmethylimipramine). Likewise, the desmethyl derivative of amitriptyline (nortriptyline) is less dampening. In nondepressive patients whose complaints are of predominantly psychogenic origin, the anxiolytic-sedative effect may be useful in efforts to bring about a temporary “psychosomatic uncoupling.” In this connection, clinical use as “co-analgesics”  may be noted. The side effects of tricyclic antidepressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances.

 

The serotonin pathways in panic disorder

These effects develop acutely. Antagonism at muscarinic cholinoceptors leads to atropinelike effects such as tachycardia, inhibition of exocrine glands, constipation, impaired micturition, and blurred vision. Changes in adrenergic function are complex. Inhibition of neuronal catecholamine reuptake gives rise to superimposed indirect sympathomimetic stimulation. Patients are supersensitive to catecholamines (e.g., epinephrine in local anesthetic injections must be avoided). On the other hand, blockade of б1-receptors may lead to orthostatic hypotension. Due to their cationic amphiphilic nature, the TCA exert membrane-stabilizing effects that can lead to disturbances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appetite. Maprotiline, a tetracyclic compound, largely resembles tricyclic agents in terms of its pharmacological and clinical actions. Mianserine also possesses a tetracyclic structure, but differs insofar as it increases intrasynaptic concentrations of norepinephrine by blocking presynaptic б2-receptors, rather than reuptake.

Distinguishing Features: The tricyclic antidepressants can be differentiated by several features. The most important clinical distinction is based on the number of ligands bonded to the nitrogen on the "tail" attached to the tricyclic ring system: tertiary or secondary amines. The tertiary-amine tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, and trimipramine) tend to be more sedating and have greater anticholinergic effects. The secondary amines (desipramine and nortriptyline) are metabolites of the tertiary amines (imipramine and amitriptyline, respectively). The secondary-amine tricyclic antidepressants are generally better tolerated.

Besides major depression, the tricyclic antidepressants are useful in a number of other clinical conditions. Imipramine has been used for childhood enuresis, amitriptyline has been successful for short-term treatment of fibromyalgia, and protriptyline has been used as a respiratory stimulant in patients with chronic obstructive pulmonary disease. Amitriptyline, desipramine, doxepin and presumably other tricyclic antidepressants with activity on norepinephrine are effective agents for diabetic neuropathy. Tricyclic antidepressants have also been used in the management of neurogenic pain, attention-deficit hyperactivity disorder (ADHD) in children over age 6 (usually only after therapy with methylphenidate and pemoline fail), eating disorders, and panic or phobic disorder, although these are not FDA-approved uses.

The tricyclic antidepressants can also be differentiated based on the dosing and plasma concentration range: amitriptyline (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range 60-200 ng/mL); clomipramine (starting dose 25 mg TID, dosage range 50-300 mg/day); desipramine (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range 125-250 ng/mL); doxepin (starting dose 25 mg TID, dosage range 75-300 mg/day, therapeutic Cp range 110-250 ng/mL); imipramine (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range >180 ng/mL); nortriptyline (starting dose 25 mg TID, dosage range 50-200 mg/day, therapeutic Cp range 50-150 ng/mL); protriptyline (starting dose 5 mg TID, dosage range 15-60 mg/day, therapeutic Cp range 100-200 ng/mL); and trimipramine (starting dose 25 mg TID, dosage range 15-90 mg/day). Of all the tricyclic antidepressants, nortriptyline has the most well-studied relationship between response and plasma concentration. Tricyclic antidepressant plasma concentrations are always measured 12 hours after the evening dose and before any morning dose. If the drug has active metabolites, they are measured as well and added together.

Adverse Reactions: A wide variety of cardiovascular side effects can result from the use of tricyclic antidepressants because they exert a direct quinidine-like action, possess strong anticholinergic activity, and potentiate norepinephrine. Drowsiness is the most frequent central nervous system (CNS) adverse effect. The adverse effect of sedation may be used therapeutically by administering the tricyclic antidepressant at bedtime. Tremors can result from norepinephrine-reuptake blockade. Seizures and alterations in EEG patterns have been observed more commonly in children than in adults.

Ocular manifestations of the high anticholinergic activity of the tricyclic antidepressants can result in blurred vision due to loss of accommodation, mydriasis, and increased intraocular pressure. Increased intraocular pressure can precipitate a crisis in patients with angle-closure glaucoma. Gastrointestinal manifestations of these drugs' high anticholinergic activity include dry mouth (xerostomia), constipation, urinary retention, paralytic ileus, abdominal cramps, nausea, vomiting, anorexia, diarrhea, and jaundice.

The effects of tricyclics on the endocrine system can cause sexual dysfunction including libido changes, impotence, testicular swelling, painful ejaculation, breast engorgement and galactorrhea in females, and gynecomastia in males. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. Glucose metabolism can be altered and should be monitored in patients with diabetes mellitus.

Photosensitivity, rash, erythema, urticaria, fever, and pruritus are generally indicative of allergic reactions.

Proposed mechanism of action of selective serotonin re-uptake inhibitors (SSRI) and tricyclic antidepressant (TCA) drugs.

 Heterocyclic antidepressants

History

Before the 1950s, opioids and amphetamines were commonly used as antidepressants. Their use was later restricted due to their addictive nature and side-effects.^[6] Extracts from the herb St John's wort had been used as a "nerve tonic" to alleviate depression.^[7]

In 1951, Irving Selikoff and Edward Robitzek, working out of Sea View Hospital on Staten Island, began clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid and iproniazid. Only patients with a poor prognosis were initially treated; nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems."^[8] The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.

In 1952, learning of the stimulating side-effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two thirds of their patients and coined the term antidepressant to describe its action.^[9] A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his pulmonology colleagues at Cochin Hospital. In 1952, before Lurie and Salzer, Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients.^[10] For reasons unrelated to its efficacy, isoniazid as an antidepressant was soon overshadowed by the more toxic iproniazid,^[9] although it remains a mainstay of tuberculosis treatment. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of diamine oxidase, coupled with a weak inhibition of monoamine oxidase A.^[11]

Selikoff and Robitzek also experimented with another anti-tuberculosis, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity.^[12] Later, Jackson Smith, Gordon Kamman, George Crane, and Frank Ayd, described the psychiatric applications of iproniazid. Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor.^[13] Nevertheless, iproniazid remained relatively obscure until Nathan Kline, the influential and flamboyant head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a "psychic energizer".^[13][14] Roche put a significant marketing effort behind iproniazid, including promoting its off-label use for depression.^[13] Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.^[13]

The antidepressant effect of a tricyclic, a three ringed compound, was first discovered in 1957 by Roland Kuhn in a Swiss psychiatric hospital. Antihistamine derivatives were used to treat surgical shock and later as neuroleptics. Although in 1955 reserpine was shown to be more effective than placebo in alleviating anxious depression, neuroleptics were being developed as sedatives and antipsychotics.^{[medical citation needed]}

Attempting to improve the effectiveness of chlorpromazine, Kuhn, in conjunction with the Geigy Pharmaceutical Company, discovered that compound "G 22355", later renamed imipramine. Imipramine had a beneficial effect in patients with depression who showed mental and motor retardation. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955-56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.^[15]

Second generation antidepressants

Antidepressants became prescription drugs in the 1950s. It was estimated that no more than 50 to 100 individuals per million suffered from the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic in marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers,^[16] which were being marketed for different uses.^[17] Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.^[17][18]

By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect serotonin as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.^{[medical citation needed]}

Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was zimelidine in 1971, while the first released clinically was indalpine. Fluoxetine was approved for commercial use by the U.S. Food and Drug Administration (FDA) in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David Wong and others.^[19][20] SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects.^[21]

St John's wort fell out of favor in most countries through the 19th and 20th centuries, except in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis.^[22] It remains an over-the-counter drug (OTC) supplement in most countries. Research continues to investigate its active component hyperforin and to elucidate its mode of action.^[23][24]

Classes of antidepressants

See also: List of antidepressants

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors, SSRIs are thought to prevent the reuptake of serotonin (also known as 5-hydroxytryptamine, or 5-HT) by the presynaptic neuron, thus initially maintaining higher levels of 5-HT in the synapse. Like all anti-depressants their mechanism of action remains unknown.

SSRI antidepressants includes:

• Citalopram (Celexa)

• Escitalopram (Lexapro, Cipralex)

• Paroxetine (Paxil, Seroxat)

• Fluoxetine (Prozac)

• Fluvoxamine (Luvox)

• Sertraline (Zoloft, Lustral)

Norepinephrine reuptake inhibitors

Selective norepinephrine reuptake inhibitors (NRIs) inhibit the reuptake of norepinephrine. The NRIs include:

• Atomoxetine (Strattera) — only indicated in English-speaking countries at least as a treatment for Attention deficit hyperactivity disorder.

• Reboxetine (Edronax) — not licensed for use in the US or Canada; licensed in Australia, UK and various European countries.

• Viloxazine (Vivalan)

Noradrenergic and specific serotonergic antidepressants (NaSSA)

Noradrenergic and specific serotonergic antidepressants NaSSA antagonise the alpha-2 adrenoceptor auto- and hetero-receptors which regulate the release of serotonin, norepinephrine and dopamine while simultaneously antagonising certain (mostly) postsynaptic serotonin receptor subtypes such as the 5-HT_2A, 5-HT_2C and 5-HT₃ receptors. Examples include:

• Mianserin (Lumin, Tolvon) — not available in the US, used in some European countries and Australia.

• Mirtazapine (Remeron, Avanza, Zispin) — FDA approved in 1996. TGA approved in 2007.

