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Transcranial Photobiomodulation Therapy for Sexual Dysfunction Associated with Depression or Induced by Antidepressant Medications

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Abstract

Sexual dysfunction (SD) is frequently encountered in patients suffering from depression. There is a bidirectional relationship between various types of SD and depression, so the presence or treatment of one condition may exacerbate or improve the other condition. The most frequent sexual problem in untreated depressed patients is declining sexual desire, while in treated depressed patients it is difficulties with erection/ejaculation and with orgasm. Numerous classes of neuropsychiatric medications, commonly used in depressed patients—such as antidepressant, antipsychotic, alpha sympathetic, and opioid drugs—may cause SD. Photobiomodulation (PBM) therapy, also called low-level light/laser therapy, is a novel neuromodulation technique for neuropsychiatric conditions, such as depression. Transcranial PBM (tPBM) targets the cellular metabolism—through the mitochondrial respiratory enzyme, cytochrome c oxidase—and has numerous cellular and physiological beneficial effects on the central nervous system. This paper represents a comprehensive review of the application of tPBM to SD, coexisting with depression or induced by antidepressant medications.
Citation: Salehpour, F.; Khademi, M.;
Vahedifard, F.; Cassano, P.
Transcranial Photobiomodulation
Therapy for Sexual Dysfunction
Associated with Depression or
Induced by Antidepressant
Medications. Photonics 2022,9, 330.
https://doi.org/10.3390/
photonics9050330
Received: 31 March 2022
Accepted: 15 April 2022
Published: 11 May 2022
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photonics
hv
Review
Transcranial Photobiomodulation Therapy for Sexual
Dysfunction Associated with Depression or Induced by
Antidepressant Medications
Farzad Salehpour 1,2 , Mahsa Khademi 3, Farzan Vahedifard 4and Paolo Cassano 5,6,7,8,*
1College for Light Medicine and Photobiomodulation, D-82319 Starnberg, Germany;
fsalehpour@proneurolight.com
2ProNeuroLIGHT LLC, Phoenix, AZ 85083, USA
3Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz 51666, Iran;
drmahsakhademi@gmail.com
4Division of Neuroradiology, Rush University, Chicago, IL 60612, USA; farzan_vahedifard@rush.edu
5Department of Psychiatry, Harvard Medical School, Boston, MA 02110, USA
6
Department of Psychiatry, Division of Neuropsychiatry, Massachusetts General Hospital, Boston, MA 02110, USA
7Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital,
Boston, MA 02110, USA
8Center for Anxiety and Traumatic Stress Disorders, Department of Psychiatry, Massachusetts General
Hospital, Boston, MA 02110, USA
*Correspondence: pcassano@mgh.harvard.edu; Tel.: +1-617-643-9622
Abstract:
Sexual dysfunction (SD) is frequently encountered in patients suffering from depression.
There is a bidirectional relationship between various types of SD and depression, so the presence or
treatment of one condition may exacerbate or improve the other condition. The most frequent sexual
problem in untreated depressed patients is declining sexual desire, while in treated depressed patients
it is difficulties with erection/ejaculation and with orgasm. Numerous classes of neuropsychiatric
medications, commonly used in depressed patients—such as antidepressant, antipsychotic, alpha
sympathetic, and opioid drugs—may cause SD. Photobiomodulation (PBM) therapy, also called low-
level light/laser therapy, is a novel neuromodulation technique for neuropsychiatric conditions, such
as depression. Transcranial PBM (tPBM) targets the cellular metabolism—through the mitochondrial
respiratory enzyme, cytochrome c oxidase—and has numerous cellular and physiological beneficial
effects on the central nervous system. This paper represents a comprehensive review of the application
of tPBM to SD, coexisting with depression or induced by antidepressant medications.
Keywords:
depression; antidepressant medications; sexual dysfunction; photobiomodulation;
low-level light; laser therapy
This review aims to evaluate the transcranial photobiomodulation therapy for sex-
ual dysfunction associated with depression or induced by antidepressant medications.
The databases for the search were MEDLINE using PubMed, SCOPUS, Web of Science,
EMBASE, Cochrane Library, and Google Scholar, up to March 2022. First, we searched
keywords including “near-infrared laser”, “transcranial photobiomodulation”, “photo-
biomodulation”, “low-level light therapy”, “laser therapy”, “phototherapy”, as well as
“Depression”, “Sexual Dysfunction”, “Depression + Sexual dysfunction”, “Selective sero-
tonin reuptake inhibitors + Sexual Dysfunction”, and “Antidepressant”. Only relevant
studies on sexual dysfunction and transcranial photobiomodulation were included. All
studies regarding applying photobiomodulation on other sites such as the nasal cavity,
lumbar, and genital were excluded. We also excluded almost all animal studies, unless they
were most relevant to our aim and scope.
Photonics 2022,9, 330. https://doi.org/10.3390/photonics9050330 https://www.mdpi.com/journal/photonics
Photonics 2022,9, 330 2 of 15
1. Sexual Dysfunction: Definition, Classification, and Association with Depression
The term “sexual dysfunction” comprises any decrease in desire or libido, reduced
arousal (decreased vaginal lubrication in women or erectile dysfunction in men), as well
as a remarkable decline in intercourse frequency in couples, or an undesirable delay in
orgasm, up to an inability to achieve orgasm [
1
]. Epidemiological surveys demonstrate
high rates of sexual dysfunction (SD) in the general population. In the United States, more
than 40% of women and 30% of men have some degree of sexual dysfunction, the most
prevalent disorders being low sexual desire in women (22%) and premature ejaculation
in men (21%) [
2
]. Similarly high was the prevalence of sexual dysfunction across eight
European countries, with low sexual desire in up to 34% of women and 15% of men [3].
