Umberto Ciabatti & Massimo Donalisio
INTRODUCTION
There has been an increasing interest in the obsessive-compulsive nature of paraphilias and whether they lie in the OCD spectrum.
Analogous aspects between paraphilias and obsessive-compulsive diseases have been evidenced by the analysis of behavior in many types of patients.
The observation suggested a therapeutic trial in order to study the involvement of a common biochemical disfunction in the genesis of both disorders.
The clinical response to serotonin reuptake inhibitors has strenghthened the hypothesis that sexual paraphilias could be part of the OCD spectrum.
This may encourage psychiatrists to use SSRIs instead of anti-androgens to treat this kind of disorder, protecting patients from anti-androgens strong side effects.
No reports of the use of paroxetine with cases of paraphilias were found in literature.
SSRIs act inhibiting the serotonin reuptake in the synaptic cleft, leading to an increased concentration of serotonin in the cleft, followed by an increased transmission of serotoninergic signals.
MECHANISM OF ACTION OF PAROXETINE
Paroxetine, a phenylpiperidine derivative, is the most potent inhibitor of the reuptake of serotonin out of all currently available antidepressants including the class of SSRIs.
It is a very weak inhibitor of norepinephrine (NE) uptake but it is still more potent at this site than the other SSRIs.
In vitro, it is approximately 3- to 5-fold more potent at inhibiting serotonin than noradrenaline reuptake.
Paroxetine has little affinity for muscarinic cholinergic, histamine H1, dopaminergic and adrenergic receptors and by comparison with tricyclic antidepressants (TCAs) has, therefore, reduced propensity to cause central and autonomic side effects.
Paroxetine is also a nitric oxide synthase inhibitor, hence serum nitrite and nitrate levels are reduced in paroxetine users.
Paroxetine potently and selectively inhibits neuronal serotonin reuptake through antagonism of the serotonin transporter.
Its antidepressant, antiobsessional, and antipanic activities are presumed to be linked with potentiation of serotonergic activity in the central nervous system (CNS).
Paroxetine inhibits the active membrane transport mechanism for reuptake of serotonin, which increases concentration of the neurotransmitter at the synaptic cleft and prolongs its activity at synaptic receptor sites.
Inhibition of serotonin reuptake also enhances serotonergic neurotransmission by reducing turnover of the neurotransmitter through a negative feedback mechanism.
Paroxetine inhibits serotonin reuptake in vitro more selectively and more potently than do fluoxetine, sertraline, fluvoxamine, zimeldine, or clomipramine.
CASE REPORTS
In a study lead by Abouesh and Clayton (Compulsive voyeurism and exhibitionism: a clinical response to paroxetine, 1999) two patients are presented: Patient A is a voyeurist and divorced; Patient B is an exhibitionist and is married.
Both patient had some college education and were working at the time they presented.
Neither had medical or neurological problem.
They presented with recurrent and persistent thoughts and impulses to act in a voyeuristic and exhibitionistic fashion, respectively.
These thoughts were sexually exiting for them, but were followed by a deep sense of shame.
Both patients were successfully treated with paroxetine.
CASE REPORT A: Mr. A, a 50 yrs old divorced white male and father of two children, was self referred for the evaluation and management of his voyeuristic behavior.
He reported long standing erotic compulsion to look up women's skirts using a mirror in public places. He did not remember the first time he did this, but remember episodes during his teen years, involving his sisters. He also spent several hours a day watching naked women in pornographic movies while masturbating 4-7 times a day. He continued his erotic behavior during his early adulthood, describing feeling flushed and aroused by his voyeuristic behavior. He would then go home and masturbate. He states that throughout his marriage his wife had no knowledge of this behavior. He went home drunk one night and attempted to videotape his daughter in the shower.
At the time of his presentation he reported continued voyeuristic behavior in the manner described above.