Serotonin–norepinephrine reuptake inhibitors

Serotonin–norepinephrine reuptake inhibitors (SNRIs) inhibit reuptake of serotonin and norepinephrine. These include:

• Desvenlafaxine (Pristiq)

• Duloxetine (Cymbalta)

• Milnacipran (Ixel, Savella)

• Venlafaxine (Effexor)

• Levomilnacipran (Fetzima)

Serotonin antagonist and reuptake inhibitor/Serotonin modulator and stimulators

These two drug classes are very similar in pharmacology with the only difference being that serotonin modulators and stimulators also have partial/full agonist activity at certain serotonin receptors whereas serotonin antagonists and reuptake inhibitors have solely (direct; not taking into consideration indirect agonistic actions at other serotonin receptor subtypes) antagonistic actions at serotonin receptors (Although the reuptake inhibiting actions of these drugs could be considered to be indirectly agonistic at the serotonin receptor subtypes that are not antagonised by the drug in question). The Serotonin antagonist and reuptake inhibitors (SARIs) include:

• Etoperidone (Axiomin, Etonin)

• Nefazodone (Serzone, Nefadar)

• Trazodone (Desyrel)

Whereas serotonin modulator and stimulators (SMSs) include:

• Vilazodone (Viibryd). FDA approved in January 2011.

• Vortioxetine (Brintellix). FDA approved in September 2013.

Norepinephrine-dopamine reuptake inhibitors

Norepinephrine-dopamine reuptake inhibitors inhibit the neuronal reuptake of dopamine and norepinephrine.^[25] These include:

• Bupropion (Wellbutrin, Zyban)

Norepinephrine-dopamine disinhibitors/Melatonin agonists

Norepinephrine-dopamine disinhibitors (NDDIs) act by antagonizing the serotonin 5-HT_2C receptor, which normally acts to inhibit norepinephrine and dopamine release, thereby promoting outflow of these neurotransmitters. The only indisputable clinically-available member of this class is agomelatine which is also a melatonin receptor agonist.

• Agomelatine (Valdoxan, Melitor, Thymanax) — recently introduced (2010 into the Australian market)

Tricyclic antidepressants

Tricyclic antidepressants typically block the reuptake of norepinephrine and serotonin, although there are exceptions.

The tricyclics include:

Tertiary amine tricyclic antidepressants:

• Amitriptyline (Elavil, Endep)

• Amoxapine (Asendin) (Note: Amoxapine is in some texts referred to as a tetracyclic antidepressant, while others class it with the tertiary amine tricyclic antidepressants)

• Clomipramine (Anafranil)

• Doxepin (Adapin, Sinequan)

• Imipramine (Tofranil)

• Trimipramine (Surmontil)

Secondary amine tricyclic antidepressants

• Desipramine (Norpramin)

• Nortriptyline (Pamelor, Aventyl, Noritren)

• Protriptyline (Vivactil)

Selective serotonin reuptake enhancers:

• Tianeptine (Stablon, Coaxil, Tatinol)

Dopamine Reuptake Inhibitors:

• Amineptine (Survector)

Sigma agonists:

• Opipramol (Insidon, Pramolan, Ensidon, Oprimol)

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) inhibit the enzyme monoamine oxidase, which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine. There are two types with regard to the effect on the enzyme, the irreversible and the newer reversible inhibitors. As there are potentially fatal interactions between irreversible MAOIs and certain foods (particularly those containing tyramine), as well as certain drugs, classic irreversible MAOIs are rarely prescribed any more. However, this does not apply to Emsam, Emsam is the transdermal patch form of selegiline, which due to its bypassing of the stomach has a lesser propensity to induce such events.^[26] Reversible inhibitors such as moclobemide do not require dietary restrictions.^[27][28]

Irreversible monoamine oxidase inhibitors:

• Isocarboxazid (Marplan)

• Phenelzine (Nardil)

• Selegiline (Eldepryl, Emsam)

• Tranylcypromine (Parnate)

Reversible monoamine oxidase inhibitors:

• Moclobemide (Aurorix, Manerix)

• Pirlindole (Pirazidol)

The heterocyclic antidepressants are a chemically and pharmacologically diverse group of drugs. Many of the antidepressants in this category (e.g., amoxapine, maprotiline, and trazodone) are now considered third or fourth line agents. At this time, the most important subgroup of the heterocyclic antidepressants are the serotonin specific reuptake inhibitors (SSRIs) which have revolutionized the treatment of depression. Fluoxetine, released in 1987, is the prototype of the SSRIs. Fluoxetine has been used in the treatment of major depression, alcohol dependence, anorexia nervosa, borderline personality disorder, bulemia nervosa, eating disorders, obesity, obsessive-compulsive disorder, and panic disorder. Since then, sertraline (1991), paroxetine (1992), and fluvoxamine (1994) have been approved for use.

Mechanism of Action: The precise mechanism of action of antidepressants is not fully understood. It is thought these drugs interfere with the reuptake of various neurotransmitters at the neuronal membrane. The SSRIs are very specific in their ability to inhibit the reuptake of serotonin resulting in potentiation of the neurotransmitter at the post-synaptic receptor.

Mood-elevation occurs only in depressed individuals and may require 2-3 weeksof therapy. Adverse effects, however, may be seen within a few hours. The delayed antidepressant effect has led to reconsideration of the reuptake theory, since blockade of neurotransmitter reuptake occurs much more rapidly the a clinical antidepressant action. Improvement in the depressive state may result from the correction of an abnormal neurotransmitter-receptor relationship.

Distinguishing Features: All of the antidepressants have clinically indistinguishable efficacy, with the possible exception of trazodone. Trazodone may have significantly lower efficacy than other antidepressants, based on meta-analysis of double blind clinical trials.

The most important clinical distinction of the SSRIs from all other antidepressants is their very high specificity for blocking the reuptake of serotonin compared to their effects on other known neurotransmitters such as norepinephrine, acetylcholine, histamine, or dopamine. Fluoxetine has the longest half-life of all the SSRIs. Half-life values for paroxetine, sertraline, and newly-released fluvoxamine range 15-26 hours in patients without hepatic disease. None of these 3 antidepressants have active metabolites. Fluoxetine has an elimination T1/2 of 2-3 days and an active metabolite with an elimination T1/2 of 7-9 days.

Adverse Reactions: Nausea, vomiting, diarrhea, dyspepsia, and anorexia are the most commonly experienced adverse reactions. Nausea usually subsides after a few weeks therapy, but occasionally is severe enough to necessitate discontinuation of the drug, and occurs more frequently with SSRIs than with tricyclic antidepressant drugs or the other heterocyclic antidepressants. Fluvoxamine has been associated with a higher incidence of nausea (37%) than the other SSRI antidepressants, but this may have been due, in part, to excessively high initial dosages. Diarrhea, anorexia, xerostomia, and dyspepsia are also fairly common and may require medical attention if severe. Weight loss exceeding 5% of body weight has been reported in 10-15% of fluoxetine treated patients, mostly at higher doses. All of the gastrointestinal effects appear to be dose-related and respond in most patients to dosage reduction.

CNS side effects occur in a number of patients and include, anxiety, nervousness, insomnia, drowsiness, fatigue, dizziness, tremor, and headache. Among the SSRI antidepressants, fluvoxamine and paroxetine are more sedating while fluoxetine and sertraline are more excitatory. Headache is a commonly reported ADR. All effective antidepressants can cause a switch from depression to mania in predisposed individuals. Overdose or a pre-existing seizure disorder may cause a drug-induced seizure, particularly with bupropion. Extrapyramidal symptoms (dystonia, torticollis, and akathisia) have occurred in some patients, particularly with amoxapine. The possibility of tardive dyskinesia from amoxapine, limits its use to patients with psychotic depression. All antidepressants should be used with caution because of the possibility of suicidal ideation. Despite the widespread attention that fluoxetine has received, there is no evidence that one antidepressant has a higher potential for inducing patients to attempt suicide.

Hypoglycemia has been observed rarely in patients treated with SSRIs. Hyperglycemia has been observed following discontinuation of SSRIs. . Patients experience visual disturbance, including blurred vision in ~3% of cases. Sexual dysfunction (including delayed ejaculation or impotence in men, anorgasmia in women) have been reported in a significant number of patients, most commonly when sertraline is used. Rash and other dermatologic reactions can occur with any drug, however, this is most common with maprotiline.

 

Some commonly observed adverse effects of selective serotonin re-uptake inhibitors.

 

Pruritus and rash occur during the first few weeks of therapy in a small number of patients receiving heterocyclic antidepressants.

Overdoses of amoxapine are characterized by severe neurotoxicity, with seizures that are difficult to control. Overdoses of maprotiline also have a tendency to cause seizures as well as cardiotoxicity.

Overdoses of the other heterocyclic drugs appear to create only minor problems and can usually be managed with purely supportive measures. For example, in one recorded case even 11 g of nefazodone failed to cause serious injury.

Moreover, it has less pronounced atropine-like activity. Fluoxetine, along with sertraline, fluvoxamine, and paroxetine, belongs to the more recently developed group of SSRI. The clinical efficacy of SSRI is considered comparable to that of established antidepressants. Added advantages include: absence of cardiotoxicity, fewer autonomic nervous side effects, and relative safety with overdosage. Fluoxetine causes loss of appetite and weight reduction. Its main adverse effects include: overarousal, insomnia, tremor, akathisia, anxiety, and disturbances of sexual function.

Moclobemide is a new representative of the group of MAO inhibitors. Inhibition of intraneuronal degradation of serotonin and norepinephrine causes an increase in extracellular amine levels.

A psychomotor stimulant thymeretic action is the predominant feature of MAO inhibitors. An older member of this group, tranylcypromine, causes irreversible inhibition of the two isozymes MAOA and MAOB.

Therefore, presystemic elimination in the liver of biogenic amines, such as tyramine, which are ingested in food (e.g., aged cheese and Chianti), will be impaired.