According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5), SD in men and women is classified into several categories: delayed ejaculation,
erectile disorder, female orgasmic disorder, female sexual interest/arousal disorder, genito-
pelvic pain/penetration disorder, male hypoactive sexual desire disorder, premature (early)
ejaculation, substance/medication-induced sexual dysfunction, other specified SD, and
unspecified SD [
4
]. DSM-5 emphasizes that SD diagnosis requires ruling out problems
better explained by a nonsexual mental disorder. In this review, we take the approach
of emphasizing the comorbidity of SD with major depressive disorder (MDD), especially
when the latter is treated with pharmacotherapy. We hereby provide relevant explanations
about SD syndromes and emphasize their frequent overlap with depression and with
antidepressant treatment. According to DSM-5, if the SD is consequential to a mood
disorder or to its treatment, a proper diagnosis of SD disorder cannot be made. In clinical
practice, recognizing the different syndromes of SD, even when comorbid with MDD
or coexistent with antidepressant medications, is still critically important to address the
impairment in sexual function.
-Delayed Ejaculation:
The major differential diagnoses for delayed ejaculation are
medical illness, injury, psychogenic, idiopathic, or combined psychological/medical
etiology. In addition, antidepressants, antipsychotics, alpha sympathetic drugs, and
opioid drugs may lead to delayed ejaculation. Furthermore, it should be ascertained
whether the complaint is indeed delayed ejaculation (occurs in the genitals) or rather
the sensation of delayed orgasm (primarily subjective), or both. Some evidence
supports that delayed ejaculation is more common in severe MDD.
-Erectile Disorders
: MDD and erectile dysfunction are closely associated, and erectile
dysfunction may have co-occurrence with MDD. Many men with erectile disorder may
experience a depressed affect. The “lifelong erectile disorder” is associated more with
psychological factors (responsive to psychological interventions), whereas the acquired
erectile disorder is related to biological factors. Alexithymia (deficits in cognitive
processing of emotions) is common in men with “psychogenic” erectile dysfunction.
Overall, erectile problems are common in men with MDD and posttraumatic stress
disorder.
-Female Orgasmic Disorder:
consists in difficulty in experiencing orgasm and/or
markedly reduced intensity of orgasmic sensations. There is a strong association
between mental health and orgasm difficulties in women. Psychological factors (such
as anxiety) can interfere with a woman’s ability to experience orgasm. Severe relation-
ship distress or significant stressors are associated with orgasmic difficulties. Women
with other nonsexual mental disorders—such as MDD—may have lower sexual inter-
est/arousal, indirectly increasing orgasmic problems. MDD should be considered as
an important differential diagnosis. MDD is characterized by significantly diminished
interest or pleasure, which may explain the female orgasmic disorder. In addition,
selective serotonin reuptake inhibitors (SSRIs) can delay or inhibit orgasm in women.
-Female Sexual Interest/Arousal Disorder:
defined by the lack of, or significantly
reduced, sexual interest/arousal. It manifests in absent/reduced interest in sexual
activities, and sexual/erotic thoughts or fantasies. A lack of pleasure is a common
complaint in women with low desire. Relationship difficulties and mood disorders
Photonics 2022,9, 330 3 of 15
are associated features of female sexual interest/arousal disorder. Negative cognitive
distortions and attitudes over sexuality and history of mental disorders are predispos-
ing factors to this disorder. MDD may explain the lack of sexual interest/arousal, due
to the cardinal depressive symptom of “markedly diminished interest or pleasure in
all (or almost all) activities most of the day, nearly every day”. Other differential diag-
noses are: substance or medication use, diabetes mellitus, endothelial disease, thyroid
dysfunction, central nervous system disease, interpersonal factors, and inadequate or
absent sexual stimuli. Frequently associated with low sexual desire are depression,
sexual and physical abuse in adulthood, impaired global mental functioning, and
excessive alcohol use.
-Genito-Pelvic Pain/Penetration Disorder:
includes four symptoms: (1) difficulty
having intercourse, (2) genito-pelvic pain, (3) fear of pain or vaginal penetration,
and (4) tension of the pelvic floor muscles. They are associated with other sexual
dysfunctions, such as reduced sexual desire and interest. Avoidance of gynecological
examinations is frequent, like in phobic disorders. Endometriosis, pelvic inflammatory
disease, and vulvovaginal atrophy are the differential diagnoses.
-Male Hypoactive Sexual Desire Disorder:
consists of persistently or recurrently
deficient (or absent) sexual thoughts or fantasies and desire for sexual activity. It is
sometimes associated with erectile and/or ejaculatory problems. The normative age-
related decline in sexual desire should be considered. Mood and anxiety symptoms are
strong predictors of low desire in men. Up to 50% of men with a history of psychiatric
symptoms have moderate to severe loss of desire, while only 15% of those without
such a history do. MDD may also explain the lack of sexual desire.
-Premature (Early) Ejaculation:
20–30% of men aged 18–70 years have some concern
about premature ejaculation; however, only 1–3% of men are diagnosed with this
disorder. It is not to be confused with the scenario of males with normal ejaculatory
latencies, who want longer ejaculatory latencies, and of males who have episodic
premature ejaculation (e.g., during the first sexual encounter). None of these situations
is a premature (early) ejaculation disorder, no matter the associated distress level.
Premature ejaculation is more common in men with anxiety disorders, especially
social anxiety disorder.
-Substance/Medication-Induced Sexual Dysfunction:
intoxication with alcohol, opi-
oids, sedatives, hypnotics, anxiolytics, stimulants (including cocaine), and unknown
substances may lead to SD. In addition, withdrawal from alcohol, opioids, sedatives,
hypnotics, anxiolytics, and other (or unknown) substances can cause SD. Finally, some
drugs can cause SD directly, such as antidepressant and antipsychotic medications and
hormonal contraceptives. The most common side effect of antidepressant medications
is orgasm or ejaculation problems. Desire and erection problems are less frequent.
Bupropion and mirtazapine are typically free from sexual side effects. Overall, up to
50% of individuals taking antipsychotic medications have adverse sexual side effects
(such as deficits in sexual desire, erection, lubrication, ejaculation, or orgasm).