He noted a sense of relief afterwards, associated with frustration over his inability to control his behavior. He was also spending several hours a night on the Internet at pornographic websites. He was treated with fluoxetine and paroxetine and noticed a significant relief of his symptoms. He was started on 10 mg of paroxetine at bedtime.
Four weeks later he reported an improvement in his ability to control his impulses, but continued to have the recurring thoughts, at which time the dose was increased to 20 mg at bedtime.
There was a noticeable decrease in his voyeuristic behaviors with a decrease in the frequency as well as a reduction in the intensity of his urges and thoughts.
He decided to put a block on the pornographic Internet sites, with no recurring incidents of voyeurism in 3 months of treatment.
CASE REPORT B: Mr. B, a 29 yrs old married white male, a father of two, was self-referred after an incident in which he exposed himself to a woman at his home that resulted in legal charges.
He worked at a local branch of a cellular-phone company and was a college graduate. He had no medical problems.
The patient stated that his problems started at age 9 years when he was forced by his sister and her boyfriend to touch her genitals so as to make her have an orgasm. He reported other episodes of physical abuse by his sister, who was 5 years older than he.
At 14, he started having compulsive thoughts of exposing himself to women.
He described being sexually aroused when seeing a pretty woman, and would start planning how to lure her to a safe place and then expose himself to her.
In each of these occasions, the patient described being sexually excited prior to exposing, but then would have a deep sense of shame and guilt and would develop depression symptoms.
These incidents recurred until he was arrested and spent several months in jail.
He was court-ordered to attend a sex-offenders program, but that did not help.
For the past 4 years he has had recurring thoughts of exposing himself, but had not acted on them until several months ago. He developed intense thoughts of exposing himself to a family friend, then lured her into his bedroom and exposed himself. He was arrested and charged, but the woman was willing to drop the charges provided he sought treatment. He was started on paroxetine10 mg at bedtime, and after 4 weeks, the patient reported a decrease in the recurrent thoughts and an ability to control the impulses to act. He described watching the "college girls" while he was at work, but was able to resist the impulse to expose himself.
His paroxetine dose was increased to 20 mg at bedtime.
Three weeks later he requested a dosage increase, due to thoughts of exposing himself to the daughter of his wife`s friend. He did not act on these thoughts.
He continued to do well on 30 mg a day for 2 1/2 months before being lost to follow-up.
Analogous cases of paraphilias treated with SSRIs are presented in other studies, like:
DISCUSSION
Both patients reported obsessive rumination and anticipatory anxiety (as well as sexual excitation) prior to acting out, and relief after they acted out, which resembled the relief noted by patients with obsessive-compulsive disorders.
They also acted in an impulsive manner, with little regard to avoiding harmful and painful consequences.
Kafka (Paraphilia-related disorders--common, neglected, and misunderstood, 1994) hypothesized that paraphilic sexual fantasies belong to the OCD spectrum, and therefore would be improved by SSRIs.
Greenburg and Bradford (A comparison of treatment of paraphilias with three serotonin reuptake inhibitors: a retrospective study, 1998) hypothesized that paraphilic disorders are disorders of aberrant sexual desire.
Serotonin is known to play a role in sexual appetites, therefore SSRIs may exert their therapeutic action by altering the balance of a dysfunctional serotoninergic system.
Another aspect of deviant sexual behavior to be considered is that of sexual addiction, defined as non-paraphilic sexual interests and behaviors that increase in frequency or intensity so as to significantly interfere with the desired capacity for a sustained intimate sexual relationship.
Kafka during a clinical trial noticed improvement in both paraphilic and non-paraphilic symptoms in patients treated with fluoxetine, and suggested that the behaviors can be conceptualized as a sexual disregulation that has two dimensions: an increase of non-conventional sexual interests and an increase in sexual desire.
These results are consistent with Greenburg and Bradford`s hypothesis.
Another aspect involved in the treatment of sexual paraphilias with serotoninergic medication is the effect these medications have on sexual function.