To avoid the danger of a hypertensive crisis, therapy with tranylcypromine or other nonselective MAO inhibitors calls for stringent dietary rules. With moclobemide, this hazard is much reduced because it inactivates only MAOA and does so in a reversible manner.

II. Mania

The manic phase is characterized by exaggerated elation, flight of ideas, and a pathologically increased psychomotor drive. This is symbolically illustrated in A by a disjointed structure and aggressive color tones. The patients are overconfident, continuously active, show  progressive incoherence of thought and loosening of associations, and act irresponsibly (financially, sexually etc.).

Lithium ions

 Lithium salts (e.g., acetate, carbonate) are effective in controlling the manic phase. The effect becomes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li+ serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting morning blood samples. At higher values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin leads to polyuria and thirst. Thyroid function is impaired, with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemically, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and potassium. Apart from interference with transmembrane cation fluxes (via ion  channels and pumps), a lithium effect of major significance appears to be membrane depletion of phosphatidylinositol  bisphosphates, the principal lipid substrate used by various receptors in transmembrane signalling. Blockade of this important signal transduction pathway leads to impaired ability of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal transduction initiated by formation of the agonist-  receptor complex. Rapid control of an acute attack of mania may require the use of a neuroleptic.

Alternate treatments. Mood-stabilization and control of manic or hypomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively.

 III. Prophylaxis With continued treatment for 6 to 12 months, lithium salts prevent the recurrence of either manic or depressive states, effectively stabilizing mood at a

normal level.

 

 

Preparations Available

Tricyclics

Amitriptyline (generic, Elavil, others)

Oral: 10, 25, 50, 75, 100, 150 mg tablets

Parenteral: 10 mg/mL for IM injection

Clomipramine (generic, Anafranil; labeled only for obsessive-compulsive disorder)

Oral: 25, 50, 75 mg capsules

Desipramine (generic, Norpramin, Pertofrane)

Oral: 10, 25, 50, 75, 100, 150 mg tablets

Doxepin (generic, Sinequan, others)

Oral: 10, 25, 50, 75, 100, 150 mg capsules; 10 mg/mL concentrate

Imipramine (generic, Tofranil, others)

Oral: 10, 25, 50 mg tablets (as hydrochloride); 75, 100, 125, 150 mg capsules (as pamoate)

Parenteral: 25 mg/2 mL for IM injection

Nortriptyline (generic, Aventyl, Pamelor)

Oral: 10, 25, 50, 75 mg capsules; 10 mg/5 mL solution

Protriptyline (generic, Vivactil)

Oral: 5, 10 mg tablets

Trimipramine (Surmontil)

Oral: 25, 50, 100 mg capsules

Second- & Third-Generation Drugs

Amoxapine (generic, Asendin)

Oral: 25, 50, 100, 150 mg tablets

Bupropion (generic, Wellbutrin)

Oral: 75, 100 mg tablets; 100, 150 mg sustained-release tablets

Maprotiline (generic, Ludiomil)

Oral: 25, 50, 75 mg tablets

Mirtazapine (Remeron)

Oral: 15, 30, 45 mg tablets

Nefazodone (Serzone)

Oral: 50, 100, 150, 200, 250 mg tablets

Trazodone (generic, Desyrel)

Oral: 50, 100, 150, 300 mg tablets

Venlafaxine (Effexor)

Oral: 25, 37.5, 50, 75, 100 mg tablets; 37.5, 75, 150 mg extended-release tablets

Selective Serotonin Reuptake Inhibitors

Citalopram (Celexa)

Oral: 20, 40 mg tablets

Escitalopram (Lexapro)

Oral: 5, 10, 20 mg tablets

Fluoxetine (generic, Prozac)

Oral: 10, 20 mg pulvules; 10 mg tablets; 20 mg/5 mL liquid

Oral delayed release (Prozac Weekly): 90 mg capsules

Fluvoxamine (Luvox, labeled only for obsessive- compulsive disorder)

Oral: 25, 50, 100 mg tablets

Paroxetine (Paxil)

Oral: 10, 20, 30, 40 mg tablets; 10 mg/5 mL suspension; 12.5, 25, 37.5 mg controlled-release tablets

Sertraline (Zoloft)

Oral: 25, 50, 100 mg tablets

Monoamine Oxidase Inhibitors

Phenelzine (Nardil)

Oral: 15 mg tablets

Tranylcypromine (Parnate)

Oral: 10 mg tablets

Other

Atomoxetine (Strattera)

Oral: 10, 18, 25, 40, 60 mg capsules

Proposed mechanism of action of selective serotonin/norepinephrine re-uptake inhibitor antidepressant drugs.

 

Activating CNS drugs: analeptics, antidepressants, metabolic cerebral protectors and adaptogens

The central nervous system (CNS) represents the largest part of the nervous system, including the brain and the spinal cord. Together with the peripheral nervous system, it has a fundamental role in the control of behavior. The CNS is contained within the dorsal cavity, with the brain within the cranial subcavity, and the spinal cord in the spinal cavity.

Since the strong theoretical influence of cybernetics in the fifties, the CNS is conceived as a system devoted to information processing, where an appropriate motor output is computed as a response to a sensory input. Yet, many threads of research suggest that motor activity exists well before the maturation of the sensory systems and then, that the senses only influence behavior without dictating it. This has brought the conception of the CNS as an autonomous system.
See main article on Brain Function

In the developing fetus, the CNS originates from the neural plate, a specialised region of the ectoderm, the most external of the three embryonic layers. During embryonic development, the neural plate folds and forms the neural tube. The internal cavity of the neural tube will give rise to the ventricular system. The regions of the neural tube will differentiate progressively into transversal systems. First, the whole neural tube will differentiate into its two major subdivisions: spinal cord (caudal) and brain (rostral/cephalic). Consecutively, the brain will differentiate into brainstem and prosencephalon. Later, the brainstem will subdivide into rhombencephalon and mesencephalon, and the prosencephalon into diencephalon and telencephalon.See main article on Neural development

The CNS is covered by the meninges, the brain is protected by the skull and the spinal cord by the vertebrae. The rhombencephalon gives rise to the pons, the cerebellum and the medulla oblongata, its cavity becomes the fourth ventricle. The mesencephalon gives rise to the tectum, pretectum, cerebral peduncle and its cavity develops into the mesencephalic duct or cerebral aqueduct. The diencephalon give rise to the subthalamus, hypothalamus, thalamus and epithalamus, its cavity to the third ventricle. Finally, the telencephalon gives rise to the striatum (caudate nucleus and putamen), the hippocampus and the neocortex, its cavity becomes the lateral (first and second) ventricles.

See main article on Neuroanatomy

The basic pattern of the CNS is highly conserved throughout the different species of vertebrates and during evolution. The major trend that can be observed is towards a progressive telencephalisation: while in the reptilian brain that region is only an appendix to the large olfactory bulb, it represent most of the volume of the mammalian CNS. In the human brain, the telencephalon covers most of the diencephalon and the mesencephalon. Indeed, the allometric study of brain size among different species shows a striking continuity from rats to whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts.

In the developing fetus, the CNS originates from the neural plate, a specialised region of the ectoderm, the most external of the three embryonic layers. During embryonic development, the neural plate folds and forms the neural tube. The internal cavity of the neural tube will give rise to the ventricular system. The regions of the neural tube will differentiate progressively into transversal systems. First, the whole neural tube will differentiate into its two major subdivisions: spinal cord (caudal) and brain (rostral/cephalic). Consecutively, the brain will differentiate into brainstem and prosencephalon. Later, the brainstem will subdivide into rhombencephalon and mesencephalon, and the prosencephalon into diencephalon and telencephalon.

The CNS is covered by the meninges, the brain is protected by the skull and the spinal cord by the vertebrae. The rhombencephalon gives rise to the pons, the cerebellum and the medulla oblongata, its cavity becomes the fourth ventricle. The mesencephalon gives rise to the tectum, pretectum, cerebral peduncle and its cavity develops into the mesencephalic duct or cerebral aqueduct. The diencephalon give rise to the subthalamus, hypothalamus, thalamus and epithalamus, its cavity to the third ventricle. Finally, the telencephalon gives rise to the striatum (caudate nucleus and putamen), the hippocampus and the neocortex, its cavity becomes the lateral (first and second) ventricles.

Neuroanatomy

The basic pattern of the CNS is highly conserved throughout the different species of vertebrates and during evolution. The major trend that can be observed is towards a progressive telencephalisation: while in the reptilian brain that region is only an appendix to the large olfactory bulb, it represent most of the volume of the mammalian CNS. In the human brain, the telencephalon covers most of the diencephalon and the mesencephalon. Indeed, the allometric study of brain size among different species shows a striking continuity from rats to whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts.

 

Therapy of Manic-Depressive Illness

Manic-depressive illness connotes a psychotic disorder of affect that occurs episodically without external cause. In endogenous depression (melancholia), mood is persistently low. Mania refers to the opposite condition. Patients may oscillate between these two extremes with interludes of normal mood. Depending on the type of disorder, mood swings may alternate between the two directions (bipolar depression, cyclothymia) or occur in only one direction (unipolar depression).

I. Endogenous Depression

In this condition, the patient experiences profound misery (beyond the observer’s empathy) and feelings of severe guilt because of imaginary misconduct. The drive to act or move is inhibited. In addition, there are disturbances mostly of a somatic nature (insomnia, loss of appetite, constipation, palpitations, loss of libido, impotence, etc.). Although the patient may have suicidal thoughts, psychomotor retardation prevents suicidal impulses from being carried out. In A, endogenous depression is illustrated by the layers of somber colors; psychomotor drive, symbolized by a sine oscillation, is strongly reduced. Therapeutic agents fall into two groups:

_ Thymoleptics, possessing a pronounced ability to re-elevate depressed mood e.g., the tricyclic antidepressants;

_ Thymeretics, having a predominant  activating effect on psychomotor drive, e g., monoamine oxidase inhibitors.