Differentiating a substance/medication-induced sexual dysfunction from the presenta-
tion of an underlying mental disorder is vital and sometimes difficult. A close relationship
between substance/medication initiation, or discontinuation should be observed, for mak-
ing the diagnosis of substance/medication-induced SD. Most of these side effects occur
shortly after initiation or discontinuation (if induced by withdrawal). Therefore, sexual
side effects which occur after chronic use may represent a diagnostic challenge.
2. Sexual Dysfunction and Brain Disorders
2.1. Major Depressive Disorder and Other Psychiatric Disorders
MDD is a complex mental disorder that significantly impacts individuals’ lives, regard-
less of differences in nationality, age, and social and cultural groups [
5
]. It is established
that SD in depressed patients is higher than in the general population [
6
,
7
]. During the
COVID-19 pandemic, a significant reverse correlation was found between total sexual
Photonics 2022,9, 330 4 of 15
function score and depression [
8
]. The overall prevalence of SD was reported to be twice as
great in depressed patients than in controls (50% vs. 24%) [
7
]. Depression symptoms are
significant predictors of perceived SD [
9
]. The most frequent SD in untreated depressed
patients is a decline in sexual desire (about 40% of men and 50% of women), while dys-
functions in erection/ejaculation (22% of men) or in orgasm (15% of women) are reported
less frequently [
10
]. In another study on SD—in both treated and untreated depressed
patients—a low libido was reported in about two-thirds of the sample [
11
]. Overall, a strong
relationship was observed between the prevalence of SD and the presence, worsening, and
recurrence of a depressive episode [
11
,
12
]. There is a bidirectional relationship between SD
and depression: the presence and treatment of depression may cause or exacerbate SD, and
the treatment of SD may improve depression symptomatology [13,14].
Other psychiatric disorders—namely anxiety disorders and substance use disorders, for
instance—are also associated with SD, either due to the neurobiology of the disorder or due
to the associated use of medications or of illicit substances or alcohol. These other psychiatric
disorders are marginally discussed hereby, due to the focus on depression. Of note, although
DSM-5 draws rigid criteria for the differential diagnosis of mood, anxiety, and psychotic
disorders, truly there is very high syndromal and subsyndromal overlap in symptomatology
and treatment; thereby rendering a detailed, disease-specific account less meaningful.
2.2. Neurological Disorders
Although neurological disorders are also beyond the focus of this paper, it is important
for us to exemplify the relationship between brain lesions and SD. In fact, SD might prompt
a neurological work-up and not just a psychiatric evaluation, depending on risk factors and
concomitant symptoms. Several neurological disorders may cause SD, such as spinal cord
injury (SCI), Parkinson’s disease (PD), traumatic brain injury (TBI), and multiple sclerosis
(MS) [15]. Up to 85% of women with MS, 43% of women with PD, and women with other
neurological diseases have some degree of SD, such as loss of libido, decreased lubrication,
problems in orgasm, dyspareunia, and an overall reduction in sexual satisfaction [15].
In patients with SCI, different types of SD are reported depending on the location,
extent, and severity of the lesion [
16
,
17
]; the most common being erectile dysfunction and
ejaculation disorders [
18
]. Although women may have a normal sexual function after
SCI [19], it has been estimated that 59% of women reported at least one SD after SCI [20].
Sexual dysfunction has been reported as one of the most common and annoying
problems among patients with multiple sclerosis (MS). Among patients with MS, SD affects
about 40–80% of women and 50–90% of men [
21
]. A study of 271 patients with MS found
that about 63% of women with MS show signs of SD [
22
]. The most prevalent SD in men
with MS is erectile dysfunction, while in women, they are reduced libido, difficulty in
achieving orgasm, reduction in the tactile sensations originating from the thighs and genital
regions, and vaginal dryness with consequent dyspareunia [2325].
In patients with PD, the prevalence of SD is much higher than in the general population.
Gender differences in prevalence and type of SD were also reported in this population [
24
].
The most common SD in men with PD are erectile dysfunction (ED), premature ejaculation
(PE), hypersexuality, and difficulty in reaching orgasm. The most common SD in women
with PD are low sexual desire, urination during sex, reduced lubrication, and difficulty
in arousal and reaching orgasm [
26
,
27
]. Both genders have reported a loss of desire and
dissatisfaction in their sexual life when suffering from PD [27].
Because MDD is frequently comorbid in patients suffering from PD and other neuro-
logical disorders, it is possible that some patients with SD might be affected by both PD
and MDD. The treatment approach will likely be more complex and will need to address
both underlying medical conditions to improve SD.
3. The Neurobiology of Sexual Function
Sexual function results from a complex interaction between biological, sociocultural,
and psychological factors. The exact neurobiology of sexual function and dysfunction
Photonics 2022,9, 330 5 of 15
is still debated [
28
]. For the neurobiological assessment of sexual function, the effect
of neurotransmitters, neuropeptides, hormones, and the overall function of the central
nervous system (CNS) should be examined, in relation to sexual desire, arousal, orgasm,
and ejaculation [
28
]. Neurotransmitters or neuropeptides involved in the neurobiology of
sexual function include: nitric oxide (NO) [
29
], dopamine [
30
], histamine [
31
], serotonin [
32
],
epinephrine [
33
], norepinephrine [
34
], opioids [
35
], acetylcholine [
36
], and
γ
-Aminobutyric
acid (GABA) [37].
NO is a critical component to penile induction and probably clitoral vasocongestion
and tumescence as well. NO production is elevated following the sexual stimulation, which
then leads to the activation of guanylate cyclase. Guanylate cyclase has a role in converting
the guanosine triphosphate to its cyclic monophosphate form (cGMP). Finally, cGMP causes
the relaxation of the smooth muscle of the penile arteries, resulting in increased penile
blood flow and in tumescence of the corpus cavernosum [
38
,
39
]. Some studies suggest that
an analogous process might also happen in women’s clitoris [40].
