As studies on kanna are limited it may be appropriate to include also the general side effects of selective serotonin reuptake inhibitors. There is insufficient data available to confirm which
of these are, and are not associated with kanna.

As taken from Wikipedia: (

General side effects

General side effects are mostly present during the first 14 weeks while the body adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment). In fact, it often takes 68 weeks for the drug to begin reaching its full potential (the slow onset is considered a downside to treatment with SSRIs). Almost all SSRIs are known to cause one or more of these symptoms:

* anhedonia
* apathy
* nausea
* drowsiness or somnolence
* headache
* clenching of teeth
* extremely vivid and strange dreams
* dizziness
* changes in appetite
* weight loss/gain (measured by a change in bodyweight of 7 pounds)
* may result in a double risk of bone fractures and injuries
* changes in sexual behaviour (see the next section)
* increased feelings of depression and anxiety (which may sometimes provoke panic attacks)
* tremors
* autonomic dysfunction including orthostatic hypotension, increased or reduced sweating
* akathisia
* liver or renal impairment
* suicidal ideation (thoughts of suicide)
* Photosensitivity (increased risk of sunburn) (Use protective clothing, such as long sleeves and hats, and sunscreen to decrease the risk of sunburn.)

Common gastrointestinal side effects include nausea, vomiting, and diarrhea, which are brought about by the actions of serotonin on the gastrointestinal tract.

Most side effects usually disappear after the adaptation phase, when the antidepressive effects begin to show. However, despite being called general, the side effects and their durations are highly individual and drug-specific. Usually the treatment is begun with a small dose to see how the patient's body reacts to the drug, after that either the dose can be adjusted (eg. Prozac in the UK is begun at a 20 mg dose, and then adjusted as necessary to 40 mg or 60 mg). Should the drug prove not to be effective, or the side effects intolerable to the patient, another common route is to switch treatment to either another SSRI, or an SNRI.

Mania or hypomania is a possible side-effect. Users with some type of bipolar disorder are at a much higher risk, however SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar diagnosis.

[edit] Sexual side effects
See also: Post SSRI Sexual Dysfunction

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido. Initial studies found that such side effects occur in less than 10% of patients, but since these studies relied on unprompted reporting, the frequency was probably underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in between 17% and 41% of patients. This dysfunction occasionally disappears spontaneously without stopping the SSRI, and in most cases resolves after discontinuation. In some cases, however, it does not; this is known as Post SSRI Sexual Dysfunction (PSSD).

It is believed that sexual dysfunction is caused by an SSRI induced reduction in dopamine[citation needed]. Stimulation of postsynaptic 5-HT2 and 5-HT3 receptors decreases dopamine release from the Substantia Nigra. A number of drugs are not associated with sexual side-effects (bupropion, mirtazapine (Remeron), maprotiline (Ludiomil), tianeptine (Stablon) (some of these are also not associated with weight gain). As a result, sexual dysfunction caused by SSRIs can sometimes be mitigated by several different drugs. These include:

* bupropion (norepinephrine and dopamine reuptake inhibitor)
* buspirone (serotonin receptor agonist)
* methylphenidate (stimulant)
* mirtazapine (noradrenergic and specific serotonergic antidepressant (NaSSA))
* amphetamine (stimulant)
* amantadine (antiviral)
* pramipexole (dopamine agonist) and
* ropinirole (dopamine agonist)

On the other hand, the effect of SSRIs to slow down sexual stimulation may be used as treatment; SSRIs have been proposed as a drug to treat premature ejaculation.

[edit] Cardiovascular side effects

Cardiovascular side effects are very rare with SSRI use, with a reported incidence of less than 0.0003 percent. SSRIs inhibit cardiac and vascular sodium, calcium and potassium channels and prolong QT intervals. However, a number of large studies of patients without known pre-existing heart disease have reported no EKG changes related to SSRI use. In overdose, fluoxetine has been reported to cause sinus tachycardia, myocardial infarction, junctional rhythms and trigeminy. Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRI's.

Discontinuation syndrome
Main article: SSRI discontinuation syndrome

Antidepressants such as SSRIs have some dependence producing effects, most notibly a withdrawal syndrome. However, their dependence producing properties are not as significant as benzodiazepines. For example SSRIs have little to no abuse potential unlike benzodiazepines. SSRIs are addictive as discontinuing their use is known to produce both somatic and psychological withdrawal symptoms. Since physical dependence is a reality, discontinuation should be discussed with a medical practitioner before beginning treatment with this class of drugs.

Suicidality and aggression

Similarly to other antidepressants, SSRIs can cause suicidality in children. Analyses of the risks of SSRIs by governing bodies in the United States and United Kingdom have produced warnings about suicidality and aggression when the medications are used with children and adolescents.

A 2004 Food and Drug Administration (FDA) analysis of clinical trials on children with major depressive disorder found statistically significant increases of the risks of "possible suicidal ideation and suicidal behavior" by about 80%, and of agitation and hostility by about 130%. An additional analysis by the FDA also indicated 1.5-fold increase of suicidality in the 18–24 age group.[37][38] This resulted in a black box warning on SSRI and other antidepressant medications regarding the increased risk of suicidality in patients younger than 24.

In 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom judged fluoxetine (Prozac) to be the only antidepressant that offered a favorable risk-benefit ratio in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation. Only two SSRIs are licensed for use with children in the UK, sertraline (Zoloft) and fluvoxamine (Luvox), and only for the treatment of obsessive-compulsive disorder. Fluoxetine, despite having a favorable risk-benefit ratio for use with depression in adolescents and children, is not licensed for this use.