It would be wrong to administer  drive-enhancing drugs, such as amphetamines,to a patient with endogenous depression. Because this therapy fails to elevate mood but removes psychomotor inhibition (A), the danger of suicide increases.

History: Imipramine is considered the prototype tricyclic antidepressant. The tricyclic antidepressants are chemically derived from a three-ring aromatic nucleus that has three forms: dibenzazepine (imipramine), dibenzocycloheptene (amitriptyline), or dibenzoxepin (doxepin).

Imipramine was first synthesized in the late 1940s and was approved for use for depression in 1959 and for enuresis in 1973. Recently, clomipramine was introduced, but it is indicated for treatment of obsessive-compulsive disorder, not depression. Since the introduction of the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (see Heterocyclic Antidepressants Overview), the use of tricyclic antidepressants has decreased. The SSRIs have a more well-tolerated adverse effect profile than the tricyclic type antidepressants in depression and obsessive-compulsive disorder. Fluoxetine, and presumably other serotonin-specific agents, appear to be inferior, however, to desipramine and other norepinephrine-active drugs in the treatment of diabetic neuropathy.

 

Tricyclic antidepressants (TCA; prototype: imipramine)

 

have had the longest and most extensive therapeutic use; however, in the past decade, they have been increasingly superseded by the serotonin-selective reuptake inhibitors (SSRI; prototype: fluoxetine). The central seven-membered ring of the TCAs imposes a 120° angle between the two flanking aromatic rings, in contradistinction to the flat ring system present in phenothiazine type neuroleptics. The side chain nitrogen is predominantly protonated at physiological pH. The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal reuptake of norepinephrine  and serotonin is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, б-adrenoceptors, and certain 5-HT and histamine (H1) receptors are blocked. Interference  with the dopamine system is relatively minor. How interference with these transmitter/ modulator substances translates into an antidepressant effect is still hypothetical. The clinical effect emerges only after prolonged intake, i.e., 2–3 wk, as evidenced by an elevation of mood and drive. However, the alteration in monoamine metabolism occurs as soon as therapy is started. Conceivably, adaptive processes (such as downregulation of cortical serotonin and в-adrenoceptors) are ultimately responsible. In healthy subjects, the TCAs do not improve mood (no euphoria). Apart from the antidepressant effect, acute effects occur that are evident also in healthy individuals. These vary in degree among individual substances and thus provide a rationale for differentiated clinical use, based upon the divergent patterns of interference with amine transmitters/modulators.

 

Mechanism of action antidepressants

The precise mechanism of action of tricyclic antidepressants is not fully understood. It is believed that these drugs interfere with the reuptake of various neurotransmitters at the neuronal membrane. This results in a potentiation of the neurotransmitter at the post-synaptic receptor. Imipramine, a tertiary amine, inhibits the reuptake of serotonin more than do secondary amines, which inhibit primarily norepinephrine. Because imipramine is metabolized to a secondary amine (desipramine), however, classification of tricyclic antidepressants according to type of neurotransmitter affected is problematic.

 

The mechanism of action of tricyclic antidepressants (adverse effects)

 

Mood elevation secondary to antidepressant therapy occurs only in depressed individuals and may require 2-3 weeks of therapy. Adverse effects, however, can be seen within a few hours. The delayed antidepressant effect has led to reconsideration of the reuptake theory because blockade of neurotransmitter reuptake occurs much more rapidly than the clinical antidepressant effect. Improvement in the depressive state might result from the correction of an abnormal neurotransmitter-receptor relationship.

 

Amitriptyline exerts anxiolytic, sedative and psychomotor dampening effects. These are useful in depressive patients who are anxious and agitated.

Effect of Amitriptyline

In contrast, desipramine produces psychomotor activation. Imipramine occupies an intermediate position. It should be noted that, in the organism, biotransformation of imipramine leads to desipramine (N-desmethylimipramine). Likewise, the desmethyl derivative of amitriptyline (nortriptyline) is less dampening. In nondepressive patients whose complaints are of predominantly psychogenic origin, the anxiolytic-sedative effect may be useful in efforts to bring about a temporary “psychosomatic uncoupling.” In this connection, clinical use as “co-analgesics”  may be noted. The side effects of tricyclic antidepressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances.

 

The serotonin pathways in panic disorder

 

These effects develop acutely. Antagonism at muscarinic cholinoceptors leads to atropinelike effects such as tachycardia, inhibition of exocrine glands, constipation, impaired micturition, and blurred vision. Changes in adrenergic function are complex. Inhibition of neuronal catecholamine reuptake gives rise to superimposed indirect sympathomimetic stimulation. Patients are supersensitive to catecholamines (e.g., epinephrine in local anesthetic injections must be avoided). On the other hand, blockade of б1-receptors may lead to orthostatic hypotension. Due to their cationic amphiphilic nature, the TCA exert membrane-stabilizing effects that can lead to disturbances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appetite. Maprotiline, a tetracyclic compound, largely resembles tricyclic agents in terms of its pharmacological and clinical actions. Mianserine also possesses a tetracyclic structure, but differs insofar as it increases intrasynaptic concentrations of norepinephrine by blocking presynaptic б2-receptors, rather than reuptake.

Distinguishing Features: The tricyclic antidepressants can be differentiated by several features. The most important clinical distinction is based on the number of ligands bonded to the nitrogen on the "tail" attached to the tricyclic ring system: tertiary or secondary amines. The tertiary-amine tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, and trimipramine) tend to be more sedating and have greater anticholinergic effects. The secondary amines (desipramine and nortriptyline) are metabolites of the tertiary amines (imipramine and amitriptyline, respectively). The secondary-amine tricyclic antidepressants are generally better tolerated.

Besides major depression, the tricyclic antidepressants are useful in a number of other clinical conditions. Imipramine has been used for childhood enuresis, amitriptyline has been successful for short-term treatment of fibromyalgia, and protriptyline has been used as a respiratory stimulant in patients with chronic obstructive pulmonary disease. Amitriptyline, desipramine, doxepin and presumably other tricyclic antidepressants with activity on norepinephrine are effective agents for diabetic neuropathy. Tricyclic antidepressants have also been used in the management of neurogenic pain, attention-deficit hyperactivity disorder (ADHD) in children over age 6 (usually only after therapy with methylphenidate and pemoline fail), eating disorders, and panic or phobic disorder, although these are not FDA-approved uses.

 

The tricyclic antidepressants can also be differentiated based on the dosing and plasma concentration range: amitriptyline (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range 60-200 ng/mL); clomipramine (starting dose 25 mg TID, dosage range 50-300 mg/day); desipramine (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range 125-250 ng/mL); doxepin (starting dose 25 mg TID, dosage range 75-300 mg/day, therapeutic Cp range 110-250 ng/mL); imipramine (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range >180 ng/mL); nortriptyline (starting dose 25 mg TID, dosage range 50-200 mg/day, therapeutic Cp range 50-150 ng/mL); protriptyline (starting dose 5 mg TID, dosage range 15-60 mg/day, therapeutic Cp range 100-200 ng/mL); and trimipramine (starting dose 25 mg TID, dosage range 15-90 mg/day). Of all the tricyclic antidepressants, nortriptyline has the most well-studied relationship between response and plasma concentration. Tricyclic antidepressant plasma concentrations are always measured 12 hours after the evening dose and before any morning dose. If the drug has active metabolites, they are measured as well and added together.

Adverse Reactions: A wide variety of cardiovascular side effects can result from the use of tricyclic antidepressants because they exert a direct quinidine-like action, possess strong anticholinergic activity, and potentiate norepinephrine. Drowsiness is the most frequent central nervous system (CNS) adverse effect. The adverse effect of sedation may be used therapeutically by administering the tricyclic antidepressant at bedtime. Tremors can result from norepinephrine-reuptake blockade. Seizures and alterations in EEG patterns have been observed more commonly in children than in adults.

Ocular manifestations of the high anticholinergic activity of the tricyclic antidepressants can result in blurred vision due to loss of accommodation, mydriasis, and increased intraocular pressure. Increased intraocular pressure can precipitate a crisis in patients with angle-closure glaucoma. Gastrointestinal manifestations of these drugs' high anticholinergic activity include dry mouth (xerostomia), constipation, urinary retention, paralytic ileus, abdominal cramps, nausea, vomiting, anorexia, diarrhea, and jaundice.

The effects of tricyclics on the endocrine system can cause sexual dysfunction including libido changes, impotence, testicular swelling, painful ejaculation, breast engorgement and galactorrhea in females, and gynecomastia in males. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. Glucose metabolism can be altered and should be monitored in patients with diabetes mellitus.

Photosensitivity, rash, erythema, urticaria, fever, and pruritus are generally indicative of allergic reactions.

Heterocyclic antidepressants

History: The heterocyclic antidepressants are a chemically and pharmacologically diverse group of drugs. Many of the antidepressants in this category (e.g., amoxapine, maprotiline, and trazodone) are now considered third or fourth line agents. At this time, the most important subgroup of the heterocyclic antidepressants are the serotonin specific reuptake inhibitors (SSRIs) which have revolutionized the treatment of depression. Fluoxetine, released in 1987, is the prototype of the SSRIs. Fluoxetine has been used in the treatment of major depression, alcohol dependence, anorexia nervosa, borderline personality disorder, bulemia nervosa, eating disorders, obesity, obsessive-compulsive disorder, and panic disorder. Since then, sertraline (1991), paroxetine (1992), and fluvoxamine (1994) have been approved for use.