In terms of neurotransmitters, the role of dopamine in triggering an erection has been
suggested by several studies, which showed such effect after the intake of levodopa, a
medication prescribed for Parkinson’s disease [
41
,
42
]. Of note, few studies have focused
on the role of dopamine in sexual function in women [
43
]. Interestingly, women who
took antipsychotic medications which decrease dopamine drive—such as fluphenazine,
thioridazine, and trifluoperazine—experienced a delay or inhibition in orgasm [
44
]. Con-
trary to dopamine, serotonin has been negatively implicated with sexual function, via
the constriction of the smooth muscles in genital organs and via altered peripheral nerve
function. These mechanisms might explain difficulties with arousal and erection, as well
as the numbing of genital sensations in depressed patients treated with SSRIs. The role of
epinephrine in sexual function is in maintaining the penis in the flaccid state. This action is
necessary for sexual activity, however counterintuitive, given that muscles contractions and
elevation are also involved. In women, epinephrine causes an increase in the vaginal pulse
amplitude, a measure of vaginal vasocongestion possibly reflective of clitoral blood flow
and therefore of arousal. Norepinephrine is analogous to epinephrine; it is a neurotransmit-
ter involved in sexual function, and it increases with arousal and sexual activity in both
genders [
45
]. Acetylcholine has been involved in penile erection. Experimental and clinical
studies have reported that GABA activity could inhibit sexual behaviors in males, such as
mounting, intromitting, erection, and ejaculation [
28
]. Oxytocin, as a bonding hormone, is
increased in sexual arousal and orgasm in both sexes and facilitates ejaculation. In addition,
oxytocin can induce penile erection and increase dopamine concentration in the nucleus
accumbens [46].
Given the profound impact of the central nervous system (CNS) and of the peripheral
nervous system (PNS) neurotransmitters on sexual functioning, it is unsurprising that CNS
medications commonly alter sexual function and that many cause sexual dysfunction [
47
].
4. Pathophysiology of Sexual Dysfunction in Depression
The brain plays a central role in sexual response, which involves an interplay be-
tween neurogenic, psychogenic, vascular, and hormonal factors mediated through the
hypothalamus, limbic system, and cerebral cortex [
17
]. Sexual response is divided into
four phases: desire, arousal, orgasm, and refractory [
48
]. Imaging studies have shown
the pathways which are involved in the sexual desire phase, including: activation of the
right temporal and orbitofrontal cortex (OFC), deactivation of the medial and left OFC
and medial hippocampus, activation of the ventral striatum, temporary activation of the
amygdala, and activation of the claustrum, insula, and anterior cingulate cortex [
49
51
].
The arousal and orgasm phases are related to decreased amygdala and ventromedial pre-
frontal cortex activity. The refractory phase is associated with increased activation in the
amygdala, hypothalamus, and orbitofrontal cortex [
52
]. Several neurotransmitters and
neuropeptides have been involved in the sexual response. Dopamine is known as the
primary neurotransmitter in the modulation of sexual desire. The ventral tegmental area
Photonics 2022,9, 330 6 of 15
(VTA) is the primary source of dopamine to the mesolimbic and mesocortical pathways.
The mesolimbic pathway connects the VTA to the nucleus accumbens, and the mesocortical
pathway links the VTA to the frontal cortex [53].
SD has been correlated to increased serotonin, to reduced dopamine, to anticholiner-
gic drugs, to
α1
adrenergic receptors blockade, to inhibition of NO synthesis, and to the
elevation of prolactin levels [
54
]. SD is a common symptom of depression. In depressed
patients, increased activity of the amygdala and medial OFC, together with reduced ven-
tral striatum and hypothalamus activity, lead to lower sexual desire and arousal [
55
57
].
Moreover, increased serotonin availability (e.g., reuptake inhibition, as with SSRIs) can
reduce the effects of dopamine on sexual function [
58
] and inhibit sexual desire, ejaculation,
and orgasm—predominantly via 5-hydroxytryptamines 2 and 3 (5-HT2 and 5-HT3) recep-
tor agonisms—while dopamine release (e.g., atypical antidepressant medications such as
bupropion) increases sexual function [17].
The dopamine-lowering properties of antipsychotic augmentation—and its interfer-
ence with the brain circuitry for sexual pleasure—also contribute to lessened desire and
arousal in depressed patients, similarly to psychotic patients. In addition, ejaculatory vol-
ume and spontaneous ejaculation are decreased because of the side effects of alpha-blocking
drugs [
59
,
60
]. In addition, SD in depressed patients might result from the high rates of
comorbidity with anxiety disorders such as separation anxiety disorder, selective mutism,
specific phobias, social phobia, panic disorder, and agoraphobia [
61
,
62
]. It has been demon-
strated that sexual arousal occurs by para-sympathetic activation while anxious arousal by
sympathetic activation, and when anxiety and sexual arousal occur concurrently, the more
robust response (anxiety) typically inhibits the weaker response, leading to reduced sexual
arousal [63].
5. Current Interventions for Treatment-Emergent Sexual Dysfunction in Depression
As already mentioned, SD is a common and long-lasting side effect of treatment with
most antidepressant medications. Orgasm retardation and decreased sexual desire are the
most common presentations of treatment-emergent SD (TESD) in depression. TESD is one
of the key reasons for premature treatment discontinuation of antidepressant medications.
SSRIs are the most frequently prescribed antidepressants—relative to antidepressants tar-
geting the norepinephrine, dopamine, and melatonin systems—and have major effects on
arousal and orgasm [
1
]. The side effects that are least tolerated by patients, particularly
males, are anorgasmia or absence of ejaculation [
64
,
65
]. Venlafaxine and clomipramine
are the antidepressants most frequently associated with TESD, while non-serotoninergic
ADs (bupropion, mirtazapine, agomelatine, and moclobemide) seem to be associated with
a lower prevalence of TESD. If TESD cannot be prevented, it is important to offset it, at
least partially. Evidence on TESD remedies is scarce, if not rare; therefore, much of what
we report relies on uncontrolled naturalistic studies on a wide variety of pharmacological
interventions [
66
,
67
]. These medications may be administered daily or a few hours before
intimate relationships. They are categorized according to their mechanisms into differ-
ent groups, namely: serotoninergic antagonists (e.g., cyproheptadine), pro-dopaminergic
drugs (e.g., amantadine), 5HT1A receptor stimulants (e.g., buspirone), pro-cholinergic
drugs (e.g., neostigmine and bethanechol), adrenergic antagonists (e.g., yohimbine), or
through unclearly understood mechanisms, such as Gingko Biloba extract [
68
70
]. In all
fairness, these interventions for TESD are not devoid from side-effects. There is also little
evidence to support the use of most of the interventions mentioned above, as many studies
have included brief case series or anecdotal case reports with contradictory findings. An
exception appears to be the addition of bupropion (with adrenergic and dopaminergic
effects), with robust empirical evidence supporting its therapeutic utility for TESD [
71
]. In
particular, there were three randomized, double-blind, placebo-controlled trials in which
bupropion was established as a strategy to enhance sexual function. However, clinicians
should be mindful that the addition of bupropion can exacerbate anxiety in certain patients.