Other studies on SSRIs and suicide among adolescents are equivocal; rates of suicide attempts in high-risk populations appear to be unaffected by SSRI prescriptions in adults. There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlational, the true nature of the relationship is unclear. The introduction of a warning regarding the association between SSRIs and suicide led to a decrease in prescriptions for the medications in 2003 and 2004, and these decreases in prescriptions were associated with an increase in actual number of teenage suicide.

In adults SSRIs overall reduce the incidence of suicide, however, in susceptible patients paradoxical adverse effects can still occur which may precipitate suicide.

SSRIs and pregnancy

The U.S. Food and Drug Administration issued a warning on July 19, 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians.

When taken by pregnant women, selective serotonin reuptake inhibitors (SSRIs) cross the placenta and have the potential to affect newborns. Sertraline and paroxetine have been associated with congenital malformations. Some evidence suggests that SSRIs are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension (PPHN).

Neonatal abstinence syndrome

Neonatal abstinence syndrome is a withdrawal syndrome in newborn babies. It has been documented in SSRI treatment. By November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a Lancet study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.

Permanent neuropsychological changes

Since the early 80's scientists have used a technique called neonatal clomipramine to produce animals used in depression research. If rats are given the tricyclic antidepressant clomipramine when they are 8–21 days old they will develop behavioural changes in adulthood which resembles depression in humans. In 1997 Lundbeck found that treatment with the SSRI LU-10-134-C, which only differs from their product citalopram by two atoms could give similar results as clomipramine. Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants. By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.

But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and noradrenaline has different effects in the developing brain. For humans, the developmental stage sensitive to SSRI:s corresponds with the last trimester to the first years of life. A study showed that 4-year old children perinatally exposed to SSRI:s behave normally, however the young mice and rats also seems to be normal until they reach puberty and develop their behavioural disturbances.

The mechanism is currently unknown, but it seems that early life overstimulation of the 5HT-1 receptor which acts like a thermostat for the serotonin production results in low serotonin production after puberty.

Persistent pulmonary hypertension

Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but rare, lung condition that occurs soon after birth of the newborn. Newborn babies with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. About 1 to 2 babies per 1000 babies born in the U.S. develop PPHN shortly after birth, and often they need intensive medical care. One study has found that PPHN is six times more common in babies whose mothers take an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers do not take an antidepressant.

Interaction with carbohydrate metabolism

Serotonin is also involved in regulation of carbohydrate metabolism. Few analyses of the role of SSRIs in treating depression cover the effects on carbohydrate metabolism from intervening in serotonin handling by the body.

SSRIs appear to be safer in overdose when compared with traditional antidepressants such as the tricyclic antidepressants. This relative safety is supported both by case series and studies of deaths per numbers of prescriptions. However, case reports of SSRI poisoning have indicated that severe toxicity can occur and deaths have been reported following massive single ingestions, although this is exceedingly uncommon when compared to the tricyclic antidepressants.

Because of the wide therapeutic index of the SSRIs, most patients will have mild or no symptoms following moderate overdoses. The most commonly reported severe effect following SSRI overdose is serotonin syndrome; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion. Other reported significant effects include coma, seizures, and cardiac toxicity.

Treatment for SSRI overdose is mainly based on symptomatic and supportive care. Medical care may be required for agitation, maintenance of the airways, and treatment for serotonin syndrome. ECG monitoring is usually indicated to detect any cardiac abnormalities.

In late 2004 media attention was given to a proposed link between SSRI use and juvenile suicide. For this reason, the use of SSRIs in pediatric cases of depression is now recognized by the United States FDA as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a family doctor. The FDA's currently required packaging insert for SSRIs includes a warning (known as a "black box warning") that a pooled analysis of placebo controlled trials of 9 antidepressant drugs (including multiple SSRIs) resulted in a risk of suicidality that was twice that of placebo. At the same time, in adults SSRIs do not increase the risk of suicide.

Critics of SSRIs claim that the widely-disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do and deceiving the public.

The criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalances. Without accurately measuring patients' neurotransmitter levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that SSRIs can actually cause chemical imbalances and abnormal brain states. Hence it is purported that when a patient discontinues an SSRI, they may have a chemical imbalance due to the rapid cessation of the drug which is causing the discontinuation syndrome.

One possible mechanism is by inhibition of dopaminergic neurotransmission.

Biopsychiatrists believe that, among other factors, the balance of neurotransmitters in the brain is a biological regulator of mental health. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as clinical depression, reflect an imbalance. Psychiatrists claim that medications regulate neurotransmitters, and many if not most psychiatrists also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit (though the efficacy of antidepressants and antipsychotics is not undisputed). On the other hand, Elliot Valenstein, a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence.

One controversial critic of antidepressants, Peter Breggin, a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted iatrogenic issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is David Healy.

A widely-reported meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, and two non-SSRI antidepressants nefazodone and venlafaxine). The authors found that although the antidepressants were statistically superior to placebo they did not exceed the NICE criteria for a 'clinically significant' effect. In particular they found that the effect size was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression. The relationship between severity and efficacy was attributed to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication.

A study in the New England Journal of Medicine on a possible publication bias regarding the efficacy of SSRI medications in the treatment of depression suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. Of 74 studies registered with the United States FDA, 37 with positive results were published in academic journals, while 22 studies with negative results were not published and 11 with negative results were published in a way that conveyed a positive outcome (one positive study was not published and three negative studies were published with results that were portrayed as negative). Overall, 94% of studies actually published were positive outcomes; when published and unpublished studies were included for analysis, the percentage of positive outcomes was 51%.
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