Mechanism of Action: The precise mechanism of action of antidepressants is not fully understood. It is thought these drugs interfere with the reuptake of various neurotransmitters at the neuronal membrane. The SSRIs are very specific in their ability to inhibit the reuptake of serotonin resulting in potentiation of the neurotransmitter at the post-synaptic receptor.

 

Mood-elevation occurs only in depressed individuals and may require 2-3 weeksof therapy. Adverse effects, however, may be seen within a few hours. The delayed antidepressant effect has led to reconsideration of the reuptake theory, since blockade of neurotransmitter reuptake occurs much more rapidly the a clinical antidepressant action. Improvement in the depressive state may result from the correction of an abnormal neurotransmitter-receptor relationship.

Distinguishing Features: All of the antidepressants have clinically indistinguishable efficacy, with the possible exception of trazodone. Trazodone may have significantly lower efficacy than other antidepressants, based on meta-analysis of double blind clinical trials.

The most important clinical distinction of the SSRIs from all other antidepressants is their very high specificity for blocking the reuptake of serotonin compared to their effects on other known neurotransmitters such as norepinephrine, acetylcholine, histamine, or dopamine. Fluoxetine has the longest half-life of all the SSRIs. Half-life values for paroxetine, sertraline, and newly-released fluvoxamine range 15-26 hours in patients without hepatic disease. None of these 3 antidepressants have active metabolites. Fluoxetine has an elimination T1/2 of 2-3 days and an active metabolite with an elimination T1/2 of 7-9 days.

Adverse Reactions: Nausea, vomiting, diarrhea, dyspepsia, and anorexia are the most commonly experienced adverse reactions. Nausea usually subsides after a few weeks therapy, but occasionally is severe enough to necessitate discontinuation of the drug, and occurs more frequently with SSRIs than with tricyclic antidepressant drugs or the other heterocyclic antidepressants. Fluvoxamine has been associated with a higher incidence of nausea (37%) than the other SSRI antidepressants, but this may have been due, in part, to excessively high initial dosages. Diarrhea, anorexia, xerostomia, and dyspepsia are also fairly common and may require medical attention if severe. Weight loss exceeding 5% of body weight has been reported in 10-15% of fluoxetine treated patients, mostly at higher doses. All of the gastrointestinal effects appear to be dose-related and respond in most patients to dosage reduction.

CNS side effects occur in a number of patients and include, anxiety, nervousness, insomnia, drowsiness, fatigue, dizziness, tremor, and headache. Among the SSRI antidepressants, fluvoxamine and paroxetine are more sedating while fluoxetine and sertraline are more excitatory. Headache is a commonly reported ADR. All effective antidepressants can cause a switch from depression to mania in predisposed individuals. Overdose or a pre-existing seizure disorder may cause a drug-induced seizure, particularly with bupropion. Extrapyramidal symptoms (dystonia, torticollis, and akathisia) have occurred in some patients, particularly with amoxapine. The possibility of tardive dyskinesia from amoxapine, limits its use to patients with psychotic depression. All antidepressants should be used with caution because of the possibility of suicidal ideation. Despite the widespread attention that fluoxetine has received, there is no evidence that one antidepressant has a higher potential for inducing patients to attempt suicide.

Hypoglycemia has been observed rarely in patients treated with SSRIs. Hyperglycemia has been observed following discontinuation of SSRIs. . Patients experience visual disturbance, including blurred vision in ~3% of cases. Sexual dysfunction (including delayed ejaculation or impotence in men, anorgasmia in women) have been reported in a significant number of patients, most commonly when sertraline is used. Rash and other dermatologic reactions can occur with any drug, however, this is most common with maprotiline.

Pruritus and rash occur during the first few weeks of therapy in a small number of patients receiving heterocyclic antidepressants.

Overdoses of amoxapine are characterized by severe neurotoxicity, with seizures that are difficult to control. Overdoses of maprotiline also have a tendency to cause seizures as well as cardiotoxicity.

Overdoses of the other heterocyclic drugs appear to create only minor problems and can usually be managed with purely supportive measures. For example, in one recorded case even 11 g of nefazodone failed to cause serious injury.

Moreover, it has less pronounced atropine-like activity. Fluoxetine, along with sertraline, fluvoxamine, and paroxetine, belongs to the more recently developed group of SSRI. The clinical efficacy of SSRI is considered comparable to that of established antidepressants. Added advantages include: absence of cardiotoxicity, fewer autonomic nervous side effects, and relative safety with overdosage. Fluoxetine causes loss of appetite and weight reduction. Its main adverse effects include: overarousal, insomnia, tremor, akathisia, anxiety, and disturbances of sexual function.

 

Moclobemide is a new representative of the group of MAO inhibitors. Inhibition of intraneuronal degradation of serotonin and norepinephrine causes an increase in extracellular amine levels.

 

A psychomotor stimulant thymeretic action is the predominant feature of MAO inhibitors. An older member of this group, tranylcypromine, causes irreversible inhibition of the two isozymes MAOA and MAOB.

 

Therefore, presystemic elimination in the liver of biogenic amines, such as tyramine, which are ingested in food (e.g., aged cheese and Chianti), will be impaired.

 

To avoid the danger of a hypertensive crisis, therapy with tranylcypromine or other nonselective MAO inhibitors calls for stringent dietary rules. With moclobemide, this hazard is much reduced because it inactivates only MAOA and does so in a reversible manner.

 

 

 Two types of depressive mood disorders (bipolar and unipolar) and their drug treatments.

Depression and Mania
Clinical depression is a syndrome that may include:  sustained mood disturbances  impaired memory and concentration  disturbed sleep  reduced energy level  reduced libido  impaired sleep.	Patient complaints suggestive of depression may include:  Pain (headaches, body aches)  A mood of apathy, anxiety, or irritability  Sexual complaints  low energy, excessive tiredness  reduced capacity for enjoyment.

 

Drug Treatment for clinical depression--Second generation drugs are preferred and include:

selective serotonin reuptake inhibitors (SSRIs)

trazodone (Desyrel)

bupropion (Wellbutrin)

venlafaxine (Effexor)

nefazodone (Serzone)

 

Definitive diagnosis of depression references the American Psychiatric Association Criteria for Diagnosis of Major Depression:

At least five of the following symptoms must be present within a two week period. At least one symptoms must be depressed mood or loss of interest or pleasure.

 Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g. feels sad or empty) or observation made by others (e.g., appears tearful) Note: In children and adolescents, this can be irritable mood.

 Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day, as indicated by either subjective account or observation made by others).

 Significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month) or decrease or increase in appetite nearly every day. Note: in children, consider failure to make expected weight gains.

 Insomnia or hypersomnia nearly every day.

 Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).

 Fatigue or loss of energy nearly every day.

 Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guild about being sick).

 Diminished ability to think or concentrate or indecisiveness, nearly every day.

 Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan or a suicide attempt or specific plan for committing suicide.

[Source: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC; America Psychiatric Association, 1994]; Boyer, W., and Nemeroff, C.B., Mood Disorders: Depression and Mania, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, pp. 22-23

 

Definitive diagnosis of mania references the American Psychiatric Association Criteria for Diagnosis of Mania

 A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least one week (or any duration if hospitalization is necessitated)

 During the period of mood disturbance, three (or more) of the following symptoms have persisted (for if the mood is only irritable) and have been present to a significant degree:

  Inflated self-esteem or grandiosity.

  Decreased need for sleep (e.g. feels rested after only 3 hours of sleep)

  More talkative than usual or pressure to keep talking.

  Flight of ideas or subjective experience that thoughts are racing.

  Distractibility.

  Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation.

  Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g. engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments.

 Mood disturbances must be sufficient to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

  Mania is a syndrome that may include

 sustained, abnormal, clear mood elevation

  extreme, unrealistic confidence

  acceleration of psychomotor function, including a significant decreased need for sleep, rapid thoughts and speech

  Patient behaviors suggestive of mania include:

lack of sleeping

active all the time

 spending excessive amounts of money

 hypersexuality

 impatience

 feels that nothing is wrong.

Drug Treatment for Mania

Lithium is the mainstay for treatment.

Adjunctive treatment may include:

  haloperidol (Haldol)

  benzodiazepines  

For patients not responding to lithium, valproic acid (Depakene, Depakote) or carbamazepine (Tegretol) may be effective. Valproic acid (Depakene, Depakote) is considered as effective as lithium in treating acute mania.

[Source: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC; America Psychiatric Association, 1994]; Boyer, W., and Nemeroff, C.B., Mood Disorders: Depression and Mania, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, pp. 22-23

 Three classes of antidepressant Medications

Tricyclic antidepressants (TCA)

Monoamine oxidase inhibitors (MAOI)

Second generation agents, including serotonin-specific reuptake inhibitors (SSRIs)

 

Some Contemporary Agents (Second Generation)

Serotonin-Specific Reuptake Inhibitors (SSRIs)

fluoxetine (Prozac)

clomipramine (Anafranil)

sertraline (Zoloft)

paroxetine (Paxil)

Second Generation Drugs (not including SSRIs)

amoxapine (Asendin)

bupropion (Wellbutrin)

nefazodone (Serzone)

trazodone (Desyrel)

Older Agents (First Generation and MAO enzyme inhibitors)

Tricyclic antidepressants (TCAs)

amitriptyline (Elavil, Endep)

imipramine (Tofranil)

desipramine (Norpramin)

doxepin (Sinequan)

clomipramine (Anafranil, also a SSRI)

maprotiline (Ludiomil)

nortriptyline (Aventyl, Pamelor)

protriptyline (Vivactil)

Monoamine oxidase inhibitors (MAO-I's)

phenelzine (Nardil)

tranylcypromine (Parnate)

clorgyline (specific for MAO type A)

isocarboxazid

Other

mirtazapine (Temeron)

venlafaxine (Effexor)

Serotonin-Specific Reuptake Inhibitors and Atypical Antidepressants

The SSRIs have an advantage over most other antidepressant drugs because they're less likely to cause important anticholinergic side effects or cardiovascular side effects.  Also, in the setting of overdosage, these agents tend to be less likely to cause death.  Examples of SSRIs in contemporary use include fluoxetine, paroxetine, sertraline,  fluvoxamine, citalopram along with its enantiomer escitalopram.1

 An example of an atypical antidepressant is buproprion (generic, Wellbutrin).1  Buproprion may exert its effect by means of the dopaminergic system, although actions may extend to the noradrenergic and nicotinic pathways.2 Probably buproprion acts through inhibition of the dopamine reuptake system.3

Possible Mechanisms of Action of Antidepressant Drugs

Tricyclic Antidepressants

Tricyclic agents are thought to enhance the actions of biogenic amines by inhibiting reuptake which is the primary mechanism of termination of action.