The addition of 5HT2-blocker antidepressants may also have good effects in reversing
Photonics 2022,9, 330 7 of 15
TESD, but the resulting weight gain, especially in women, can be poorly tolerated [
72
]. The
augmentation with aripiprazole—likely due to its partial agonist dopaminergic effect and
to its 5HT2 receptor antagonism—has proven to be successful in enhancing sexual desire
and sexual pleasure in depression that is resistant to monotherapy, but only in women [
73
].
The addition of testosterone gel has also been shown to be effective in treating TESD [74].
On the other hand, phosphodiesterase (PDE)-5 inhibitors (e.g., sildenafil, vardenafil,
and tadalafil) have been shown to be helpful in treating erectile dysfunction secondary to
psychoactive drugs [
75
]. Moreover, using pycnogenol as an add-on to escitalopram has
shown promising results, especially when used in the first month of therapy, resulting in
a decrease in TESD [
76
]. This may be due to its potential—through its antioxidant, anti-
inflammatory, vasodilatory, and anticoagulant action—to enhance endothelial functions.
However, increased heart rate has been reported as a side effect, so caution is advised in
patients with cardiovascular disease whenever prescribing pycnogenol.
6. Photobiomodulation as a Therapeutic Strategy for Sexual Dysfunction in Depression
Photobiomodulation (PBM) therapy, also called “low-level light/laser therapy”, is a
novel light-driven treatment under development for numerous medical conditions [
77
].
PBM applies low-level (power) lasers or light-emitting diodes (LEDs) to deliver red, far-red,
or near-infrared (NIR) light targeting to modulate cellular metabolism and the functioning
of a variety of tissues, including the CNS and the brain [
77
,
78
]. A mitochondrial respiratory
enzyme, cytochrome c oxidase (CCO), is considered the primary chromophore for the
modulatory effects of low levels of red and NIR light [
79
]. Technically, the peak light
absorption by the CCO occurs at four various wavelengths (e.g., 620, 670, 760, and 825 nm).
Obviously, one of these peaks occurs with wavelengths between 810 and 850 nm [
80
], which
also coincides with the wavelengths with the best penetration through the scalp, skull,
and brain tissues. Red/NIR light delivers photon energy to the CCO and stimulates the
mitochondrial respiratory chain, resulting in increased mitochondrial membrane potential
and ATP formation [79].
Most research on PBM for psychiatric disorders focuses on the transcranial light deliv-
ery approach [
81
]. This modality delivers photons to the head (scalp), aiming to modulate
the cortical regions subjacent to the stimulation area. Nevertheless, the neurotherapeutic
benefits of systemic [
82
] and intranasal [
83
] PBM approach in psychiatric disorders have
also been shown in some clinical reports. In the systemic or remote PBM technique, the
light is delivered transcutaneously to other body parts (i.e., not necessarily to the scalp).
In this case, the possible beneficial effect on the brain would be mediated by components
of peripheral tissues and cells (e.g., blood cells, bone marrow-derived mesenchymal stem
cells, and immune cells) [
82
,
84
]. The intranasal PBM technique is also interesting as a
nose-mediated therapeutic approach, based on inserting one or two small laser/LEDs,
equipped with portable applicators, into the nostrils. This PBM technique could be applied
either alone or in combination to transcranial devices [
85
]. The repeated application of
intranasal PBM therapy has been shown to enhance blood rheology and cerebral blood flow
(CBF), and it has been suggested to treat a wide range of neurological and neuropsychiatric
disorders [83,85].
So far, there is only limited evidence for the use of PBM therapy to the brain for
the treatment of SD. Herein, we review the current literature highlighting the observed
effects and the possible neurobiological mechanisms mediating these brain PBM-induced
outcomes. This review refers only tangentially to the local use of PBM on sex organs.
In the only published double-blind clinical trial [
86
], our research group from Mas-
sachusetts General Hospital conducted a secondary analysis of data—obtained from the
ELATED-2 pilot trial [
87
]—on the effect of transcranial PBM (tPBM) on SD. In the stud-
ied cohort, all patients had a diagnosis of MDD and various medical and psychiatric
comorbidities and concomitant pharmacological therapies, which might have contributed
to SD. Twenty adult subjects (age 18–65 years) meeting the DSM-IV SCID criteria for
MDD—depression
severity rated at least moderate (Hamilton Depression Rating Scale,
Photonics 2022,9, 330 8 of 15
HAM-D
17
total score ranging 14–24)—were enrolled in the study after providing written
informed consent. The patients received real-tPBM (n = 9) or sham-tPBM therapy (n = 11)
twice a week for eight weeks. The treatment protocol consisted of transcranial irradiation of
an 823 nm LEDs device (Omnilux New U, Photomedex Inc., Horsham, PA, USA) bilaterally
to the dorsolateral prefrontal cortex (dlPFC) (EEG sites F3 and F4). The apparent behaviors
(i.e., all visible and audible indicators) of the real or sham tPBM devices were identical.