SSRIs have been associated with a high rate of sexual side effects including decreased libido, delayed orgasm, anorgasmia, and erectile dysfunction (SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients, 1997).
Hence, the response noted in paraphilics could possibly be indirectly related to an overall reduction in sexual drive, rather than a direct response to modulation of the neurotransmitter system involved in paraphilic behaviors.
Many other studies shows that the OCD spectrum model for paraphilias is not necessary to explain the effectiveness of SSRI treatment; however modern theories hypothesize that paraphilias are made out of two components: the sexual component as well as the OCD component, so the treatment with SSRIs would act on both components.
FOCUS ON SEROTONINE TRANSPORTER MUTATIONS
SERT is the serotonin transporter responsable for the reuptake of serotonin from the synaptic cleft. Recent studies has shown strong involvement of mutations of the gene hSERT codifying for SERT protein, in the genesis of OCDs.
Particularly, a substitution of Val425 for Ile425 in the sequence (from now on called "I425V mutation") seems to significantly increase the serotonine transport activity of the protein. "...this is also probably the first report of a modification in a transporter gene resulting in a gain rather than a decrease in function," commented Thomas Insel, M.D., Director of the National Institute of Mental Health.
Fusun Killic (A human serotonin transporter mutation causes constitutive activation of transport activity, 2003)tested consequences of the hSERT variant. The report is considered the first to identify a coding mutation in a transporter linked to a psychiatric condition. Researchers found that the I425V mutation of hSERT increased the transport activity of this protein, capturing more serotonin and most likely reducing effects at the receiving neuron's receptors, outperforming the common transporter, with an increased Vmax and a decreased Km.
According to a Zhang's study (Serotonin transporter phosphorylation by cGMP-dependent protein kinase is altered by a mutation associated with obsessive compulsive disorder, 2007), the elevated transport is thought to be caused by altered cGMP-dependent protein kinase (PKG) activity. The I425V mutation results in a costitutive activation of SERT similarly to the way NO stimulates wild-type SERT (PKG pathway). The stimulation of SERT by cGMP is disrupted in the I425V mutant. Thr276 is the site of PKG phosphorylation on SERT, located in the second intracellular loop of the protein, between TMH4 and TMH5. Ile425 is predicted to reside in the middle of TMH8, and there are two hypothesis on how I425V mutation increases SERT activity.
1-I425V mutation makes thr276 phosphorylation irrilevant.
2-I425V mutation indirectly increases the level of thr276 phosphorilation by interfering with the activity of a phosphatase.
In a study lead by Lesch, a polymorphism has also been reported in the promoter region of hSERT (SERT gene), consisting in an insertion or deletion of a 44bp sequence that results in a long (L) or short (S) allele termed the 5-HTTLPR.
The S variant displays threefold reduced gene transcriprion leading to a decreased transporter expression and therefore serotonin uptake. Patients with OCD who are homozygous for L variant (L/L), or heterozygous (L/S) respond better to SSRI treatment, than those who are homozygous for the S allele (The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication, 1996).
The S allele is associated with an increased risk of depression, OCD and ADHD.
CONCLUSIONS
Many studies agree that SSRIs are effective in the treatment of sexual paraphilias, but further studies are requested to define the contribute of the effects on the OCD component and the contribute of the effecs on the sexual serotoninergic system dysfunction component in the overall effectiveness of the treatment.
The side effect profile is also less potentially serious than anti-androgen treatment.
This makes SSRIs a good weapon against paraphilias, especially in pharmacological treatment of females and adolescent as previous anti-androgen treatment was difficult to implement in these patients.
Furthermore the synergy shown between SSRIs and anti-androgen drugs, suggested a combined treatment for severe cases of paraphilia, such as pedophilia, to lower the risk of serious side effects: to achieve the same result, a much lesser dose of anti-androgen was needed if combined with SSRIs.
This synergy is probably explained by a serotoninergic system association with hypothalamic control of testosterone.