Imipramine (Tofranil), a prototypic tricyclic antidepressant blocks norepinephrine reuptake. Tricyclics with tertiary amine side chains also have effects on other neurotransmitters, like serotonin.

Among the tricyclics, clomipramine (Anafranil) has prominent actions on the serotonin system and has been shown effective in treating obsessive compulsive disorder.

Serotonin-Specific Reuptake Inhibitors (SSRIS)

Fluoxetine (Prozac) and other inhibitors of serotonin reuptake are relatively selective in their effects, with little direct action at other neurotransmitter sites.

Venlafaxine (Effexor) has actions at both serotonin and norepinephrine sites, with about five times greater selectivity for serotonin.

Paroxetine (Paxil) has about ten times greater serotonin selectivity compared to norepinephrine.

Generalizations

  Blockade of dopamine transport produces a stumulant effect.

  Inhibition of serotonin uptake may result in antidepressant effects.

  Inhibition of norepinephrine reuptake consistently produces an antidepressant action.

  Inhibition of these uptake systems may not be sufficient to cause the antidepressant effects since the time course of clinical antidepressant effects is much longer (weeks) compared to inhibition of blockade itself.

[Baldessarini, R. J., Drugs and the Treatment of Psychiatric Disorders: Depression and Mania In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.436-438.

Side effects for TCA, MAOI, and second generation drugs.

Serotonin-Specific Reuptake Inhibitors (SSRI's)

Adverse Effects

Most Common Adverse Effects:

Nausea

Headache

 Insomnia

Nervousness

Fatigue

 Sexual Dysfunction

Less common Adverse Effects:

 Inappropriate ADH secretion

 rashes

extrapyrmidal effects early in treatment akathisia. dystonia, oro-lingual dyskinesia

SSRI: Withdrawal Effects

Dizziness

Nausea

Parathesias

Palpitations

Tremor

Anxiety

Vivid dreams

 Tricyclic Antidepressants: Most Common Adverse Effects

Urinary retention

Constipation

Weight Gain

Sexual Dysfunction

Confusion/Delirium

Orthostatic Hypotension

MAO Inhibitors: Most Common Adverse Effects

Sleep disturbances

Orthostatic Hypotension

Weight Gain

Sexual Dysfunction

Drug/Food Interactions*

*Concurrent use of MAO inhibitors with serotonergic agents such as clomipramine, an SSRi or narcotics (merpidine) can cause a "serotonin syndrome" which includes hyperpyrexia, agitation, neuromuscular irritibility, hypotension, coma, and death.

Other Agents: Adverse Effects

Venlafaxine (Effexor): similar to SSRI, except at higher doses, a dose-dependent increase in diastolic blood pressure is seen

Bupropion (Wellbutrin): agitation, anxiety, insomnia, headache, nausea, and at high doses seizures (contraindicated in pateints who have an increased risk of seizure).

Trazodone (Desyrel) :common adverse effects: sedation, orthostatic hypotension, nausea; rare side effect: :priapism, sometimes leading to permanent loss of erectile function.

The Medical Letter on Drugs and Therapeutics, vol. 39 (issue 998) April 11, 1997, The Medical Letter, Inc., New Rochelle, N.Y.

 

Clinical advantages of serotonin-selective reuptake inhibitors (SSRI).

Considerations

No conclusive evidence that any antidepressant acts faster or is substantially more effective than another.

 However, there is a wide range of differences in:

side effects 

dangers of drug-drug interactions 

interactions with other illnesses 

toxicity in overdosage and dosing schedules 

Boyer, W. and Nemeroff, C. Mood Disorders: Depression and Mania, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, p. 25.

Basis for prescribing one antidepressant over another in a given patient

Overall Considerations

SSRIs (second generation drugs generally have: fewer side effects, decreased risk of drug-drug interactions, reduced chance of worsening other illnesses, and reduced toxicity in overdosage:

[Medical Letter, vol 39, issue 998, April 11, 1997; Amseterdam, J and Hornig-Rohan, M, Psychiatr Clin North Am, 19:371, 1996; Robillard, M and Lieff, S, Can J Psychiatry, 40: 639, 1995]

Boyer, W. and Nemeroff, C. Mood Disorders: Depression and Mania, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, p. 25

[Medical Letter, vol 39, issue 998, April 11, 1997; Amseterdam, J and Hornig-Rohan, M, Psychiatr Clin North Am, 19:371, 1996; Robillard, M and Lieff, S, Can J Psychiatry, 40: 639, 1995]

 

Antidepressants: Major Drug-Drug and Drug Food Interactions

MAO Inhibitors:   Example: Phenelzine Sulfate (Nardil)

  Drug-Drug Interactions:

Tricyclic Antidepressants: Hyperpyrexia, Seizures

Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil): Hyperthermia, Diaphoreis, Seizures, Delirium

Sympathomimetic Drugs (e.g. amphetamine, phenylephrine (Neo-Synephrine), phenylpropanolamine, guanethidine (Ismelin), reserpine): Hypertensive Crisis,

CNS Depressants: Additive Effects

Opioid Analgesics (particularly meperidine (Demerol)): Hypertensive crisis; circulatory collapse

Buspirone (BuSpar): Hypertension

General Anesthetics: Prolonged hypotensive and CNS depressive effects

Drug-Food Interactions: tyramine containing foods-- may cause Hypertensive Crisis.(if patient on MAOIs)

 

 

Tricyclic Antidepressants:  Example: Imipramine Hydrochloride (Tofranil)

Drug-Drug Interactions

 MAO Inhibitors: Hypertensive Crisis, Tachycardia, Seizures

 Antihypertensive Medications: Potentiation of Orthostatic Hypotension,

CNS Depressants: Additive

 Sympathomimetics: Increased Cardiotoxicity,

  Cimetidine (Tagamet): Decreased liver metabolism resulting in higher imipramine levels

Serotonin-Specific Reuptake Inhibitors (SSRIs):  Example: Fluoxetine Hydrochloride (Prozac)

Drug-Drug Interactions

Tryptophan: may cause agitation, restlessness;

MAO Inhibitors: Insufficient Data (1995)

Tricyclic Antidepressans may increase toxicity

Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, p.617

 

Symptoms of overdose and the treatments

Antidepressants: Management of Overdosage

 

Antidepressant Classification

Tricyclic antidepressants (TCAs)

Amitriptyline (Elavil, Endep)

Overview:

inhibits norepinephrine and serotonin reuptake

anticholinergic properties: greater than imipramine

antihistaminic properties

orthostatic hypotension due to alpha receptor blockade

sedation: greater than imipramine

mild analgesic

Clinical uses: 

endogenous depression

prophylaxis for migrane 

intractable pain 

eating disorder associated with depression 

sedative for non-depressed patients

Imipramine (Tofranil)

Overview:

inhibits norepinephrine and serotonin reuptake

anticholinergic properties: greater than imipramine

antihistaminic properties

orthostatic hypotension due to alpha receptor blockade

sedation: greater than imipramine

mild analgesic

Clinical uses: 

 endogenous depression

 occasionally reactive depression

 treatment of enuresis in children older than six

alcoholism 

cocaine withdrawal 

attention deficit disorders 

with amphetamine or methyphenidate for narcolepsy 

phobic anxiety 

panic disorder 

agoraphobia 

obsessive compulsive disorder

 Adverse Effects

Central Nervous System: sedation, drowsiness, lowering of seizure threshold

Cardiovascular System: orthostatic hypotension, arrhythmias, hypertension/hypotension, heart block, ECG changes, myocardial infarction.

Endocrine: gynecomostia, testicular swelling, ejaculatory and erectile disturbances

Ocular: Blurred vision, mydriasis

GI: Dry mouth, constipation

GU: Urinary retention

Hematologic: bone marrow suppression, agranulocytosis

 Drug Interactions

MAO Inhibitors: hyperpyrexic crisis, seizures

Antihypertensive agents: potentiation of postural hypotension

CNS depression: additive

Norepinephrine: increase in cardiac toxicity

Methylphenidate (Ritalin) inhibits imipramine metabolism, which may lead to imipramine toxicity

Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 616-619

Desipramine (Norpramin)

Doxepin (Sinequan)

Clomipramine (Anafranil), also a SSRI

Overview

inhibits norepinephrine and serotonin reuptake

anticholinergic properties

hypotension, tachycardia

Clinical Uses:

obsessive-compulsive disorder

panic disorder/agoraphobia

agoraphobia

Adverse Effects

Central Nervous System: mania, tremor, dizziness, neuroleptic malignant syndrome.