However, only the real tPBM device produced the NIR photons. The duration of the initial
tPBM session was 20 min, and after reaching week 4 and week 6 (after 6 and 10 sessions,
respectively), irradiation was extended up to 25 and 30 min, respectively, based on clinical
judgment (e.g., tolerability and efficacy). tPBM was applied with a scalp irradiance up
to 36.2 mW/cm
2
and fluence up to 65.2 J/cm
2
(over 30 min), with a treatment window
of 28.7 cm
2
at each of the two irradiation spots. All but three patients remained on sta-
ble antidepressant treatment during the study; their data were censored after changing
concomitant antidepressant therapies. Results showed a significant decrease in depres-
sion severity in the real-tPBM group compared to the sham group (
10.8
±
7.55 versus
4.4 ±6.65
). Response (decrease in HAM-D
17
scores
50%) was observed in 50% of those
who received the real-tPBM and 27% in the sham-tPBM.
We also assessed sexual desire, arousal, and orgasm using the Systematic Assessment
for Treatment-Emergent Effects Specific Inquiry (SAFTEE-SI). The mean change in SAFTEE
sex total score in real tPBM-treated patients was significantly greater than in patients
receiving the sham-tPBM in the whole sample (real (n = 9)
2.55
±
1.88 vs. sham (n = 11)
0.45
±
1.21; z = 2.548, p< 0.01) and in the completers (real (n = 5)
3.4
±
1.95 vs. sham
(
n=7
)
0.14
±
1.21; z = 2.576, p< 0.01). The comparison of the mean change in the “loss of
sexual interest or libido” item approached statistical significance in the whole sample (real
(n = 9)
1.2
±
1.09 vs. sham (n = 11)
0.4
±
0.67; z = 1.930, p= 0.05) and was significant in
the completers (real (n = 5)
1.8
±
1.09 vs. sham (n = 7)
0.3
±
0.49; z = 2.276,
p< 0.05
).
The comparison of the mean change in the “problems with sexual arousal (erection or
lubrication)” item reached significance in the whole sample (real (n = 9)
0.8
±
0.67 vs.
sham (n = 11)
0.1
±
0.30; z = 2.633, p< 0.001) but failed to in the completers (real (
n=5
)
0.8
±
0.84 vs. sham (n = 7)
0.1
±
0.38; z = 1.659, p= ns). Moreover, the comparison
of the mean change in the “delayed or absent orgasm” item was only significant in the
completers (real (n = 9)
0.6
±
0.73 vs. sham (n = 11)
0.0
±
0.89; z = 1.738, p= ns; real
(n = 5)
0.8
±
0.84 vs. sham (n = 7)
0.3
±
0.76; z = 2.228, p< 0.05). Intriguingly, while
there were fewer men than women in the study, the magnitude of the reduction in the
severity of SD was somewhat similar across genders—even though it was slightly greater
in men (80% in male vs. 75% in female)—when receiving real-tPBM. Presumably due to
the small sample of male participants, statistical significance was not found in the men.
It is also noteworthy that the timing and the magnitude of the positive effect of tPBM on
SD were much faster and far greater than for its effect on depression; this contradicts any
assumption that sexual function improved because of the amelioration of the depressive
symptoms. In other words, it is suggested that tPBM could likely benefit sexual function
independently from the outcome of depression [86].
Another pilot case series study from our MGH lab [
88
] showed a promising beneficial
effect of transcranial NIR PBM therapy on sexual function in four patients with type-I bipolar
disorder. All patients were white non-Hispanic, and two were female; their average age was
38.5
±
13 years. Despite reaching overall stabilization after treatment with lithium for at
least four years, all patients still experienced residuals such as pervasive anhedonia, anxiety,
irritability, impulsivity, sleep disturbances, decreased libido, and SD. The treatment protocol
consisted of the bilateral administration of a transcranial 830 nm LEDs device (Omnilux New
U (28 LED) handheld probe; Photomedex, Inc., Montgomeryville, PA, USA) to the F3 and
F4 EEG points, twice a week for four weeks. The irradiation parameters were: continuous
wave with average scalp irradiance of 33.2 mW/cm
2
, average fluence of 40 J/cm
2
, treatment
window of 28.7 cm
2×
2, and total energy (dose) of 2.3 kJ per session. Interestingly, all four
Photonics 2022,9, 330 9 of 15
patients reported a noticeable decrease in anhedonia/apathy and increased libido, along
with isolated benefits in anxiety, sleep quality, irritability, and impulsivity.
Finally, the last report in this respect is about a 44-year-old married woman, mother of
two preadolescent children, who was quite dissatisfied with her pharmacological antide-
pressant treatment with venlafaxine, prescribed for her 5-month recurrence of MDD [
89
].
She had been treated with venlafaxine (75 mg) once daily for six weeks, and despite the low
dose, venlafaxine had caused SD (e.g., decreased libido, decreased lubrication, and anor-
gasmia). It should be noted that the patient had reported no SD before starting venlafaxine,
despite being depressed; instead, her libido had declined markedly with venlafaxine. tPBM,
using an 823 nm LEDs device (Omnilux New U, Photomedex Inc., USA), was added to
venlafaxine to treat her depression. tPBM was performed twice a week for eight consecutive
weeks. At each tPBM session, two LEDs devices were applied simultaneously to F3 and
F4 points, and irradiation lasted 25 min. After ten sessions of tPBM—despite continuing
her venlafaxine—she experienced full recovery from her severe loss of libido, from mild
problems with sexual lubrication, and from moderately delayed orgasm.
Interestingly, the sexual side effects of antidepressants could also improve with local
PBM (laser) on sex organs. In a case report of paroxetine-induced persistent penile anes-
thesia, local PBM successfully reversed this side-effect. Pathophysiologically, SSRIs may
interfere with the transient receptor potential (TRP) ion channels of mechano-, thermo-,
and chemo-sensitive nerve endings, leading to penile anesthesia. The patient carried a
diagnosis of depressive disorder and was treated with 20 mg/day of paroxetine. After
only one week, he developed penile anesthesia, scrotum hypoesthesia, anejaculation, and
erectile difficulties, while maintaining normal sexual desire. His genital and sexual com-
plaints persisted during the 2.5 years of treatment with paroxetine, and for the 2 years
after paroxetine discontinuation. The authors of this case report describe that, after a single
session (about 15–20 min) of local PBM, penile touch and temperature sensations increased
until glans penis sensitivity returned [90].