Cardiovascular System: orthostatic hypotension, tachycardia

Endocrine: galactorrhea, hyperprolactinemia, amorrhea, weight gain

GI: Dry mouth, constipation

GU: delayed ejaculation, anorgasmia

Hematologic:leukopenia, agranulocytosis, thrombocytopenia, anemia

Drug Interactions

 MAO Inhibitors: hyperpyrexic crisis, seizures

 Antihypertensive agents: potentiation of postural hypotension

CNS depression: additive

 Norepinephrine: increase in cardiac toxicity

 Methylphenidate inhibits imipramine metabolism, which may lead to imipramine toxicity

maprotiline (Ludiomil)

nortriptyline (Aventyl, Pamelor)

protriptyline (Vivactil)

Monoamine oxidase inhibitors (MAO-Is)

Phenelzine (Nardil)

Overview:

Hydrazine MAO inhibitor with amphetamine-like activity

Termination of drug action requires new MAO synthesis

May cause Hypertensive crisis

Clinical Uses

treatment of endogenous depression

management of depressive phase of bipolar disorder

treatment of severe reactive depression not responsive to other drugs.

Some Adverse Effects 

constipation

dry mouth

orthostatic hypotension

insomnia

nausea

anorexia

hypertensive crisis

Drug-Drug & Drug-Food Interactions

Tricyclic Antidepressants: hyperpyrexia, seizures 

SSRI's (fluoxetine, sertraline, paroxetine, etc): hyperthermia (serotonin syndrome), diaphoresis, tremors, seizures, delirium 

Sympathomimetic drugs (amphetamine, phenylpropanolamine, guanetidine, reserpine, phenylephrine): hypertensive crisis 

CNS depressants: Additive effects

Opiate Analgesics (especially meperidine): hypertensive crisis, circulatory collapse 

Buspirone (BuSpar): hypertension

General Anesthetics: prolonged hypotension and CNS depression

Dopamine, L-DOPA, methyldopa, tryptophan: headache, hypertension, hyperexciability: 

Metrizamide: increased seizure risk 

FOOD: aged meats, cheezes, anchovies, sausages, figs, bananas, avacados, chocolate, soy sausce, fava beans, bean curd, natural yogurt, [tyramine-containing foods): HYPERTENSIVE CRISIS  (Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 904-905)

tranylcypromine (Parnate)

clorgyline (specific for MAO type A)

isocarboxazid

Second Generation Drugs (not including SSRIs)

Amoxapine (Asendin) (Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 125-126.)

Overview:

dopamine receptor blocker

inhibits presynaptic neuronal norepinephrine and serotonin reuptake

Clinical Uses

 endogenous depression

 neurotic depression with anxiety

 Adverse Effects

Central Nervous System: drowsiness, sedation (less than TCA's)

 Cardiovascular System: orthostatic hypotension, arrhythmias

 GI: constipation, diarrhea, flatulence, dry mouth

 Endocrine effects related to amoxipine's structural similarity to the antipsychotic agent loxapine

 Drug Interactions

Antihypertensives: decreased response to antihypertensive

CNS Depressants: increased

bupropion (Wellbutrin)

nefazodone (Serzone)

trazodone (Desyrel)

Serotonin-Specific Reuptake Inhibitors (SSRIs)

Fluoxetine (Prozac) [Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 535]

Overview:

inhibits presynaptic neuronal serotonin reuptake

Clinical Uses:

endogenous depression

obsessive-compulsive disorder

obseity

bulimia nervosa

Adverse Effects:

Central Nervous System: headache, nervousness, anxiety, insomnia

Cardiovascular System: palpitations, chest pain

GI: nausea, diarrhea

GU: Urinary retention

 Drug Interactions

MAO Inhibitors: use cautiously (hyperthermia (serotonin syndrome), diaphoresis, tremors, seizures, delirium)

Tricyclic Antidepressants: Increased toxicity

Clomipramine (Anafranil) -- see above

Sertraline (Zoloft)

Paroxetine (Paxil)

Other

Mirtazapine (Temeron)

Venlafaxine (Effexor)

 

II. Mania

The manic phase is characterized by exaggerated elation, flight of ideas, and a pathologically increased psychomotor drive. This is symbolically illustrated in A by a disjointed structure and aggressive color tones. The patients are overconfident, continuously active, show  progressive incoherence of thought and loosening of associations, and act irresponsibly (financially, sexually etc.).

Lithium ions

 

Lithium salts (e.g., acetate, carbonate) are effective in controlling the manic phase. The effect becomes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li+ serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting morning blood samples. At higher values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin leads to polyuria and thirst. Thyroid function is impaired, with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemically, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and potassium. Apart from interference with transmembrane cation fluxes (via ion  channels and pumps), a lithium effect of major significance appears to be membrane depletion of phosphatidylinositol  bisphosphates, the principal lipid substrate used by various receptors in transmembrane signalling. Blockade of this important signal transduction pathway leads to impaired ability of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal transduction initiated by formation of the agonist-  receptor complex. Rapid control of an acute attack of mania may require the use of a neuroleptic.

Alternate treatments. Mood-stabilization and control of manic or hypomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively.

 III. Prophylaxis With continued treatment for 6 to 12 months, lithium salts prevent the recurrence of either manic or depressive states, effectively stabilizing mood at a

normal level.

 

Preparations Available

Tricyclics

Amitriptyline (generic, Elavil, others)

Oral: 10, 25, 50, 75, 100, 150 mg tablets

Parenteral: 10 mg/mL for IM injection

Clomipramine (generic, Anafranil; labeled only for obsessive-compulsive disorder)

 

Oral: 25, 50, 75 mg capsules

Desipramine (generic, Norpramin, Pertofrane)

Oral: 10, 25, 50, 75, 100, 150 mg tablets

Doxepin (generic, Sinequan, others)

Oral: 10, 25, 50, 75, 100, 150 mg capsules; 10 mg/mL concentrate

Imipramine (generic, Tofranil, others)

Oral: 10, 25, 50 mg tablets (as hydrochloride); 75, 100, 125, 150 mg capsules (as pamoate)

Parenteral: 25 mg/2 mL for IM injection

Nortriptyline (generic, Aventyl, Pamelor)

Oral: 10, 25, 50, 75 mg capsules; 10 mg/5 mL solution

Protriptyline (generic, Vivactil)

Oral: 5, 10 mg tablets

Trimipramine (Surmontil)

Oral: 25, 50, 100 mg capsules

Second- & Third-Generation Drugs

Amoxapine (generic, Asendin)

Oral: 25, 50, 100, 150 mg tablets

Bupropion (generic, Wellbutrin)

Oral: 75, 100 mg tablets; 100, 150 mg sustained-release tablets

Maprotiline (generic, Ludiomil)

Oral: 25, 50, 75 mg tablets

Mirtazapine (Remeron)

Oral: 15, 30, 45 mg tablets

Nefazodone (Serzone)

Oral: 50, 100, 150, 200, 250 mg tablets

Trazodone (generic, Desyrel)

Oral: 50, 100, 150, 300 mg tablets

Venlafaxine (Effexor)

Oral: 25, 37.5, 50, 75, 100 mg tablets; 37.5, 75, 150 mg extended-release tablets

Selective Serotonin Reuptake Inhibitors

Citalopram (Celexa)

Oral: 20, 40 mg tablets

Escitalopram (Lexapro)

Oral: 5, 10, 20 mg tablets

Fluoxetine (generic, Prozac)

Oral: 10, 20 mg pulvules; 10 mg tablets; 20 mg/5 mL liquid

Oral delayed release (Prozac Weekly): 90 mg capsules

Fluoxetine

 

Fluoxetine (also known by the tradenames Prozac, Sarafem, Ladose and Fontex, among others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine was first documented in 1974 by scientists from Eli Lilly and Company.^[1] It was presented to the U.S. Food and Drug Administration in February 1977, with Eli Lilly receiving final approval to market the drug in December 1987. Fluoxetine went off-patent in August 2001.^[2]

Fluoxetine is approved for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder.^[3] In addition, fluoxetine is used to treat trichotillomania if cognitive behaviour therapy is unsuccessful.^[4] In combination with olanzapine it is known as Symbyax, which is approved for Bipolar I disorder and Treatment-resistant depression.

Despite the availability of newer agents, fluoxetine remains extremely popular. In 2010, over 24.4 million prescriptions for generic formulations of fluoxetine were filled in the United States alone,^[5] making it the third most prescribed antidepressant after sertraline (SSRI; became generic in 2006) and citalopram (SSRI; became generic in 2003).^[5] In 2011, 6 million prescriptions for fluoxetine were handed out in the UK.^[6]

Medical uses

Fluoxetine is frequently used to treat major depression, obsessive compulsive disorder, post-traumatic stress disorder, bulimia nervosa, panic disorder, body dysmorphic disorder,^[7] premenstrual dysphoric disorder, and trichotillomania.^{[4][8][9][10]} A recent clinical trial found that in bipolar II disorder fluoxetine was equally effective as lithium in preventing future mood episodes.^[11] It has also been used for cataplexy, obesity, and alcohol dependence,^[12] as well as binge eating disorder.^[13]

Depression

Fluoxetine was shown to be effective for depression in six-week-long double-blind controlled trials, where it also alleviated anxiety and improved sleep. Fluoxetine was better than placebo for the prevention of depression recurrence when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric, as well as pediatric, depression was also demonstrated in placebo-controlled trials.^[14] However two meta-analyses of randomized placebo-controlled trials suggested that in patients with mild or moderate symptoms, the efficacy is clinically insignificant.^[15][16] It has also been argued that any improvements in mood found in trials for fluoxetine (and other SSRIs) are simply a product of an exaggerated placebo effect, regardless of the severity of depression.^[17]

Research suggests that a significant part of the resistance to the SSRIs paroxetine (Paxil) and citalopram (Celexa) can be explained by the genetic variation of Pgp transporter. Paroxetine and citalopram, which are Pgp substrates, are actively transported from the brain by this protein. Fluoxetine is not a substrate of Pgp, and thus a switch from paroxetine or citalopram to fluoxetine may be beneficial to the nonresponders.^[18][19]

Fluoxetine is considered the most stimulating of the SSRIs (that is it is most prone to causing insomnia and agitation).^[20][20]

Obsessive-compulsive disorder

OCD was successfully treated by fluoxetine in two adult and one pediatric placebo-controlled 13-week trials. The higher doses of fluoxetine appeared to result in better response, while the reverse relationship was observed in the treatment of depression.^[14] Fluoxetine dramatically, by 40–50%, decreased the frequency of panic attacks in two controlled trials of panic disorder patients. In three double-blind trials, fluoxetine significantly decreased the number of binge-eating and purging episodes of bulimia nervosa. Continued year-long treatment of the patients, who originally responded to fluoxetine, was more effective than placebo for the prevention of bulimia nervosa episodes.^[14]

Adverse effects

Sexual dysfunction is a common side effect with SSRIs. Specifically, side effects often include difficulty becoming aroused, erectile dysfunction, lack of interest in sex, and anorgasmia (inability to achieve orgasm). Genital anesthesia,^[23] loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, these sexual side effects can last for months, years, or permanently after the drug has been completely withdrawn.^[24] This is known as Post SSRI Sexual Dysfunction.

According to the manufacturer of Prozac brand of fluoxetine, Eli Lilly, fluoxetine is contraindicated in individuals taking monoamine oxidase inhibitors, pimozide (Orap) or thioridazine (Mellaril).^[14] The prescribing information recommends that the treatment of the patients with liver impairment "must be approached with caution". The elimination of fluoxetine and its metabolite norfluoxetine is about half as fast in these patients, resulting in the proportionate increase of exposure to the drug.^[14] Ibuprofen used in combination with fluoxetine can cause significant intestinal bleeding after a period of use.

 

Fluoxetine capsules (20 mg), as prescribed in the United Kingdom.

Among the common adverse effects associated with fluoxetine and listed in the prescribing information, the effects with the greatest difference from placebo are nausea (22% vs 9% for placebo), insomnia (19% vs 10% for placebo), somnolence (12% vs 5% for placebo), anorexia (10% vs 3% for placebo), anxiety (12% vs 6% for placebo), nervousness (13% vs 8% for placebo), asthenia (11% vs 6% for placebo) and tremor (9% vs 2% for placebo). Those that most often resulted in interruption of the treatment were anxiety, insomnia, and nervousness (1–2% each), and in pediatric trials—mania (2%).

Similarly to other SSRIs, sexual side effects are common with fluoxetine; they include anorgasmia and reduced libido.^{[citation needed]}

In addition, rash or urticaria, sometimes serious, was observed in 7% patients in clinical trials; one-third of these cases resulted in discontinuation of the treatment. Postmarketing reports note several cases of complications developed in patients with rash. The symptoms included vasculitis and lupus-like syndrome. Death has been reported to occur in association with these systemic events.^[14]

Akathisia, that is inner tension, restlessness, and the inability to stay still, often accompanied by "constant pacing, purposeless movements of the feet and legs, and marked anxiety", is a common side effect of fluoxetine.^[29][30] Akathisia usually begins after the initiation of the treatment or increase of the dose and disappears after fluoxetine is stopped or its dose is decreased, or after treatment with propranolol.^[29][31][32] There are case reports directly linking akathisia with suicidal attempts, with patients feeling better after the withdrawal of fluoxetine, and again developing severe akathisia on repeated exposure to fluoxetine. These patients described "that the development of the akathisia made them feel suicidal and that it had precipitated their prior suicide attempts".^[32] The experts note that because of the link of akathisia with suicide and the distress it causes to the patient, "it is of vital importance to increase awareness amongst staff and patients of the symptoms of this relatively common condition".^[33][34] More rarely, fluoxetine has been associated with related movement disorders acute dystonia and tardive dyskinesia.^[30][35][36]

Fluoxetine taken during pregnancy also increases rate of poor neonatal adaptation.^[37] Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.^[38] A study of fluoxetine administered to newborn mice found that early postnatal exposure of the drug later caused the adult mice to exhibit depressive and anxious behavior similar to those of induced depression, which could be relieved by fluoxetine.^[39] The American Association of Pediatrics classifies fluoxetine as a drug for which the effect on the nursing infant is unknown but may be of concern.^[40]

 

Fluoxetine 20 mg capsules.

Prozac in popular culture

Prozac has had numerous references to it in popular culture, including many books, movies, and songs.

• The book Listening to Prozac was written in 1993 by psychiatrist Peter D. Kramer.

• The memoir Prozac Nation was written in 1994 by Elizabeth Wurtzel; it was made into a film of the same name in 2001, starring Christina Ricci as Wurtzel.

• The 1995 song Country House by Blur sings the lyrics "He's reading Balzac and knocking back Prozac/ It's the helping hand that makes you feel wonderfully bland."

• A well-known book critical of the drug, Talking Back to Prozac, was written by psychiatrist Peter Breggin and published in 1994 (ISBN 0312114869)

• It is mentioned in the Superman graphic novel Red Son, where Brainiac uses it to control people's mood in the Superman's Empire.^[94]

• Alison Bechdel's comic book series Dykes to Watch Out For features the character Lois taking Prozac in the 1997 book Hot, Throbbing Dykes to Watch Out for.

• Prozac Diary is a 1998 confessional memoir by Lauren Slater.

• Plato, Not Prozac! is the title of 1999 self help book by Lou Marinoff which proposes classical philosophy as an alternative to conventional pro-pharmaceutical approaches to psychotherapy.

• The Bowling for Soup song 1985 describes a nervous breakdown/midlife crisis of a suburban housewife. It opens with the line "Debbie just hit the wall/she never had it all/One Prozac a day/husband's a CPA..."

• Pets on Prozac was the name of an underground UK house music band which appeared in 2010.

• Prosac (a play on Prozac) is among the more notable works by progressive house artist Tomcraft. The main lyrics of the song read from the drug's pharmacological description and indication usages.

• Bernard Sumner (of New Order and Joy Division) chronicled his experience with Prozac and its influence on his creativity in the BBC documentary Prozac Diaries.

• Prozac is often referenced throughout the popular comedic series Ally McBeal where in Season 3 the eponymous character (played by Calista Flockheart) is convinced by her psychiatrist Dr. Shirley Flott (played by Betty White) to take the medication. Flott opines the wondrous benefits of Prozac to almost eucharistic proportions explaining to Ally that she "won't find happiness through love or God: it comes in a pill." Flott also asserts that she herself takes Prozac in suppository form. Though Ally is initially persuaded to take Prozac in order to combat her hallucinations she is later dissuaded by a friend and coworker and ultimately ends up disposing the pills by flushing them down a toilet.

• In the HBO series The Sopranos, mobster Tony Soprano (played by James Gandolfini) is prone to panic attacks. His psychiatrist Dr. Jennifer Melfi (played by Lorraine Bracco) prescribes Prozac as a result.

• Prozac plays an integral role in the plot to the film Love and Other Drugs starring Jake Gyllenhaal who plays a drug salesman for Pfizer who is attempting to promote Zoloft. He discards a large portion of Prozac that is later recovered by hobos and is thereby distributed throughout the country.

• ProzaKc Blues is a song by progressive rock band King Crimson on their 2000 album The ConstruKction of Light.

• Prozac+ is an Italian punk band.

• In 2009, Lily Allen, a popular English recording artist, released her second studio album, It's Not Me, It's You, featuring the song Everyone's At It. It is about the widespread use of anti-depressants and other drugs. It contains the line So your daughter's depressed well, get her straight on the Prozac.

 

Fluvoxamine (Luvox, labeled only for obsessive- compulsive disorder)

Oral: 25, 50, 100 mg tablets

Paroxetine (Paxil)

Oral: 10, 20, 30, 40 mg tablets; 10 mg/5 mL suspension; 12.5, 25, 37.5 mg controlled-release tablets

Sertraline (Zoloft)

Oral: 25, 50, 100 mg tablets

Monoamine Oxidase Inhibitors

Phenelzine (Nardil)

Oral: 15 mg tablets

Tranylcypromine (Parnate)

Oral: 10 mg tablets

Other

Atomoxetine (Strattera)

Oral: 10, 18, 25, 40, 60 mg capsules

 

1.     http://www.youtube.com/watch?v=B61oprhnOuI&feature=related

2.     http://www.youtube.com/watch?v=E4lI9UU2MZo&feature=channel

3.     http://www.youtube.com/watch?v=d_-4QhO0hjY&feature=related

4.     http://www.youtube.com/watch?v=xSUAsdBgh70&feature=related

5.     http://www.youtube.com/watch?v=dBW9ZZGPQc8&feature=related

6.     http://www.youtube.com/watch?v=u5dqemGc558&feature=related

7.     http://www.youtube.com/watch?v=gk3mNOy__aM&feature=fvw

8.     http://www.youtube.com/watch?v=ITkBMqwb-0Q&feature=related

9.     http://www.youtube.com/watch?v=uaESK4ohM-I&feature=related

10. http://www.youtube.com/watch?v=KIjOZq_AUeE&feature=fvw

11. http://www.youtube.com/watch?v=AqJhWG1aSVQ&feature=channel

12. http://www.youtube.com/watch?v=rg3KgRXDB3k&feature=related

13. http://www.youtube.com/watch?v=cWx6RbBVTnA&feature=related

14. http://www.youtube.com/watch?v=ocSptPUBbuo&feature=related

15. http://www.youtube.com/watch?v=HryOhK4E7aU&feature=related

16. http://www.youtube.com/watch?v=pziYmeEM9Zg&feature=related