As concerns the main focus of this review, transcranial PBM, two different hypotheses
could be proposed for the beneficial effects of NIR tPBM on SD: its effect could be mediated
(i) by neurostimulation of the PFC and subsequent modulation of cortical oscillations [
91
]
and (ii) by an increase in the levels of tissue NO and subsequent boost of CBF [
92
]. In
fact, neuronal, intra-, or extra-cellular NO in the hypothalamus has been suggested to be
essential to the onset of puberty and to fertility, and it can directly regulate the release of
GnRH and LH [93].
6.1. PBM and Neurostimulation of PFC
When considering brain oscillation patterns in MDD, a large study consisting of
1344 participants showed increases in theta power across frontal regions of the brain [
94
].
Although discordant findings exist in the field, other studies also point to significant in-
creases in all-night slow wave activity (SWA), primarily in the bilateral prefrontal cortex, in
MDD [
95
]. Noticeably, in MDD, a high power of frontal alpha waves has been suggested as
a biomarker of a lack of libido improvement after treatment with SSRI (paroxetine) [
96
].
Overall, despite the paucity of evidence, it could be suggested that abnormal brain oscilla-
tions in the frontal areas, in MDD patients, could be associated with SD, such as decreased
libido. tPBM has been consistently reported to shift brain oscillations to higher frequency
bands, at least in healthy subjects. Our group reported on the potentiation of gamma and
beta power after tPBM [97].
6.2. PBM and Boosting of CBF
Abnormalities of the CBF have been consistently detected in MDD. A reduced CBF
in the right parahippocampus, thalamus, fusiform, and middle temporal gyri, as well as
the left and right insula, characterized patients with MDD relative to healthy controls [
98
].
Increased CBF in the middle and posterior cingulate was significantly associated with a
percent decrease in depression severity (MADRS total score). Therefore, regional increases
Photonics 2022,9, 330 10 of 15
in CBF were associated with decreases in depressive symptoms [
99
]. Perfusion in the
putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior
parietal lobule, and orbital frontal gyrus also predicted response (or lack of) to SSRI
(sertraline) in MDD [
99
]. Although there is sparce evidence for the role of abnormal
regional CBF in SD, preliminary studies suggest that the appropriate regulation of CBF is
important for normal sexual functioning, such as for sexual arousal and orgasm [100].
In addition to the electronic excitation, as discussed earlier, PBM improves mitochon-
drial function by promoting NO dissociation from the CCO during irradiation or shortly
after, thereby releasing the binding site for oxygen and restoring oxidative phosphorylation.
NO can also be produced enzymatically after an increase in the activity of NO synthase
(NOS) long after irradiation, possibly via increasing the intracellular calcium ((Ca
2+
)i) lev-
els [
101
]. A 670 nm LEDs light can also enhance NO release from nitrosylated hemoglobin
and myoglobin [
102
]. In fact, the released NO can potentially increase CBF by acting as a
local vasodilator [
103
]. In this respect, it has been shown that tPBM can improve neuronal
NO levels and CBF
in vivo
, resulting from the activation of endothelial NOS protein [
104
],
and can also increase the blood vessel diameter [
105
]. In particular, a transcranial 808 nm
laser with a scalp irradiance of 10.6 W/cm
2
has been demonstrated to increase cortical NO
levels (by 50%) in naive mice, immediately after turning on the laser. In addition, PBM
also gradually improved CBF in the laser-irradiated hemisphere (by 30%) as well as in
the opposite hemisphere (by 19%), at 45 min after starting the irradiation [
104
]. In the
first open study on tPBM for MDD, 810 nm LEDs irradiation (250 mW/cm
2
per site over
4 min, 60 J/cm
2
on the scalp) onto the forehead of depressed patients (electroencephalogra-
phy (EEG) sites F3 and F4) raised prefrontal CBF; however, the increase in CBF reached
significance only in men (Frederic Schiffer, personal communication) [106].
In addition to the above-mentioned accepted mechanism for NO’s role in improving
CBF, a clinical study performed by Nawashiro et al. [
107
] suggested a more conventional
explanation for the increase in CBF following tPBM. In healthy human cases, an 810 nm
laser tPBM onto the EEG pointed towards F3, and F4 (aiming at the dlPFC) increased
regional CBF, as assessed by blood-oxygen-level-dependent (BOLD) functional magnetic
resonance imaging (fMRI). The changes were most profound in the dlPFC just beneath the
tip of the laser fiber but were also widespread to other cerebral regions (e.g., ipsilateral
parietal cortex). Given the laser irradiation period and duration of fMRI data acquisition,
the authors claimed that the observed changes in CBF were most likely due to increased
neuronal activation in the frontoparietal network, rather than the tPBM-induced local
release of NO [107].
Another mechanism that can be considered for laser treatment of SD is a putative effect
through the pineal gland pathway, and the inhibition of melatonin secretion by the laser. In
the darkness, the pineal gland secretes the hormone melatonin, which plays an inhibitory
role on the reproductive axis. Melatonin inhibits the hypothalamic pulsatile secretion of
the gonadotrophin-releasing hormone and also acts at the gonadal level. Melatonin leads
to SD by increasing prolactin secretion. Putatively, the inhibitory role of melatonin on
sexual function could be targeted and reversed with tPBM, such as laser therapy. This
potential mechanism is however not supported by data. According to Odinokov et al., NIR
photons increase subcellular or extrapineal melatonin production through cyclic adenosine
monophosphate (AMP) or NF-kB activation.
7. Conclusions
There is a bidirectional relationship between various types of SD and depression, so
the presence or treatment of one condition may exacerbate or improve the other condition.
The most frequent sexual problem in untreated depressed patients is declining sexual
desire, while in treated depressed patients, it is difficulties with erection/ejaculation and
with orgasm.
tPBM, as a novel neurostimulation technique, could counteract SD through several,
putative molecular pathways: 1—tPBM improves the neuronal NO levels and CBF
in vivo
,
Photonics 2022,9, 330 11 of 15
resulting from the activation of the endothelial NOS protein, and also increases the blood
vessels diameter; 2—tPBM improves the mitochondrial function by promoting NO disso-
ciation from the CCO, thereby releasing this mitochondrial binding site for oxygen, and
restoring oxidative phosphorylation; and 3—tPBM could theoretically affect the pineal
gland pathway by inhibiting melatonin secretion.
Preliminary evidence suggests that tPBM could be beneficial to treat SD comorbid to
MDD. Furthermore, tPBM could be used to relieve several other syndromes commonly
associated with SD: 1—Depression and anxiety symptoms in patients with SD, as well as in
their partners (as tPBM promotes wellness in healthy individuals); 2—PTSD symptoms
as a vulnerability factor in patients with or at risk for SD; and 3—Systemic risk factors
for medical illnesses such as inflammation. Double-blind, randomized control studies
with tPBM for the treatment of SD, induced by depression or by the use of antidepressant
medications, are warranted to further test the efficacy, tolerability, and acceptability of
tPBM in sexual problems.
Author Contributions:
P.C. developed the main conceptual ideas, designed the review outline,
provided related data, and wrote and edited the manuscript. F.S. and M.K. reviewed the literature
and wrote the manuscript, focusing on the basic science sections. F.V. reviewed the literature and
wrote the manuscript, focusing on the clinical neuropsychiatry sections. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest:
Paolo Cassano consulted for Janssen Research and Development and for Niraxx
Light Therapeutics Inc. Paolo Cassano was funded by PhotoThera Inc.,LiteCure LLC, and Cerebral
Sciences Inc. to conduct studies on transcranial photobiomodulation. Paolo Cassano is a co-founder,
shareholder, and board director of Niraxx Light Therapeutics Inc. Paolo Cassano has filed several
patents related to the use of near-infrared light in psychiatry.
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Chapter
Neurons serve as an important feature in the biological system where it controls the whole body via central and autonomous system. Both the systems have a defined role and function and looking into it various chemical agents are present which help in the function and regulation of the system. They are mainly responsible for mood elevation, signal transmission, binding properties, transportation, etc. for their regulation. These chemical agents include acetylcholine, dopamine, GABA receptors, glutamate, noradrenaline, and serotonin. These chemical agents follow their own pathway and possess the chemical function and synthesis either with chemical substances or with biological pathways to accelerate the system. Thus it is very clear that most of the neuromodulators and neurotransmitters are involved in controlling the major functions of the body. This chapter enlightens about the various aspects of it.
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Multiple sclerosis (MS) is the most common chronic neurological disorder in young adults, with numerous potential effects on neurologic function. Sexual dysfunction (SD) is a common and very stressful one in persons with MS and represents a significant burden of disease. It has been shown that proportion of SD in MS is greater than in other neurological diseases, and almost five times higher than in the general population. Since there is no consistent definition in the literature for the diagnosis of SD, various studies reported a prevalence of SD of 40–80% in women and 50–90% in men with MS. The nature of sexual changes in this chronic illness is best defined as primary, secondary, and tertiary. Recently, it has been emphasized that detailed sexual history is crucial for all SD assessments and diagnoses. Committee 3 of the international consultation on sexual medicine suggested an updating algorithm for diagnostic evaluation of SD in both genders, with specific recommendations related to sexual history taking and diagnostic evaluation. Because treatments and preventive strategies might manage SD, it is necessary to increase the focus on these aspects of the disease when counselling patients. Management of SD should be comprehensive because the symptoms could be somatic, psychological, or related to relationship problems.
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The application of photobiomodulation therapy (PBMT) for neuronal stimulation has been studied in different animal models and in humans, and has been shown to improve cerebral metabolic activity and blood flow, and provide neuroprotection via anti-inflammatory and antioxidant pathways. Recently, intranasal PBMT (i-PBMT) has become an attractive and potential method for the treatment of brain conditions. Herein, we provide a summary of different intranasal light delivery approaches including a nostril-based portable method and implanted deep-nasal methods for the effective systemic or direct irradiation of the brain. Nostril-based i-PBMT devices are available, using either lasers or LEDs, and can be applied either alone or in combination to transcranial devices (the latter applied directly to the scalp) to treat a wide range of brain conditions such as mild cognitive impairment, Alzheimer’s disease, Parkinson’s disease, cerebrovascular diseases, depression and anxiety as well as insomnia. Evidence shows that nostril-based i-PBMT improves blood rheology and cerebral blood flow, so that, without needing to puncture blood vessels, i-PBMT may have equivalent results to a peripheral intravenous laser irradiation procedure. Up to now, no studies have been conducted to implant PBMT light sources deep within the nose in a clinical setting, but simulation studies suggest that deep-nasal PBMT via cribriform plate and sphenoid sinus might be an effective method to deliver light to the ventromedial part of the prefrontal and orbitofrontal cortex. Home-based i-PBMT, using inexpensive LED applicators, has potential as a novel approach for neurorehabilitation; comparative studies also testing sham and transcranial PBMT are warranted.
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Over the past few decades there has been a dramatic increase in scientific research into photobiomodulation (PBM) therapy, both to treat injury or illness and to enhance normal function or performance. More recently, substantial focus has been placed on PBM of the brain and nervous system, with a range of preclinical studies and some clinical trials yielding promising results. Naturally, almost all studies have reported on the effects of PBM when light is targeted directly at the tissue under investigation. However, a small number of studies over the years, increasing in frequency in recent times, have provided evidence that the beneficial effects of PBM are not confined to the irradiated tissue. Instead, it appears that PBM can elicit systemic effects that promote protection of remote tissues. While the mechanisms remain to be understood, this phenomenon of a body-wide response to localised PBM treatment has far-reaching implications, both for our understanding of basic biology as well as the therapeutic application of PBM, particularly for difficult-to-irradiate organs such as the brain.